tag:blogger.com,1999:blog-45993266942557402202024-02-06T23:36:36.206-05:00What the Pharma?A blog analyzing and explaining novel biotech and pharmaceutical technologies and agents with a special focus on cancer therapeutics. The economic impact of these technologies will also be analyzed. Follow me on twitter @oracleofpharma for instant updates.Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.comBlogger26125tag:blogger.com,1999:blog-4599326694255740220.post-8189299112246739672012-01-13T18:11:00.000-05:002012-01-13T18:11:20.546-05:00Beyond the Glitter of the Abstract: Analysis of Vemurafenib (Zelboraf) Phase 3 Study<div align="center" class="MsoNormal" style="margin-bottom: 4.0pt; text-align: center;"></div><table border="1" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; background-position: initial initial; background-repeat: initial initial; border-bottom-style: none; border-collapse: collapse; border-color: initial; border-image: initial; border-left-style: none; border-right-style: none; border-top-style: none; border-width: initial; margin-left: 0.9pt;"><tbody>
<tr style="mso-yfti-firstrow: yes; mso-yfti-irow: 0; page-break-inside: avoid;"><td colspan="2" style="background: black; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><h1 align="center" style="text-align: center;"><b><span style="font-size: 10pt; text-decoration: none;"><span style="color: white;">GENERAL STUDY OVERVIEW<o:p></o:p></span></span></b></h1></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Title/ Citation</span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><h1 style="line-height: 13.5pt; margin-left: 8.1pt; mso-list: l23 level1 lfo3; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt; text-decoration: none;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt; text-decoration: none;"><span style="font-weight: normal;">Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.</span></span></h1></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Funding<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l26 level1 lfo1; tab-stops: list 8.1pt; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Hoffman-La Roche<o:p></o:p></span></div></td></tr>
<tr><td style="border-bottom: none; border-left: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; border-top: none; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Trial Design<o:p></o:p></span></div></td><td style="border-right: solid windowtext 1.0pt; border: none; mso-border-left-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l30 level1 lfo2; tab-stops: list 8.1pt; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Randomized, open-label, controlled, multicenter study with parallel assignments</span><span style="font-size: 10pt;"><o:p></o:p></span></div></td></tr>
<tr><td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Objectives<o:p></o:p></span></div></td><td style="border-left: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l30 level1 lfo2; tab-stops: list 8.1pt; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Whether vemurafenib prolongs rate of overall survival (OS) or progression-free survival (PFS) as compared with dacarbazine in metastatic melanoma patients<o:p></o:p></span></div></td></tr>
<tr style="mso-yfti-irow: 5; page-break-inside: avoid;"><td colspan="2" style="background: black; border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><h1 align="center" style="text-align: center;"><b><span style="font-size: 10pt; text-decoration: none;"><span style="color: white;">BACKGROUND<o:p></o:p></span></span></b></h1></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Background<o:p></o:p></span></div></td><td style="border-right: solid windowtext 1.0pt; border: none; mso-border-left-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Melanoma is a form of skin cancer that typically arises from epidermal melanocytes, but can arise in other sites in which melanocytes are found such as the retina<a href="" name="_Ref314078864"></a><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn1" name="_ednref1" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[1]</span></span></span></a><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Although curable if treated in early stage, malignant melanoma has a poor prognosis</span><sup><span style="font-size: 10pt;">1</span></sup><span style="font-size: 10pt;"><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">The median survival from diagnosis for stage IV melanoma is 8-18 months depending on substage<sup>1</sup><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">68,130 new cases and 8700 deaths due to melanoma in the US in 2010<a href="" name="_Ref314079238"></a><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn2" name="_ednref2" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[2]</span></span></span></a> <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Risk factors: positive family history; prior melanoma; multiple atypical moles or nevi; genetic mutations (rare); sunburns; light skin color<sup>2</sup><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Most patients (85%) present with localized disease, 10-13% with regional disease, and 2-5% with distant metastases<sup>2</sup><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">5 year survival rates: > 90% for patients with localized disease; 20-70% for regional disease depending on lymph node tumor burden; < 10% for those with distant metastases</span><sup><span style="font-size: 10pt;">2</span></sup><span style="font-size: 10pt;"><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Clinical Staging</span><sup><span style="font-size: 10pt;">2</span></sup><span style="font-size: 10pt;">:<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l10 level1 lfo21; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Stage 0: melanoma in situ<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l10 level1 lfo21; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Stage IA: <u><</u> 1 mm in thickness, mitotic rate < 1/mm2, and no ulceration<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l10 level1 lfo21; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Stage IB-II: <u><</u> 1 mm thickness with ulceration or mitotic rate <u>></u> 1/mm2<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l10 level1 lfo21; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Stage III: positive nodes and/or in-transit disease<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l10 level1 lfo21; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Stage IV: distant metastatic disease <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">TNM staging</span><sup><span style="font-size: 10pt;">2</span></sup><sup><span style="font-size: 10pt;">,<a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn3" name="_ednref3" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[3]</span></span></span></a></span></sup><span style="font-size: 10pt;">:<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l28 level1 lfo24; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">M0: no evidence of distant metastases<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l28 level1 lfo24; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">M1a: metastases to skin, subcutaneous, or distant lymph nodes with normal lactate dehydrogenase (LDH)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l28 level1 lfo24; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">M1b: metastases to lung<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l28 level1 lfo24; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">M1c: metastases to other visceral sites or distant metastases to any site with elevated LDH<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Approximately 50% of cutaneous melanomas contain a mutation in the BRAF gene (of which 90% are the V600E mutation)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Currently FDA approved therapies for metastatic melanoma: dacarbazine and ipilimumab<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Other commonly used agents for metastatic melanoma include temozolomide, high-dose interleukin-<sup>2</sup><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">The response rate is typically less than 20% in 1<sup>st</sup> and 2<sup>nd</sup> line settings and there is little consensus regarding standard<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">NCCN Recommendation for Stage III</span><sup><span style="font-size: 10pt;">2</span></sup><span style="font-size: 10pt;"><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l14 level1 lfo25; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Single or small # of in-transit metastases- surgical resection with negative margins if feasible<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l14 level1 lfo25; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Limited # of in-transit unresectable metastases- local injections of BCG or interferon alfa or topical imiquimod<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l14 level1 lfo25; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Multiple, regional in-transit metastases- regional chemotherapy and systemic therapy after failure.<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">NCCN Recommendation for Stage IV without brain metastases</span><sup><span style="font-size: 10pt;">2</span></sup><span style="font-size: 10pt;"><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l25 level1 lfo26; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Resection if feasible<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l25 level1 lfo26; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Clinical trial (recommended)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l25 level1 lfo26; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Ipilimumab (category 1)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l25 level1 lfo26; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Vemurafenib (category 1)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l25 level1 lfo26; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Dacarbazine, temozolomide, or high dose IL-2<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Opinions vary regarding optimal duration and schedule of follow-up. Most patients who relapse do so in first 5 years</span><sup><span style="font-size: 10pt;">2</span></sup><span style="font-size: 10pt;"><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Dacarbazine is an alkylating agent approved for the treatment of various cancers including malignant melanoma.<a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn4" name="_ednref4" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[4]</span></span></span></a> <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l6 level1 lfo22; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">It is administered intravenously. <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l6 level1 lfo22; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Typical dosing for malignant melanoma: 850 mg/m<sup>2</sup> every 3 weeks or 150-250 mg/m<sup>2</sup> days 1-5 every 3-4 weeks infused over 30-60 min. <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l6 level1 lfo22; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Onset of action- 18-24 days<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l6 level1 lfo22; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Renal adjustment necessary based on study (not on FDA approved labeling)<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l6 level1 lfo22; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Common ADRs: prominent nausea and vomiting (can be dose limiting); myelosuppression; and hepatotoxicity<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Ipilimumab is a monoclonal antibody directed to cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor. It binds to CTLA-4 and prevents interaction of CTLA-4 and ligands, CD80/86 resulting in augmentation of T cell activation and proliferation.<sup>2,<a href="" name="_Ref314079911"></a><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn5" name="_ednref5" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[5]</span></span></span></a>,<a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn6" name="_ednref6" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[6]</span></span></span></a></sup><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l21 level1 lfo33; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">56% of Grade 3 and 4 adverse events when ipilimumab + dacarbazine was studied. Most events were immune related: diarrhea; rash; pruritus; hepatic enzyme elevations<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l8 level1 lfo23; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">3 year survival: 20.8% ipilimumab + dacarbazine <o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l8 level1 lfo23; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">OS: ipilimumab alone 10.2 months<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: 8.1pt; margin-right: 0in; margin-top: 0in; mso-list: l31 level1 lfo4; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Vemurafenib is a small molecule inhibitor of mutated BRAF kinase, specifically BRAF V600E, which is constitutively active in absence of growth factors.<a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn7" name="_ednref7" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[7]</span></span></span></a><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">It is FDA approved for unresectable or metastatic melanoma with V600E mutation.<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Patients must be tested for V600E using the cobas ® 4800 BRAF V600E Mutation Test<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">It is available as 240 mg oral tablets, which simplifies dose adjustments<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Phase 1 study: recommended Phase 2 dose of 960 mg twice daily, with increases limited due to Grade 2 or 3 rash, fatigue, and arthalgia.<a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_edn8" name="_ednref8" title=""><span class="MsoEndnoteReference"><span class="MsoEndnoteReference"><span style="font-family: 'Times New Roman', serif; font-size: 10pt;">[8]</span></span></span></a><o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Most common ADRs include arthalgia, rash, alopecia, fatigue, photosensitivity reaction, nauseas, pruritus, and skin papilloma.<o:p></o:p></span></div><div style="margin-bottom: .0001pt; margin-bottom: 0in; margin-left: .5in; margin-right: 0in; margin-top: 0in; mso-list: l5 level1 lfo28; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Package insert contains warnings for SJS/TEN, QT prolongation, liver lab abnormalities, and new primary malignant melanomas. <o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Relevant Trials<o:p></o:p></span></div></td><td style="border-left: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l30 level1 lfo2; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Joseph EW, Pratilas CA, Poulikakos PI, et al. The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in V600E BRAF-selective manner. Proc Natl Acad Sci USA 2010;107:14903-8.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l30 level1 lfo2; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Ribas A, Kim KB, Schucter LM, et al. BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive melanoma. J Clin Oncol 2011;29:Suppl:8509. <o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Why this study?<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l7 level1 lfo12; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Prognosis for malignant melanoma remains poor and current approved therapies provide marginal benefits. Resistance due to the BRAF V600E mutation hampers optimal therapy. Vemurafenib can prolong overall survival (OS) and progression free survival (PFS) in patients with the BRAF V600E mutation.<o:p></o:p></span></div></td></tr>
<tr style="mso-yfti-irow: 9; page-break-inside: avoid;"><td colspan="2" style="background: black; border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><h1 align="center" style="text-align: center;"><b><span style="font-size: 10pt; text-decoration: none;"><span style="color: white;">METHODS<o:p></o:p></span></span></b></h1></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Inclusion criteria<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l16 level1 lfo6; mso-pagination: widow-orphan; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Unresectable, previously untreated stage IIIC or IV melanoma positive for BRAF V600E mutation<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l16 level1 lfo6; mso-pagination: widow-orphan; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Age <u>></u> 18 years<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l16 level1 lfo6; mso-pagination: widow-orphan; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Life expectancy <u>></u> 3 months<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l16 level1 lfo6; mso-pagination: widow-orphan; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">ECOG performance status of 0 or 1<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l16 level1 lfo6; mso-pagination: widow-orphan; tab-stops: list 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Adequate hematologic, hepatic, and renal function<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Exclusion criteria<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l7 level1 lfo12; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">History of cancer within past 5 years (except basal- or squamous- cell carcinoma of the skin or carcinoma of the cervix) or metastases to central nervous system, unless metastases were definitely treated 3 months previously with no progression and no required glucocorticoid therapy<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l7 level1 lfo12; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Concomitant treatment with other anticancer therapy<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Interventions<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l4 level1 lfo11; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span class="hitorg"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Vemurafenib</span></span><span class="apple-converted-space"><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">960 mg twice a day</span><span style="font-size: 10pt;"><o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l2 level1 lfo17; tab-stops: 17.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Intolerable Grade 2 toxic effect or worse: administration interrupted until resolution to Grade 1 and restarted at 720 mg twice daily (480 mg twice daily for Grade 4 events). </span><span style="font-size: 10pt;"><o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l2 level1 lfo17; tab-stops: 17.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Dose reduction to 480 mg twice daily if toxic effects recurred. Permanent discontinuation of toxic effect did not improve or recurred at 480 mg twice daily dose</span><span style="font-size: 10pt;"><o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l4 level1 lfo11; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Dacarbazine 1000 mg/m<sup>2</sup> by IV infusion every 3 weeks</span><span style="font-size: 10pt;"><o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l19 level1 lfo16; tab-stops: 17.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="background-attachment: initial; background-clip: initial; background-color: white; background-image: initial; background-origin: initial; font-size: 10pt;">Administration interrupted for Grade 3 and 4 toxic effects and restarted on recovery within 1 week to Grade 1 (full dose) or Grade 2(75% dose) or 75% dose for Grade 4 neutropenia or febrile neutropenia</span><span style="font-size: 10pt;"><o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Outcome measures<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l9 level1 lfo8; tab-stops: 8.1pt; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Primary outcomes: <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l27 level1 lfo30; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Rate of overall survival (OS): time from randomization to death <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l27 level1 lfo30; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Progression-free survival (PFS): time from randomization to documented progression or death<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l9 level1 lfo8; tab-stops: 8.1pt; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Secondary outcomes: <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l29 level1 lfo31; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Confirmed response <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l29 level1 lfo31; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Duration of response <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: .5in; mso-list: l29 level1 lfo31; tab-stops: 8.1pt; text-indent: -.25in;"><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Time to response<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l13 level1 lfo32; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Tumor assessments performed at baseline, weeks 6 and 12, and every 9 weeks afterwards<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l13 level1 lfo32; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Tumor response determined by Response Evaluation Criteria in Solid Tumors (RECIST)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Statistical analyses <o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Designed for 680 patients to be randomly assigned<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Final analysis after 196 deaths (Log-rank test, P<u><</u> 0.0247) and interim analysis after 50% of projected deaths (Pocock boundary, P<u><</u> 0.028) <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Final analysis of PFS performed at time of interim analysis of OS<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Power of 80% to detect hazard ratio of 0.65 for OS with alpha of 0.045 ( increase in median survival from 8 months for dacarbazine to 12.3 months for vemurafenib)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Power of 90% to detect hazard ratio of 0.55 for PFS with alpha of 0.005 (increase in median survival from 2.5 months for dacarbazine to 4.5 months for vemurafenib)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Survival- time from randomization to death from any cause<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">PFS- time from randomization to documented disease progression or death<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Two-sided unstratified log-rank test to compare survival<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Hazard ratios estimated using unstratified Cox regression<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Event-time distributions estimated using Kaplan-Meier<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">P values are two-sided<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Confidence intervals are at 95% level<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l11 level1 lfo7; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Efficacy analyses performed in intention-to-treat population<o:p></o:p></span></div></td></tr>
<tr style="mso-yfti-irow: 15; page-break-inside: avoid;"><td colspan="2" style="background: black; border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><div class="MsoNormal"><b><span style="font-size: 10pt;"><span style="color: white;"> RESULTS <o:p></o:p></span></span></b></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Enrollment<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l3 level1 lfo9; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">2107 patients screened from January 2010 through December 2010 at 104 centers in 12 countries<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l3 level1 lfo9; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">675 patients randomly assigned in 1:1 ratio to receive vemurafenib or dacarbazine<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l3 level1 lfo9; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Negative test for BRAF mutation was most common reason for screening failure<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l3 level1 lfo9; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">20 patients with non-V600E mutation enrolled (19 with V600K and 1 with V600D)<o:p></o:p></span></div></td></tr>
<tr><td style="border-bottom: none; border-left: solid windowtext 1.0pt; border-right: solid windowtext 1.0pt; border-top: none; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Baseline characteristics<o:p></o:p></span></div></td><td style="border-right: solid windowtext 1.0pt; border: none; mso-border-left-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><table border="1" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-border-insideh: .5pt solid windowtext; mso-border-insidev: .5pt solid windowtext; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-table-layout-alt: fixed; mso-yfti-tbllook: 1184;"><tbody>
<tr><td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div align="center" class="MsoNormal" style="margin-left: -11.05pt; text-align: center;"><b><span style="font-size: 9pt;">Characteristic<o:p></o:p></span></b></div></td><td style="border-left: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div class="MsoNormal"><b><span style="font-size: 9pt;">Vemurafenib (N = 337)<o:p></o:p></span></b></div></td><td style="border-left: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div class="MsoNormal"><b><span style="font-size: 9pt;">Dacarbazine (N = 338)<o:p></o:p></span></b></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">Median age (range)- years<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">56 (21-86)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">52 (17-86)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">Male sex- no. (%)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">200 (59)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">181 (54)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">White race- no. (%)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">333 (99)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">338 (100)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">ECOG performance status- no. (%)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 9pt;"> 0<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 9pt;"> 1<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">229 (68)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">108 (32)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">230 (68)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">108 (32)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">Extent of metastatic melanoma- no. (%)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><span style="font-size: 9pt;">M1c<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><span style="font-size: 9pt;">M1b<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><span style="font-size: 9pt;">M1a<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><span style="font-size: 9pt;">Unresectable IIIC<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">221 (66)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">62 (18)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">34 (10)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">20 (6)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">220 (56)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">65 (19)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">40 (12)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">13 (4)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 43.16%;" valign="top" width="43%"><div class="MsoNormal"><span style="font-size: 9pt;">Lactate dehydrogenase- no. (%)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><u><span style="font-size: 9pt;"><</span></u><span style="font-size: 9pt;"> ULN<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 5.45pt;"><span style="font-size: 9pt;">>ULN<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">142 (42)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">195 (58)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 28.42%;" valign="top" width="28%"><div align="right" class="MsoNormal" style="text-align: right;"><br />
</div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">142 (42)<o:p></o:p></span></div><div align="right" class="MsoNormal" style="text-align: right;"><span style="font-size: 9pt;">196 (58)<o:p></o:p></span></div></td></tr>
</tbody></table><div class="MsoNormal"><span style="font-size: 10pt;"><o:p></o:p></span></div></td></tr>
<tr><td style="border-bottom: none; border: solid windowtext 1.0pt; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Efficacy <o:p></o:p></span></div></td><td style="border-bottom: none; border-left: none; border-right: solid windowtext 1.0pt; border-top: solid windowtext 1.0pt; mso-border-left-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-right-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: .5in; mso-list: l32 level1 lfo15; tab-stops: 11.1pt list .5in; text-indent: -.5in;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Total of 118 deaths at time of interim analysis<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 11.1pt; mso-list: l32 level1 lfo15; tab-stops: list 11.1pt; text-indent: -11.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Median follow-up for interim analysis: 3.8 months for vemurafenib group and 2.3 months for dacarbazine group<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 11.1pt; mso-list: l32 level1 lfo15; tab-stops: list 11.1pt; text-indent: -11.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Data and safety monitoring board determined that OS and PFS reached statistical significance in favor of vemurafenib and recommended that patients be allowed to cross over from dacarbazine to vemurafenib<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 11.1pt; mso-list: l32 level1 lfo15; tab-stops: list 11.1pt; text-indent: -11.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">672 patients evaluated for OS; HR for death in vemurafenib group was 0.37 (95% CI: 0.26-0.55; P<0.001)<o:p></o:p></span></div><ul style="margin-top: 0in;" type="circle"><li class="MsoNormal"><span style="font-size: 10pt;">Inadequate number of patients at interim analysis with follow-up beyond 7 months to provide reliable Kaplan-Meier estimate of survival curve <o:p></o:p></span></li>
<li class="MsoNormal"><span style="font-size: 10pt;">OS at 6 months: 84% (95% CI: 78-89) in vemurafenib group and 64% (95% CI: 56-73) in dacarbazine group. Further follow-up needed.<o:p></o:p></span></li>
</ul><div class="MsoNormal" style="margin-left: .5in;"><br />
</div><table border="1" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="border-collapse: collapse; border: none; mso-border-alt: solid windowtext .5pt; mso-border-insideh: .5pt solid windowtext; mso-border-insidev: .5pt solid windowtext; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-table-layout-alt: fixed; mso-yfti-tbllook: 1184;"><tbody>
<tr><td colspan="2" style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 201.35pt;" valign="top" width="268"><div align="center" class="MsoNormal" style="text-align: center;"><span style="font-size: 10pt;">Subgroup Analysis<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 93.35pt;" valign="top" width="124"><div class="MsoNormal"><span style="font-size: 10pt;">Subgroup<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.5in;" valign="top" width="144"><div class="MsoNormal"><span style="font-size: 10pt;">Hazard Ratio (95% CI)<o:p></o:p></span></div></td></tr>
<tr><td style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 93.35pt;" valign="top" width="124"><div class="MsoNormal"><span style="font-size: 10pt;">Disease stage (n)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;"> IIIC (33)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;"> M1a (74)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;"> M1b (126)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;"> M1c (439)<o:p></o:p></span></div></td><td style="border-bottom: solid windowtext 1.0pt; border-left: none; border-right: solid windowtext 1.0pt; border-top: none; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.5in;" valign="top" width="144"><div class="MsoNormal"><br />
</div><div class="MsoNormal"><span style="font-size: 10pt;">0.53 (0.07-3.76)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;">0.31 (0.07-1.47)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;">0.91 (0.33-2.52)<o:p></o:p></span></div><div class="MsoNormal"><span style="font-size: 10pt;">0.32 (0.21-0.50)<o:p></o:p></span></div></td></tr>
</tbody></table><div class="MsoNormal"><br />
</div><div class="MsoNormal" style="margin-left: 11.1pt; mso-list: l32 level1 lfo15; tab-stops: list 11.1pt; text-indent: -11.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">PFS evaluated in 549 patients. <o:p></o:p></span></div><ul style="margin-top: 0in;" type="circle"><li class="MsoNormal"><span style="font-size: 10pt;">HR for tumor progression in vemurafenib group was 0.26 (95% CI: 0.20-0.33; P<0.001)<o:p></o:p></span></li>
<li class="MsoNormal"><span style="font-size: 10pt;">Estimated median PFS was 5.3 months in vemurafenib group and 1.6 months in dacarbazine group. Superior PFS in all subgroups except for patients <u>></u> 75 years of age.<o:p></o:p></span></li>
</ul><div class="MsoNormal" style="margin-left: 11.1pt; mso-list: l32 level1 lfo15; tab-stops: list 11.1pt; text-indent: -11.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">439 (65%) patients evaluated for tumor response: <o:p></o:p></span></div><ul style="margin-top: 0in;" type="circle"><li class="MsoNormal"><span style="font-size: 10pt;">106 of 219 patients (48%; 95% CI: 42-55) assigned to vemurafenib had a confirmed objective response including 2 CR and 104 PR with median time to response of 1.45 months <o:p></o:p></span></li>
<li class="MsoNormal"><span style="font-size: 10pt;">10 patients in vemurafenib group had BRAF V600K mutation: of these 4 (40%) patients had PR<o:p></o:p></span></li>
<li class="MsoNormal"><span style="font-size: 10pt;">12 of 220 (5%; 95% CI: 3-9) patients in the dacarbazine group had an objective response (all PR) and the median time to response of 2.7 months<o:p></o:p></span></li>
<li class="MsoNormal"><span style="font-size: 10pt;">Difference in response was statistically significant (P<0.001 by chi-square test)<o:p></o:p></span></li>
</ul></td></tr>
<tr><td style="border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 1.25in;" valign="top" width="120"><div class="MsoNormal"><span style="font-size: 10pt;">Adverse events<o:p></o:p></span></div></td><td style="border-left: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-left-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 441.0pt;" valign="top" width="588"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l15 level1 lfo13; tab-stops: 8.1pt list .5in; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">618 (92%) patients underwent at least one assessment and were evaluated for toxic effects<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l15 level1 lfo13; tab-stops: 8.1pt list .5in; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Vemurafenib had higher incidences of the following Grade 2 adverse events compared with dacarbazine: arthalgia (18% vs. <1%); rash (10% vs. 0%); cutaneous squamous-cell carcinoma (12% vs. 0%); keratocanthoma (6% vs. 0%); and alopecia (8% vs. 0%).<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l15 level1 lfo13; tab-stops: 8.1pt list .5in; text-indent: -9.0pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Only 2 patients in the vemurafenib group experienced neutropenia (Grade 2 and 4) compared with 28 patients assigned to dacarbazine <o:p></o:p></span></div></td></tr>
<tr style="mso-yfti-irow: 20; page-break-inside: avoid;"><td colspan="2" style="background: black; border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><div align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-size: 10pt;"><span style="color: white;">AUTHORS’ CONCLUSIONS<o:p></o:p></span></span></b></div></td></tr>
<tr style="mso-yfti-irow: 21; mso-yfti-lastrow: yes; page-break-inside: avoid;"><td colspan="2" style="border-top: none; border: solid windowtext 1.0pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Results show a relative reduction of 63% in the risk of death and 74% in risk of tumor progression in favor of vemurafenib as compared to dacarbazine<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">48% of patients treated with vemurafenib experienced a confirmed response. Most patients had some tumor shrinkage.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Partial response seen in 4 of 10 patients with BRAF V600K mutation<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Confirmed response in dacarbazine group was 5%, which is lower than published trials. Results are reliable since patients in current study had BRAF V600E mutation, which is associated with a more aggressive and chemotherapy resistant tumor.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">48 patients (14%) assigned to dacarbazine did not receive treatment; mostly because of withdrawn consent. (29 were available for evaluation)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Patients assigned to vemurafenib reported few Grade 3 adverse events (rash, arthalgias, photosensitivity, and fatigue).<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Dose modification of vemurafenib was required for 38% patients due to adverse events<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l0 level1 lfo27; tab-stops: 8.1pt; text-indent: -8.1pt;"><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><span style="font-size: 10pt;">Squamous-cell carcinoma or keratocanthoma was reported in 18% of patient receiving vemurafenib<o:p></o:p></span></div></td></tr>
</tbody></table><br />
<div class="MsoNormal"><br />
</div><table border="1" cellpadding="0" cellspacing="0" class="MsoNormalTable" style="background: white; border-collapse: collapse; border: none; margin-left: .9pt; mso-border-alt: solid windowtext .5pt; mso-border-insideh: .5pt solid windowtext; mso-border-insidev: .5pt solid windowtext; mso-padding-alt: 0in 5.4pt 0in 5.4pt; mso-table-layout-alt: fixed;"><tbody>
<tr style="height: 3.15pt; mso-yfti-firstrow: yes; mso-yfti-irow: 0; page-break-inside: avoid;"> <td style="background: black; border: solid windowtext 1.0pt; height: 3.15pt; mso-border-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"> <div align="center" class="MsoNormal" style="text-align: center;"><b><span style="font-size: 10pt;"><span style="color: white;">GENERALIZABILITY/CRITIQUE/DISCUSSION<o:p></o:p></span></span></b></div></td> </tr>
<tr style="height: 3.15pt; mso-yfti-irow: 1; page-break-inside: avoid;"> <td style="border-top: none; border: solid windowtext 1.0pt; height: 3.15pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"> <div class="MsoNormal"><b><span style="font-size: 10pt;">Strengths<o:p></o:p></span></b></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l20 level1 lfo10; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Introduction and Rationale<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The authors are studying a novel treatment for malignant melanoma, a disease state with poor prognosis. The agent, vemurafenib, is targeted to a common mutation found the patient population.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; tab-stops: 26.1pt;"><br />
</div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l20 level1 lfo10; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Methods <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Randomized, multicenter, intention-to-treat, active control study<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Study included patients from countries/ regions with high rates of melanoma (US, Australia, Western Europe)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Baseline characteristics between groups were similar<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Primary and secondary outcomes were appropriate<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Use of RECIST criteria for tumor response is standard of care and objective measurement<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Adverse events graded according to NCI’s Common Terminology Criteria for Adverse Events <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Interim analysis was performed after 50% of projected deaths occurred<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Dosing of dacarbazine was higher than approved dosing. V600E mutation is believed to be more aggressive and therefore a higher dose might be more beneficial. <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Mutation test was performed at 1 of 5 central laboratories ensuring consistent results <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Dose reductions due to Grade 2 adverse events or worse for patients receiving vemurafenib.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Power and alpha levels were acceptable<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Statistical tests were appropriate for parameters<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Patients allowed to cross over from dacarbazine to vemurafenib due to statistically significant improvement of OS and PFS<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Authors considered effect of LDH levels on efficacy since elevated levels are correlated with poorer outcomes<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; tab-stops: 26.1pt;"><br />
</div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l20 level1 lfo10; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Results<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Unstratified results were statistically significant for OS, PFS, and tumor response<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">PFS results were statically significant for all sub-groups except patients <u>></u> 75 years of age<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Statistically significant improvement of OS in M1c disease sub-group<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">LDH levels had no effect on OS and PFS outcomes.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l20 level2 lfo10; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Vemurafenib was relatively well-tolerated (only 1 patient with Grade 4 adverse event)<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; tab-stops: 26.1pt;"><br />
</div><div class="MsoNormal"><b><span style="font-size: 10pt;">Weaknesses<o:p></o:p></span></b></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l20 level1 lfo10; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Introduction and Rationale<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l1 level1 lfo29; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Title is biased<b><o:p></o:p></b></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l1 level1 lfo29; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The introduction is brief and gives a superficial overview of disease state and current therapies.<b><o:p></o:p></b></span></div><div class="MsoNormal" style="margin-left: 26.1pt; tab-stops: 26.1pt;"><br />
</div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l17 level1 lfo5; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Methods<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Trial was designed for 680, but only 675 patients were enrolled<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Authors mention that the trial is intention-to-treat, but statistical analysis is a modified version.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The trial was open-label<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Patients were evaluated for OS, PFS, and confirmed response if randomized at least 2, 9, and 14 weeks, respectively, before the cutoff date.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">No mention of time between diagnosis of malignant melanoma and study randomization.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Majority of patients were Stage M1c. Only 2-5% of patients present at this stage. Applicability to most patients is weak.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Higher dose of dacarbazine resulted in high percentage of patients suffering from Grade 2 or worse adverse effects associated with dacarbazine (13% had Grade 2 or 3 nausea and 10% experienced Grade 2-5 neutropenia).<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Lactate dehydrogenase ULN range were not standardized among centers<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The use of anti-emetics and G-CSF was not standard across study centers <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">OS was evaluated in patients randomized at least 2 weeks before cutoff date. Based on 672 patients evaluated for OS and 549 evaluated for PFS, 123 patients evaluated for OS were randomized less than 9 weeks before analysis. This is a short time for clinically useful results.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Onset of action for dacarbazine is 18-24 days and is administered every 3 weeks. Based on these factors, OS estimation is likely to include patients who have not achieved full benefit of dacarbazine therapy. <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Trial length was too short to assess longer term toxicities and efficacy and potential resistance to therapy<o:p></o:p></span></div><div class="MsoNormal"><br />
</div></td> </tr>
<tr style="height: 271.75pt; mso-yfti-irow: 2; mso-yfti-lastrow: yes; page-break-inside: avoid;"> <td style="border-top: none; border: solid windowtext 1.0pt; height: 271.75pt; mso-border-alt: solid windowtext .5pt; mso-border-top-alt: solid windowtext .5pt; padding: 0in 5.4pt 0in 5.4pt; width: 531.0pt;" valign="top" width="708"> <div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l17 level1 lfo5; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Results<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The data was collected by the sponsor and analyzed with senior authors<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Insufficient number of patients enrolled for reliable Kaplan-Meier estimates of survival curves<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Authors do not mention how they considered patients who crossed over from dacarbazine to vemurafenib into statistical analyses or conduct analysis of patients.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The number of patients who crossed over is not mentioned<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Sub-group analysis for OS reveals that HR was not significant for melanoma subtypes with exception of M1c. The greater number of patients with this sub-type contributed immensely to unstratified OS statistical significance. <o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Data used for OS estimation included patients who did not receive treatment (48 in dacarbazine group and 2 in vemurafenib group). This is a wide discrepancy and may contribute to superior vemurafenib results.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Authors do not address duration of response, which was a secondary outcome<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Reports of secondary cancers in patients who received vemurafenib. The short trial length may underestimate the true carcinogenic potential.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 26.1pt; mso-list: l17 level2 lfo5; tab-stops: 26.1pt; text-indent: -9.0pt;"><!--[if !supportLists]--><span style="font-family: 'Courier New'; font-size: 10pt;">o<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Authors do not mention follow-up of patients in study<o:p></o:p></span></div><div class="MsoNormal"><br />
</div><div class="MsoNormal"><b><span style="font-size: 10pt;">Recommendations<o:p></o:p></span></b></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l12 level1 lfo14; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Despite insufficient number of enrolled patients and short length, vemurafenib shows superior results compared dacarbazine in terms of OS, PFS, and tumor response.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l12 level1 lfo14; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">The V600E is a common mutation in metastatic melanoma patients and vemurafenib offers a treatment for these patients.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l12 level1 lfo14; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">It would be recommended to initiate vemurafenib in patients with the BRAF V600E mutation. Due to a lack of knowledge regarding long term efficacy and safety, the use should be restricted to FDA approved indication of unresectable or metastatic melanoma with BRAF V600E mutation detected by FDA approved test.<o:p></o:p></span></div><div class="MsoNormal" style="margin-left: 8.1pt; mso-list: l12 level1 lfo14; tab-stops: 8.1pt; text-indent: -8.1pt;"><!--[if !supportLists]--><span style="font-family: Symbol; font-size: 10pt;">·<span style="font: 7.0pt "Times New Roman";"> </span></span><!--[endif]--><span style="font-size: 10pt;">Insufficient evidence exists regarding genetic testing of all melanoma patients.<o:p></o:p></span></div></td> </tr>
</tbody></table><div class="MsoNormal"><br />
</div><div class="MsoNormal"><b><span style="font-size: 10.0pt;">References:<o:p></o:p></span></b></div><div><!--[if !supportEndnotes]--><br clear="all" /> <hr align="left" size="1" width="33%" /> <!--[endif]--> <div id="edn1"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref1" name="_edn1" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[1]</span></span><!--[endif]--></span></a> Kim KB, Davies MA, Rapini RP, et al. Chapter 39. Malignant Melanoma. In: Kantarjian HM, Wolff RA, Koller CA, eds. The MD Anderson Manual of Medical Oncology. 2<sup>nd</sup> ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=8312992 Accessed Jan 9, 2012. </div></div><div id="edn2"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref2" name="_edn2" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[2]</span></span><!--[endif]--></span></a> National Comprehensive Cancer Network. Melanoma. NCCN Clinical Practice Guidelin.e in Oncology. Version 3.2012 </div></div><div id="edn3"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref3" name="_edn3" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[3]</span></span><!--[endif]--></span></a> American Joint Commission on Cancer. Melanoma of the skin Staging. http://www.cancerstaging.org/staging/posters/melanoma12x15.pdf. Accessed Jan 8, 2012 </div></div><div id="edn4"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref4" name="_edn4" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[4]</span></span><!--[endif]--></span></a> Dacarbazine [Drug]. In. Taketomo CK, Hodding JH, Kraus DM, editors. Pediatric Dosage Handbook. 16<sup>th </sup>ed. Hudson: Lexi-Comp; 2009. p. 388-9. </div></div><div id="edn5"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref5" name="_edn5" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[5]</span></span><!--[endif]--></span></a> Yervoy [package insert] Bristol-Myers Squibb; 2011. http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed Jan 10, 2012</div></div><div id="edn6"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref6" name="_edn6" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[6]</span></span><!--[endif]--></span></a> Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364: 2517-26.</div></div><div id="edn7"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref7" name="_edn7" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[7]</span></span><!--[endif]--></span></a> Zelboraf [package insert] Genentech; 2011. http://www.gene.com/gene/products/information/zelboraf/pdf/pi.pdf. Accessed Jan 8, 2012 </div></div><div id="edn8"> <div class="MsoEndnoteText"><a href="file:///C:/Documents%20and%20Settings/R/Desktop/Rotation%20Stuff/APPE%20Rotations/Cycle%207-%20Oncology/Journal%20Club-Vemurafenib-V4.doc#_ednref8" name="_edn8" title=""><span class="MsoEndnoteReference"><!--[if !supportFootnotes]--><span class="MsoEndnoteReference"><span style="font-family: "Times New Roman","serif"; font-size: 10.0pt; layout-grid-mode: line; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-US;">[8]</span></span><!--[endif]--></span></a> Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.</div></div></div>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-33876673749045704142011-12-18T19:12:00.000-05:002011-12-20T17:54:23.227-05:00Ariad: Leading the Pack to Introduce a New Generation of TKIs<br />
Ariad Pharmaceuticals, Inc. (NASDAQ: ARIA) is a cancer-focused biotechnology located in Cambridge, Massachusetts. The company is discovers and develops drugs aimed at treating human diseases at the cellular level. The main product candidates are ridaforolimus, ponatinib, and AP26113. In 2007, Ariad reached a collaboration agreement with Merck for the development of ridaforolimus. Under the agreement, Ariad received an upfront payment of $75 million and has received $53.5 million in milestone payment for the initiation of Phase 2 and 3 trials. The development, manufacturing, and commercialization costs are evenly split between the companies.<a href="http://www.ariad.com/wt/tertiarypage/ariad_collaborations">1</a><br />
<br />
<u><b>Ponatinib (AP24534) and Tyrosine Kinase Inhibitors</b></u><br />
<u><br /></u><br />
Ponatinib is a novel, orally active tyrosine kinase inhibitor (TKI). The molecule is active against a range of tyrosine kinases including all forms of BCR-ABL (therefore called a pan-BCR-ABL inhibitor). BCR-ABL is prevalent in chronic myelogenous leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). The are dozens of mutated forms of BCR-ABL and mutation is one of the resistance mechanisms employed by cancer cells. Ponatinib may also inhibit Flt3 (AML), and FGFR and VEGFR in solid tumors.<br />
<br />
An important saying in oncology is that whatever the body does normally, it can do abnormally. Since cancer cells are normal cells gone awry, they share many of the same molecular mechanisms. Tyrosine kinases are vital parts of normal cellular functioning. However mutated forms may give rise to cancerous cells. Although at first glance it may seem ideal that TKIs target a wide range of kinases, they may also interfere with the functioning of normal cells and there exists a potential for secondary malignancies. Combined with the fact that Gleevec has helped convert CML into a chronic disease, long-term monitoring is of great importance.<br />
<br />
BCR-ABL fusion gene allows for escape from growth regulation <span style="font-family: Wingdings;">à</span>
activated as functional oncogene <span style="font-family: Wingdings;">à </span><span style="font-family: inherit;">increased kinase activity </span><span style="font-family: Wingdings;">à </span><span style="font-family: inherit;">cell proliferation, inhibition of apoptosis, and malignant clones.</span><br />
<br />
Imatinib (Gleevec) was the first TKI active against BCR-ABL. Despite wonderful activity, patients' tumors develop resistance to Gleevec. This ushered in the another generation of TKIs targeting BCR-ABL, dasatinib (Sprycel, Bristol-Myers Squibb; NYSE: BMY)<a href="http://www.sprycel.com/index.aspx?TC=35615&utm_source=google&utm_medium=cpc&utm_campaign=brandedgeneral&utm_term=dasatinib&utm_content=brandedlp1_textad_home_text_tc35615">2</a> and nilotinib (Tasigna, Novartis; NYSE: NVS)<a href="http://www.us.tasigna.com/health-care-professional/index.jsp">3</a>, which both are active against BCR-ABL. Both drugs are approved for patients whose cancers no longer respond to and are intolerant to Gleevec. Sprycel and Tasigna have warning of arrhythmia known as QT interval prolongation. This concern is addressed for all new drugs and will be closely monitored for ponatinib since molecules in the same class have been shown to cause QT prolongation. <br />
<br />
ENESTnd Study- Nilotinib showed superior results compared to imatinib in terms of CCyR and MMR at 12 months for newly diagnosed patients <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0912614">4</a><br />
<br />
DASISION Study- Dasatinib showed superior results compared to imatinib in terms of CCyR and MMR at 12 months for newly diagnosed patients <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1002315">5</a><br />
<br />
<span style="color: red;"><b>There are over 40 identified mutations in Gleevec binding site in CML patients. The T315I mutations confers resistance to Gleevec, Sprycel, and Tasigna. The emergence of this mutation requires change of therapy to interferon alpha or stem cell transplant. This unmet clinical need is addressed by ponatinib since it is claimed as a pan-BCR-ABL TKI.</b></span><br />
<br />
Other TKIs include Erlotinib (Tarceva), Lapatinib (Tykerb), gefitinib (Iressa), sunitinib (Sutent), and sorafenib (Nexavar). These agents are approved for a variety of cancers such as non-small cell lung cancer, renal cell carcinoma, and breast cancer. <br />
<b><br /></b><br />
<u><b>Background on Leukemias (ALL and CML)</b></u><br />
<ul>
<li>Leukemias are malignancies of hematopoietic cells in the bone marrow and blood</li>
<li>They occur in either the myeloid lineage (basophils, eosinophils, neutrophils, monocytes, platelets, erythrocytes) or lymphoid lineage (T lymphocytes and B lymphocytes)</li>
<li>Type of leukemia reflect maturity of hematopoietic stem cells from which it developed</li>
<ul>
<li>Acute Leukemias- early cells in the myeloid (AML) or lymphoid (ALL) lineage</li>
<li>Chronic Leukemias- genetic abnormalities occur in later stages of white blood cell development </li>
</ul>
<li>Acute Lymboblastic Leukemia </li>
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</div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<ul>
<li>Incidence: 5,760 in 2009</li>
<li>Deaths: 1,400 in 2009</li>
<li>Patients typically attain remission, but it is difficult to keep them in remission</li>
<li>Poor prognostic factors: L2 or L3 (based on French American British System, 70% of adult ALL);<span class="Apple-style-span" style="color: red;"> <b>Ph+ (30% of adult ALL)</b></span>; abnormal cytogenetics; Age > 30; white blood cell >30K; platelet count < 10K; delayed remission; male > female; African american; CNS disease; enlarged liver or spleen; mediastinal mass.</li>
<li>Goal: Achieve complete remission and continue therapy. <span class="Apple-style-span" style="color: red;"><b>CR achieved in 65-85%; relapse is common.</b></span><span style="color: red;"><b> Gleevec is added to the regimen if cancer is Ph+.</b></span></li>
</ul>
</ul>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjg1O-HQ9SrKJRVS1K_ABR-XPEWQ7guEMoKK7c_T35BXIXBiB0xm1xzGv0yC0ICJ2YukqtPwCwxZuK2qiHrsoIEmk_Q1jg8ivfCxR5ZnO9URFteLAeOcYaaDr_j1nQYTIhOr9unZZNMBwc/s1600/all+treatment.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img border="0" height="75" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjg1O-HQ9SrKJRVS1K_ABR-XPEWQ7guEMoKK7c_T35BXIXBiB0xm1xzGv0yC0ICJ2YukqtPwCwxZuK2qiHrsoIEmk_Q1jg8ivfCxR5ZnO9URFteLAeOcYaaDr_j1nQYTIhOr9unZZNMBwc/s400/all+treatment.png" width="400" /></a></div>
<ul><ul>
<li>Relapsed/ Refractory ALL</li>
<ul>
<li><span class="Apple-style-span" style="color: red;"><b>60-70% of ALL patients relapse </b></span></li>
<li><span class="Apple-style-span" style="color: red;"><b>If Ph+, add dastinib or nilotinib</b></span></li>
<li><span class="Apple-style-span" style="color: red;"><b>High relapse rate increases potential need for ponatinib</b></span></li>
</ul>
</ul>
</ul>
<ul>
<li>Chronic Myelogenous Leukemia</li>
<ul>
<li>Incidence and Deaths (2009): 5,050 and 470</li>
<li>Median age at Dx: 67 years of age (Most studies report 45-55 years)</li>
<li>Male: Female = 1.5:1</li>
<li><span style="color: red;"><b>95-100% of patients have BCR-ABL fusion protein</b></span></li>
</ul>
</ul>
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<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiIvPLzKSyXBXkvufGuDfWHVyNCD0d36UglQqZYQo4GV60lhCG0v1nPs6m-9apuVv5a-CcRgSLB4D8xOPIwVN1wOBKeoH48hsGMr80mr-hq0vH2FF4hwUcS61a6x9hDPboUrpFATPkZYhs/s1600/CML.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="317" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiIvPLzKSyXBXkvufGuDfWHVyNCD0d36UglQqZYQo4GV60lhCG0v1nPs6m-9apuVv5a-CcRgSLB4D8xOPIwVN1wOBKeoH48hsGMr80mr-hq0vH2FF4hwUcS61a6x9hDPboUrpFATPkZYhs/s400/CML.png" width="400" /></a></div>
<div>
<ul>
<li>Treatment Responses</li>
<ul>
<li>Hematologic response: normalization of peripheral blood counts</li>
<li>Cytogenetic response: % of cells positive for Ph in bone marrow</li>
<ul>
<li>Complete- elimination of Ph</li>
<li>Major- <35% Ph+ cells</li>
</ul>
<li>Molecular response: most sensitive; uses PCR for quantitative number of bcr-abl transcripts</li>
</ul>
</ul>
<div>
<ul>
<li>Nicolini FE et al. Epidemiologic study on survival of chronic myeloid leukemia and Ph acute lymphoblastic leukemia patients with BCR-ABLT315I mutation. Blood 2009; 114: 5271-5278.</li>
<ul>
<li>Median age at T315I mutation detection: 54 years</li>
<li>Median time (months) between TKI treatment initiation and T315I mutation detection: 29.2(CP-CML), 15.4 (AP-CML), 5.8 (BP-CML), and 9.1 (Ph+ ALL). </li>
<li>After T315I mutation detection, dasatinib and nilotinib were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%.</li>
<li>Median OS from T315I mutation detection: 22.4, 28.4, 4.0, and 4.9 months
for CP-CML, AP-CML , BP-CML, and Ph ALL patients, respectively</li>
<li>Median PFS from T315I mutation detection: 11.5, 22.2, 1.8, and 2.5 months for CP-CML, AP-CML , BP-CML, and Ph ALL patients, respectively</li>
</ul>
</ul>
</div>
</div>
<div>
<u><b>ASH 2011</b></u></div>
<div>
<br />
Initial Findings from the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation </div>
<div>
<div>
<ul>
<li>Primary Objective: Efficacy (Endpoints: major cytogenetic response for chronic phase CML or major hematologic response for accelerated phase CML, blast phase CML, and Ph+ ALL).</li>
<li>Secondary Objective: Clinical and molecular responses; molecular genetic status of patients; safety</li>
<li>Patients assigned to 1 of 6 cohorts based on disease+stage (chronic phase CML, ) and resistance status (resistant or intolerant of nilotinib and dastinib or T315I mutation).</li>
<li>About 30% patients in chronic (64/207) or accelerated (19/60) phase CML cohorts with T315I mutation</li>
<li><span style="color: red;"><b>46 of 48 patients in blast phase and Ph+ ALL cohort had T315I mutation</b></span></li>
<li>F317L was also a common mutation</li>
<li>47% of patients in chronic phase CML cohort reached primary endpoint</li>
<li>67% of patients in accelerated CML and 37% of blast phase CML+ Ph+ ALL reached primary endpoint</li>
<li><span style="color: red;"><b>Responses for all cohorts were better than responses to most recent dasatinib or nilotinib therapy </b></span>(25% CP-CML, 33% AP-CML, 25% BP-CML + Ph+ ALL).</li>
<li>67% (301/449) patients remained on study. </li>
<li>Only 22% (21/94) in BP-CML + Ph+ ALL remain on study. Remember that these patients have the worse prognosis</li>
<li>4 on-study deaths were treatment related, but no evidence of ponatinib specific findings</li>
</ul>
</div>
</div>
<div>
<u><b>ASH 2011 Abstracts</b></u><br />
<br />
Analysis of the Potential Effect of Ponatinib on the QTc Interval in Patients with Refractory Hematologic Malignancies<br />
<br />
<ul>
<li><span style="color: red;"><b>No effect on cardiac repolarization measured by lack of significant change in QTcF at all doses</b></span></li>
</ul>
<div>
Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies</div>
<div>
<ul>
<li>81 patients (54% male) received ponatinib. 43 pts had CP-CML. </li>
<li>Best responses: MCyR in 31/43 (72%), 27 (63%) CCyR. </li>
<li>Complete Hematologic Response in 42/43 patients. </li>
<li>Major molecular response in 19/43 (44%). </li>
<li>The median time to MCyR was 12 (3-104) weeks. </li>
</ul>
</div>
<br />
<br />
ATP Dependent Efflux Transporters ABCB1 and ABCG2 are Unlikely to Impact the Efficacy, or Mediate Resistance to the Tyrosine Kinase Inhibitor, Ponatinib.<br />
<ul>
<li><span style="color: red;"><b>Ponatinib is the least susceptible TKI as a substrate for efflux pumps. Nilotinib and dasatinib are the most susceptible.</b></span></li>
</ul>
<div>
<u><b>AACR 2011</b></u></div>
<div>
<u><br /></u></div>
<div>
<div>
Ponatinib (AP24534), a potent pan-FGFR inhibitor with activity in multiple FGFR-driven cancer models with distinct mechanisms of activation</div>
</div>
<div>
<ul>
<li>In vitro and in vivo inhibition of FGFR of ponatinib versus other TKIs in clinical development</li>
<li><b><span style="color: red;">Ponatinib was more potent than other TKIs and potent against different forms of FGFR</span></b></li>
<li><span style="color: red;"><b>Inhibition levels may be achieved in humans</b></span></li>
</ul>
</div>
<div>
<u><b>ASH 2010</b></u></div>
<br />
<u><br /></u><br />
A Phase 1 Trial of Oral Ponatinib (AP24534) in Patients with Refractory Chronic Myelogenous Leukemia (CML) and Other Hematologic Malignancies: Emerging Safety and Clinical Response Findings<br />
<br />
<ul>
<li>At concentration of 40 nM in vitro, ponatinib inhibits many mutant forms of BCR-ABL. Based on this, the dose would need to be at least 30 mg</li>
<li>Primary objective: Maximum tolerated dose or recommended dose</li>
<li>Secondary objectives: safety; anti-tumor efficacy; pK/PD; pharmacogenomics</li>
<li>Intra-patient dose escalation using capsules or tablets</li>
<li>Patients with any stage CML (60 of 74 patients), AML, ALL, MDS, MM, or CLL</li>
<li>60 patients were Ph+ </li>
<ul>
<li>95% resistant to at least 2 TKIs</li>
<ul>
<li>Prior Treatment with imatinib (97%), dasatinib (90%), nilotinib (57%), dasatinib + nilotinib (52%)</li>
</ul>
</ul>
<li>28% had T315I mutant at entry; 11% with F317L mutation</li>
<li><span style="color: red;"><b>Hematologic dyscrasias most common Grade 3 AEs.</b></span> Expected based on mechanism of ponatinib</li>
<li><span style="color: red;"><b>Pancreatic DLTs at 60 mg</b></span></li>
<li>CP-CML: 66% MCyR, 53% CCyR, 42% MMR</li>
<li><span style="color: red;"><b>CP-CML with T315I: 100% MCyR, 89% CCyR, 78% MMR</b></span></li>
</ul>
<div style="text-decoration: underline;">
<u><b><span style="font-size: large;">Summary</span></b></u></div>
<div>
<ul>
<li>Ponatinib a "3rd Generation" TKI has shown great promise in terms of efficacy and safety for the treatment of CML and Ph+ ALL</li>
<li>Due to long-term therapy and high rate of resistance of ALL and CML patients, ponatinib will easily find a place in therapy.</li>
<li>Activity against T315I provides a solution for an unmet clinical need</li>
<li>Ponatinib is the most advanced TKI in clinical development that is active against the T315I mutation</li>
<li>It is encouraging that ponatinib is not likely to be a substrate for efflux pumps</li>
<li>Superior results of nilotinib and dasatinib compared to imatinib in newly diagnosed patients may allow ponatinib to play a greater role in patient therapy</li>
<li>It would not be surprising if ponatinib were to become first line agent for CML in the future; however, barriers would be potentially lower price of imatinib and substantially more data on safety and efficacy of imatinib</li>
<li>Activity versus other receptors (FGFR and VEGFR) may lead to indications for solid tumors</li>
<li>Long term efficacy and safety data still need to be collected and analyzed</li>
<li>Ariad Pharmaceuticals has become an investor favorite and should continue to see great growth due to ridaforolimus and especially due to ponatinib</li>
<li>Ariad is up 129.8% YTD and looks to be in the prime spot to see accelerated growth. It is possible that Ariad's 2011 year is Amgen's 1998.
</li>
</ul>
</div>
<div style="text-decoration: underline;">
<u><b>Sources (not listed in-text)</b></u></div>
</div>
<div>
<u><br /></u></div>
DiPiro J et al. Pharmacotherapy: A Pathophysiologic Approach.<br />
Presentations of clinical data are available from Ariad Pharmaceutical's website.<br />
CML Guideline available from National Comprehensive Cancer Network (NCCN)<br />
O'Hare T et al. Clin. Cancer Res. 2011; 17: 212-221.<br />
Gruber FX et al. Leukemia advance online publication, 5 August 2011; doi:10.1038/leu.2011.187<br />
<br />
<br />
<br />
Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-7340613437961607792011-06-29T22:21:00.000-04:002011-06-29T22:21:01.707-04:00Intrexon and Ziopharm's "Synthetic Biology" Platform More Abstract than Picasso's Art<div style="text-align: justify;">Ziopharm Oncology (NASDAQ: ZIOP), a biotechnology company headquartered in NYC, has partnered with Intrexon to develop a "synthetic biology" platform to design a treatment for cancer. Ziopharm also has other candidates in various phases of clinical trials. </div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">Its most advanced candidate is palifosfamide, which is a metabolite of ifosfamide. It is entering a Phase 3 trial called PICASSO. Ifosfamide is normally metabolized by the liver to 4-hydroxy ifosfamide, aldoifosfamide, and chloracetaldehyde (causes confusion). Intracellular conversion yields the active ifosfamide mustard and acrolein, which is a toxic molecule that causes bladder scarring (hemorrhagic cystitis). It is therefore required to administer MESNA with ifosfamide. ZIOP has designed palifosfamide to avoid the co-adminsitration of MESNA and reduce hemorrhagic cystitis. However, ifosfamide is not in extensive use and it is unlikely that the higher cost of palifosfamide will be enough to persuade oncologists to switch from ifosfamide + MESNA.</div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">Ziopharm's other small molecule, darinaparsin, is an organic arsenic being investigated for the treatment of heptacellular carcinoma and hematologic malignancies. There probably is not a large enough market for arsenic products to generate large revenues as most investors has become accustomed to seeing from biotechnology firms. </div><div style="text-align: justify;"> </div><div style="text-align: justify;">The most interesting and disappointing project undertaken by Ziopharm is a partnership with Intrexon (notice the name is derived from intron and exon) to design a synthetic biology platform. This technology should be the hallmark of the companies. Synthetic biology is the introduction of genes that are not found in nature into a living system to produce useful products. A great example is that conversion of algae to produce diesel fuel. Utilizing synthetic biology for cancer treatment has the potential to be revolutionary. The companies have partnered to design a "synthetic biology" platform to combat cancer. The inserted gene can be controlled using a ligand that the patients swallows in pill form. This overcomes the biggest pitfall of not being able to control when the gene is expressed. However, the biodistribution of the ligand has to studied and any off-target effects are of concern.</div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">However, deeper research into their studies reveals a that their "synthetic biology" appears to be no more than a euphemism for gene therapy. Gene therapy was once thought to be the next big thing, but it never worked and resulted in deaths. To date, Ziopharm and Intrexon have introduced a gene encoding interleukin-12 (IL-12) into dendritic cells. The goal is to induce dendritic cells to secrete IL-12. This will recruit and induce the immune system. This approach has some problems in itself. Dendritic cells are important immune cells, but they function by presenting antigens to T cells. To maximize efficacy, it would be wise to make dendritic cells present antigens associated with cancers such as Dendreon's Provenge and not change their functioning. Also, IL-12 will be secreted throughout the body. why not just inject the patient with IL-12? What other distal effects will this have? The procedure to modify the dendritic cells is time consuming, highly variable, and expensive. SOPs will need to be designed and implemented and training must be provided to all clinicians involved in treatment. Another disadvantage of the approach is that the modified dendritic cells are injected intratumorally. This will only treat visible tumors and miss micrometastases. Also, there is higher than normal probability of user error. </div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">Another issue with the platform is the feasibility and mechanism of action. The scientific background and support for the platform seems shabby at best and is very abstract to any person including leading scientists to fully comprehend. In order for the ligand to work, the cell has to express a ligand-inducible transcription factor and a co-activation partner, termed RheoSwitch. The gene of interest is inserted using a replication incompetent adenoviral vector. The companies do not explain and probably cannot explain how the entire system works. It is virtually impossible to control where the genes will be inserted. Gene therapy always hanging the hanging cloud of carcinogenesis. This system does not alleviate that fear. Also, the companies do not disclose how the genes for the RheoSwitch are inserted into the cell and how the protein products are transcribed and how they find the promoter region of the target gene. The lifespan of these proteins and probability of stability of the genes are other unknown factors. Long term studies will need to be conducted to evaluate any future effects of modifying the genome. Biology is complex and this system adds to the complexity of treating diseases. Often the best solutions work through elegant and simple mechanisms. </div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">Results from a Phase 1B trials in melanoma patients were very disappointing. Of 10 patients enrolled, no patients achieved a complete response, 1 had a partial response, 3 had stable disease, and 4 had disease progression. Two patients were not evaluable. This basically means that 50% of patients do not see any effect from receiving the medication. This is unacceptable given that melanoma These results cannot match the far superior results achieved by at least a half dozen other companies working on treatments for melanoma. Melanoma is very immunoresponsive when first treated with immunotherapies. It is not uncommon for melanoma patients to have complete regression of all melanoma nodules when initially treated. This adds to the disappointing results. Also, Ziopharm and Intrexon are in the newborn stage of the technology and ant meaningful progress is so far away that the Hubble telescope may be needed. The market will be loaded with therapies before Ziopharm and Intrexon can bring anything to market. </div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">These are some of the issues with the "synthetic biology" platform facing Ziopharm and Intrexon. These companies are still far away from a viable product reaching the market. Ziopharm's other candidates are not blockbusters and will not generate huge revenues. It takes approximately $1 billion to bring a drug to market. The "synthetic biology" platform does not have a well-defined pathway and the costs of pre-clinical and clinical studies and failures will be higher than normal. Investors cannot expect palifosfamide and darinaparsin to help pay. </div><div style="text-align: justify;"><br />
</div><div style="text-align: justify;">Summary</div><ul><li>Palifosfamide is a slight improvement over ifosfamide, but there is not a large market for the drug and higher cost will hinder clinical adoption.</li>
<li>Darinaparsin is a substitute for arsenic compounds. As with palifosfamide, it is a "me-too" drug and will likely not be a clinical success.</li>
<li>Ziopharm has partnered with Intrexon to develop a "synthetic biology" platform. There are many aspects that are not known and need to be understood for the development of successful therapies. Results from a Phase 1B melanoma trial were terribly disappointing. The therapy is unlikely to get approval in the next one or two decades. </li>
</ul>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com4tag:blogger.com,1999:blog-4599326694255740220.post-24225904261563246522011-06-18T20:13:00.000-04:002011-06-18T20:13:40.431-04:00All of the Pieces of the Puzzle Coming Together for BSD MedicalI have written about BSD Medical (NASDAQ: BDSM) on this blog a couple of times before. I believe that they have a solid core technology platform with microwave and radiofrequency tumor ablation systems. I believe that these forms of therapy will continue to be used as part of cancer treatment regimens. The current ineffectiveness of chemotherapy, serious health risks of radiation, increasing acceptance by oncologists, and the increasing amount of studies demonstrating tumor ablation effeciveness and safety are all factors that will contribute to BSDM's growth.<br />
<br />
However, the lack of marketing and results from treatments using their systems have hampered the company from growing at a rapid pace. BSDM has addressed these concerns and I believe they are setting the stage to become a major player in the medical device area. The company now has an established coast-tocoast distribution system in the US. Despite news about setting a distribution system, purchasing by several hospitals and healthcare systems, and other positive news, BSDM's stock price had been steadily declining. This presents the most opportune time for buying BSDM stock. <br />
<br />
Their two main competitors in the tumor ablation market are Boston Scientific (NYSE: BSX) and AngioDynamics (NASDAQ: ANGO). Neither company has a specific focus on tumor ablation. Their diversification will allow BSDM to gain considerable market share and become a leader in the field. BSDM is also testing new microwave and radiofrequency systems to be the next generation of products. This is great because lack of innovation can be the downfall of companies in all areas.<br />
<br />
Two presentations at ASCO 2011 featured the use of BSDM's hyperthermia system. I was impressed by the study analyzing regional hyperthermia treatment in combination with gemcitabine and cisplatin in pancreatic patient who had relapsed after gemcitabine therapy. These patients are in dire situations and do not have any options. 16/23 had an objective response or achieved stable disease. The overall survival was 12.9 months and the progression free survival was 5.9 months.<br />
<br />
The company also noted a study published in the prestigious scientific journal <i>PNAS </i>demonstrating the power of hyperthermia therapy. The study was reviewed in science magazine, <i>The Scientist</i>. Bascially, the study showed that hyperthermia therapy as an adjunct could expand the range of cancers for which new drugs could be used. Hyperthermia also helps to overcome tumor resistance mechanisms such as DNA repair. <br />
<br />
BSDM's stock is up 36.8% since Tuesday June 14, closing at $3.94 on Friday. However, the stock is in position to continue increasing. Reports of increased sales and re-ordering of the disposable antennas show that BSDM's systems are in wide use and are increasingly added to current forms of therapy. I expect their next quarterly results to reflect these developments. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-21426825126898817852011-05-11T20:36:00.000-04:002011-05-13T16:34:21.799-04:00Chart Analysis: Teva and Mylan Stock Prices Mirror ImagesI am not an expert trading stocks based on chart patterns, but I came across an interesting possible pattern of stock prices of Teva and Mylan. They are the 2 biggest generic manufacturers and are competitors and it makes sense that a decrease in the price of one stock would show an increase in the other. It also makes sense that these stocks may move in the same direction for reasons larger than the two companies.<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEghsb3uy9bG_CBdnjy1nAr5mUeDyfgteyaOzDQJsCmJKGAEXutO-KKE22RDfEkp6No8uKoPsqekh1vtfZ-fDlG4Hjgxpttp8Ao3l89lrerIFFJNBaT5rnpwb6cNd1GP8E9upq7A7zYL-lE/s1600/untitled.bmp" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="297" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEghsb3uy9bG_CBdnjy1nAr5mUeDyfgteyaOzDQJsCmJKGAEXutO-KKE22RDfEkp6No8uKoPsqekh1vtfZ-fDlG4Hjgxpttp8Ao3l89lrerIFFJNBaT5rnpwb6cNd1GP8E9upq7A7zYL-lE/s320/untitled.bmp" width="320" /> </a></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhFZyFzgja4hiiuu2aeG0g4UvLatS4nr7PfvCLoLn8HBsr92WysO0Rtkw8FAlVmctYOB0b3uTuO2smk6SmvU75_5_Nt5H5f27AWnquMwlDrsfH3Znry2T6uqYkIZ85PzkAIPMzcwAp05E/s1600/3mnth.bmp" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="147" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhhFZyFzgja4hiiuu2aeG0g4UvLatS4nr7PfvCLoLn8HBsr92WysO0Rtkw8FAlVmctYOB0b3uTuO2smk6SmvU75_5_Nt5H5f27AWnquMwlDrsfH3Znry2T6uqYkIZ85PzkAIPMzcwAp05E/s320/3mnth.bmp" width="320" /></a></div><div class="separator" style="clear: both; text-align: left;">The 3 month chart shows that from mid-February to end of March, both stocks have similar charts. As seen in the 5 day and 1 month charts, Teva and Mylan have been moving in opposite directions, almost at the same rate, for the past month. They appear to be mirror images. Perhaps this can be exploited by investors. Any thoughts or suggestions? </div>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-51058236161813435932011-05-11T10:23:00.000-04:002011-05-11T10:23:31.684-04:00What's Teva Getting Out of the Cephalon BuyoutTeva Pharmaceuticals made a push to join the company of big pharma by purchasing Cephalon. Big Pharma have market caps over $100 billion ranging from Sanofi at the low end to JNJ at $181 billion. The current market cap for Teva is about $45 billion. Teva can potentially join the Big Pharma club by optimizing its purchase of Cephalon. This purchase bolsters Teva's current product line-up and adds about a dozen candidates to their pipeline. Also, it adds numerous biologics to Teva's arsenal. <br />
<br />
Teva's Copaxone, which generates 20% of its revenue, will be off patent soon, so it is important for Teva to discover new sources of revenues. At first glance it may seem that Teva over-paid because Cephalon's best seller Provigil loses patent protection next year. However, examining other products and candidates justifies the $6.2 billion price tag. <br />
<br />
It is also important to consider that Teva will need to continue spending money to conduct a large number of clinical trials of drug candidates it acquired from Cephalon. The revenues generated from Cephalon's currently approved drugs will greatly aid to offset clinical trial costs.<br />
<br />
<span style="font-size: large;"><u><b>Currently Approved Products from Cephalon:</b></u></span><br />
<ol><li>Nuvigil (armodafinil)- Basically the same drug as Provigil, but it's the R-isomer. Simply, chemical compounds may have the same atoms, but the arrangement of atoms attached to a carbon may differ. In most cases resulting in mirror images (think of your hands). Typically one version is active and the other is not. It is also probable that the inactive version causes most of the side effects. Teva can begin heavily marketing Nuvigil over generic versions of Provigil.</li>
<li>Provigil (modafinil)- Accounts of 41% of revenues for Cephalon. </li>
<li>Treanda (bendamustine)- generates nearly $400 million in revenues annually. It hasn't been compared to other 1st line agents for leukemia and lymphoma, but clinical studies or patient reports are most likely ongoing that may show superiority. It has low cross sensitivity to other alkylating agents.</li>
<li>Amrix (cyclobenzaprine)- treatment of muscle spasms. This is an extended release formulation; Teva markets an immediate release formulation.</li>
<li>Fentora (fentanyl buccal tablet)- Teva has a similar oral transmucousal lozenge.</li>
<li>Actiq (oral transmucousal fentanyl citrate)- Since Teva has a generic version already, Actiq may go away </li>
<li>Trisenox (arsenic trioxide)- indicated for inducing remission in patients with acute promyelocytic leukemia</li>
<li>Gabitril (tiagabine)- treatment of partial seizures</li>
</ol><span style="font-size: large;"><u><b>Drugs in the Pipeline:</b></u></span><br />
<br />
<u>CNS Disorders </u><br />
<ol><li>Nuvigil- Phase III trial for bipolar depression.</li>
<li>CEP-26401- Phase I. H3 antagonist for treating cognition in Alzheimer's disease/ schizophrenia. H3 receptors are found in the CNS. Further applications include sleep disorders and obesity. Last year, Evotec received 1.5 million Euros to begin Phase I trials for their H3 antagonist</li>
</ol><u>Inflammatory Diseases </u><br />
<ol><li>Cinquil (reslizumab)- Phase III. Humanized monclonal antibody targeting interleukin 5. Treatment for adult eosinophilic asthma. There is no specific treatment for eosinophilic asthma. Other drugs such as corticosteroids are used to control exacerbations.</li>
<li> Lupuzor (forigerimod)- Phase II. CD4 T cell modulator for treatment of Systemic Lupus Erythematous</li>
<li>CEP-37248- Phase I. Humanized antibody targeting interleukins 12 and 23. Multiple autoimmune disorder indications are possible.</li>
</ol><u>Oncology: </u><br />
<ol><li>Treanda- Phase I, II, and III for various myeloma and lyphomas including 1st line for non-Hodgkin's lymphoma, which would be a big plus.</li>
<li>CEP-18770- Phase II. It's a proteasome inhibitor for treatment of multiple myeloma. </li>
<ul><li>Bortezomib (Velcade) by Millennium Pharmaceuticals is already approved. </li>
<li>Ritonavir, a protease inhibitor developed for AIDS, has some proteasome inhibitory activity and may have potential for treating glioma.</li>
</ul><li> Mesenchymal Precursor Cells (with Mesoblast Limited)- Phase II for bone marrow transplantation</li>
<li>CEP-9722 (PARP inhibitor)- Phase II for Non-small-cell lung cancer with gemcitabine and cisplatin. Phase II for tumors with DNA repair mismatch. Phase I for treatment of tumors with temozolomide. </li>
<ul><li>Iniparib from Sanofi is in Phase III. FDA has fast tracked it for triple-negative breast cancer </li>
</ul><li>CEP-11981- Phase I for treating solid tumors.</li>
<li>3 others in pre-clinical stages</li>
</ol><u>Pain:</u><br />
<ol><li>Fentora (fenanyl buccal tablet)- filed for breakthrough pain associated with specific chronic pain conditions. This expands the current approval which is for only cancer pain. Approval will lead to increased prescribing and revenues. Also, in Phase III for high dose safety study; which allows it to bring newer, higher dosage strengths to market.</li>
<li> CEP-33237 (tamper-deterrent hydrocodone)- Phase III. Narcotics with tamper deterrent technologies are always looked on favorably. They are adopted more quickly to replace current drugs than in other treatment areas. Tamper deterrent technology helps to fight against the rising rate of prescription drug abuse. King Pharma hit it big by investing to Remoxy, Embeda, and Acurox. Pfizer realized the potential and bought King Pharma.</li>
<li>CEP-37247 (anti-tumor necrosis factor)- Phase II for treatment of sciatica</li>
</ol><u> Cardiology:</u><br />
<ol><li>Revascor (collaboration with Mesoblast Limited)- Phase II for congestive heart failure and myocardial infarction </li>
</ol>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-91683659492612681772011-03-10T15:43:00.000-05:002011-03-10T15:43:19.846-05:00Big Pharma Giving RNAi Technology the "Silent Treatment"Soon after Andrew Fire and Craig Mello reported the mechanism of a biological process able to post-transciptionally silence gene expression (RNA intereference) in 1998, scientists were quick to dream of the possibilities it held to cure diseases such as cancer. RNAi also took over gene therapy as the hot spot of biotechnology. Big Pharma companies, biotechs, and hundreds of academic researchers (including myself) went into full gear to develop platforms for siRNA treatments. To avoid any confusion, the reader should note that simply RNAi is the process through which the macromolecule called siRNA works.<br />
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Almost 13 years later, we have yet to meet the expectations of the optimist bunch. Companies such as Novartis and Roche are beginning to abandon their research in the field. Novartis ended its collaboration with Alnylam late last year (Alnylam has approximately $300 million in cash reserves and trades for about $10. The stock price has been decreasing since 2008) and Roche is running away from its program after investing nearly $500 million into it. It seems as if these companies have become impatient with the progress and forgotten the saying, "good things come to those who wait." Or could it really be that the two biggest recent discoveries in genetics (sequencing of the human genome and discovery of RNAi) bear no fruit?<br />
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The primary challenge hindering successful treatment with siRNA (short interfering RNA) has been finding a suitable carrier to deliver siRNA to target organs or tissues and protect against degradation in the vasculature. Developing a carrier, either polymers, dendrimers, or lipid nanoparticles, is another task for pharma companies to undertake. This can significantly increase R&D costs although the company may be able to obtain a separate patent for it and use it for a variety of siRNA therapies. <br />
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Other issues such as off targeting have concerned researchers and clinicians. RNA interference is a specific therapy. However, it's aim to block the production of a protein can be performed in any cell expressing that specific protein. Researchers tend to target proteins that are over-expressed or mainly expressed in the disease cells. <br />
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Unlike monoclonal antibodies, siRNAs are easier to copy and may see generic versions sooner after patent expiration. This may be a slight deterrent for some companies.<br />
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siRNA therapy effectiveness is limited by lifetime of the targeted protein, protein turnover rate, and stability/lifetime of siRNA within the cell and association of RNA induced silencing complex. To be maximally effective, siRNA must be delivered to cells before necessary proteins are made. If delivered after protein production, the protein needs to have a high turnover. siRNA may secure a niche as an adjunct therapy to prevent resistance to chemotherapy. As a sole therapy for the treatment of cancer, siRNA therapy has been riddled with sup-optimal results and failures.<br />
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The cost of siRNA therapy, once it is proven successful, can make or break its future. A lower cost can help siRNA therapy to be used as adjunctive therapy. If cost approaches the realms of monoclonal antibodies, siRNA may have no market except in rare diseases and would need to secure Orphan Drug Status. Effectiveness of current siRNAs would be warrant such status. <br />
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Despite the exits of two giants, there is some good news for the future of RNAi therapeutics. Dicerna signed an agreement with Kyowa Hakko Kirin. Pfizer and Santaris have reached an agreement over Santaris' locked nucleic acid (LCA) technology. There are a few siRNA drugs in clinical trials, primarily in Phase 1. Alnylam, Kyowa Hakko Kirin, and cubist have collaborated on a siRNA for treatment of RSV and it is in Phase 2B trial. Pfizer has license to a siRNA drug (from Quark) for the treatment of age related macular degeneration andand diabetic macular edema. It seems that Pfizer/Quark siRNA has the greatest chance of success because of the local administration to the eye. However, it needs to compete with Lucentis, a monocloncal antibody. <br />
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siRNA therapeutics is beginning to look like the Miami Heat. Despite early anticipation of greatness, things have started to go south as of late and people are beginning to lose faith. We're all waiting for the Black Swan that will catapult siRNA therapies into the next level. <br />
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Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-68472544892107672312011-02-17T14:03:00.000-05:002011-02-17T14:03:24.502-05:00BSD Medical's MicroThermX System Used to Treat Lung CancerBSD Medical reported earlier this week that its MicroThermX microwave ablation system was used to treat a patient with lung cancer at the Comprehensive Cancer Center at Rhode Island Hospital. It is too early to know know the effects of the treatment, but so far only good things have been reported. The attending oncologist Damian E. Dupuy said that the MicroThermX is the best generator he has used. Hopefully this gets other oncologists interested to use the microwave ablation system to treat their patients in addition to surgery, chemotherapy, and radiation. The MicroThermX system has less adverse effects than chemotherapy and radiation, which will win it patient preference. Also, the system uses antennas to deliver the microwaves to designated ablation areas. These antennas are one time use, so the company will continue to have a source of revenue. The system can also be used to treat various forms of cancers. <br />
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BSDM also got a boost in stock price after 21th Century Oncology Center purchased a hyperthermia therapy system. The BSD 500 Hyperthermia System has received a pre-market approval from the FDA, a requirement for class III medical devices. 21th Century Oncology operates nearly 100 cancer treatment centers in the USA, provides advanced therapy and radiation therapy options for its patients, and recruits physicians from the most prestigious training centers. BSD Medical has a growing network of clinical centers that will be involved with continuous clinical studies of their system. <br />
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The soft tissue ablation market is growing and there is a high revenue potential. Some estimates predict a worldwide market worth $2-3 billion. With the current ineffectiveness of cancer therapy, clinicians will need to adopt newer ways to treat cancer. BSD Medical is perhaps the most advanced in developing microwave ablation and hyperthermia systems and will continue to be the leader in the coming years. Investors should become excited about the latest developments for BSD Medical and expect more good things to come. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com1tag:blogger.com,1999:blog-4599326694255740220.post-88207879668293931742011-02-11T10:26:00.000-05:002011-02-11T10:26:48.071-05:00Is There Anything Left for Mannkind?Mannkind Corporation (Nasdaq: MNKD) has taken quite a beating recently. The big blows came from the FDA when issuing a Complete Response Letter for Afrezza, a inhalable insulin delivery technology that was seen as very promising. The CRL will require Mannkind to conduct further clinical trials, which require cash. Mannkind is reported to have less than a year's worth of cash on hand. In the past, CEO Alfred E. Mann has used his own personal money to help advance Afrezza. In a conference call, Man stated that the company will be laying off employees and has not said that he will be infusing more cash into the company to conduct more clinical trials. Many think that Mann has given up, but perhaps he looking at other options to conduct these trials. It is believed that most pharmaceutical companies will shy away from inhalable insulin after the failure of Exubera. Afrezza has numerous advantages over Exubera and is a better product overall. <br />
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For investors, it is worth exploring what Mannkind has to offer if Afrezza should fail. Investors can buy Mannkind stock at a discounted price right now. At the time of writing, MNKD was down 20% with unusually high volume. It is important for Mannkind to find other sources of funds, whether from the outside or through selling rights to its intellectual property. <br />
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Besides Afrezza, Mannkind is working on an active immunotherapy platform that may be applicable to various forms of cancer. The idea is interesting and unique from current forms of therapies. However, Mannkind is still in the early stages, just completing or initiating Phase I studies. It will be also worth knowing if Mannkind will be able to finance further clinical trials for its oncology program.<br />
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Mannkind also has patent rights to the inhaler technology called the "Dreamboat." Perhaps to raise more funds, the utilization of this technology can be sold to other pharmaceutical and biotech companies studying therapies for respiratory disorders. The Dreamboat technology can possibly be used with their oncology immunotherapy program. Since the oncology program is utilizing plasmid DNA and peptides, the inhaler can be used to deliver these to the lung for the treatment of lung cancer.<br />
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Mannkind has also developed the Technosphere technology used in Afrezza and another anti-diabetic drug candidate, a GLP-1 analog. With little cash, Mannkind will find it difficult to continue development of the GLP-1 analog. The Technosphere technology may find other applications. <br />
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Mannkind may need to find a partner to help finance further clinical trials for Afrezza. A big pharma is the best option, but as mentioned earlier, there is reluctance to venture into the field of inhalable insulin. There is a risk involved, but the reward is worth it. <br />
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Investors should not avoid Mannkind like the plague. There is still things to like about Mannkind and the company is not doomed for failure. There is money to be made depending on what direction Mannkind decides to pursue. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-42871634823001283812011-02-09T20:07:00.001-05:002011-02-09T20:07:35.600-05:00Will Teva's Push to Expand Help Grow Your Portfolio?Teva Pharmaceutical Industries Limited (TEVA) is well known as a generic drug maker. However, a closer look reveals that Teva is pushing to become labeled as a "Big Pharma" company.<br />
There are several things investors have to love about Teva: <br />
<ol><li>Teva is following a similar strategy as Big Pharma by acquiring companies in areas in which it may not be a major player. An example is the acquisition of Ratiopharm GmbH and taking a bigger stake in Rexahn Pharmaceuticals. </li>
<li>Teva is conducting clinical trials for drugs such as QNAZE, a treatment for perenial allergic rhinitis. Teva also has Copaxone, a FDA approved drug for the treatment of multiple sclerosis. Copaxone has revenue of $938 million last quarter, a 26% increase over the previous quarter. The patent for Copaxone expires in 2014, but Teva believes that it will take longer than that for a generic to reach the market. A combination of generic and drug discovery operations is advantageous for pharmaceutical companies.</li>
<li>The patent cliff of 2011 and 2012 will make the coming years, the years of the generic manufacturers. Teva is the biggest generic manufacturer and with its expertize Teva will capitalize on future opportunities.</li>
<li>Teva shares have dropped over the past days because profit missed estimates. The primary reason is the deal to acquire Ratiopharm. There was also a 5% decline in generic drug sales in the US. Investors may be able to buy stocks at a slightly cheaper price this week.</li>
<li>Teva pays a dividend and the next one which will be paid at the end of the month will of $9.218, up 14% from the previous quarter.</li>
<li>A wide variety of drugs are manufactured, marketed, or sold by Teva. This will ensure a revenue stream for many years to come. </li>
</ol>Teva Pharmaceuticals is positioning itself to be in a strong position in the coming years. Investors should add Teva to their portfolios for diversification and the possibility that Teva may see greater grow than other popular pharmaceuticals stocks such as $JNJ, $PFE, and $MRK.Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-27017061881748137852011-02-07T12:45:00.000-05:002011-02-07T12:45:42.727-05:00Will Pharmaceutical Companies Be Willing to Pursue a New Indication for Statins?There has been a plethora of recent lab results showing involvement of cholesterol in cancer progression and resistance. Researchers have demonstrated delivery of statins, cholesterol lowering medications, are effective in treating a variety of cancers either alone or in combination with chemotherapeutic agents. With several statins losing patent protection in the coming years, it will be interesting to see if companies are willing to pursue a new indication that can possibly extend patent life.<br />
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A recently published <a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-512VTB1-2&_user=526750&_coverDate=12%2F20%2F2010&_rdoc=17&_fmt=high&_orig=browse&_origin=browse&_zone=rslt_list_item&_srch=doc-info%28%23toc%234944%232010%23998519996%232739739%23FLA%23display%23Volume%29&_cdi=4944&_sort=d&_docanchor=&_ct=21&_acct=C000023759&_version=1&_urlVersion=0&_userid=526750&md5=f578b718d37338958a36042c0ea53def&searchtype=a">study</a> by Peixun Zhou et al. demonstrated that leukemic stem cells had increased uptake of synthetic low density lipoproteins. By treating cancer stem cells with statins, it would reduce endogenous lipid synthesis and potentially prevent recurrence since stem cells are dormant and are later activated to multiply. <br />
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There is also evidence suggesting that cholesterol and low density lipoprotein receptors (LDL-R) are involved in multi-drug resistance by interacting with p-glycoprotein (P-gp), which is a energy driven protein that expels exogenous substances of various chemical structures from the cell [<a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-51PPSM7-1&_user=526750&_coverDate=01%2F20%2F2011&_rdoc=3&_fmt=high&_orig=browse&_origin=browse&_zone=rslt_list_item&_srch=doc-info%28%23toc%234944%232011%23998509997%232856769%23FLA%23display%23Volume%29&_cdi=4944&_sort=d&_docanchor=&_ct=17&_acct=C000023759&_version=1&_urlVersion=0&_userid=526750&md5=f70a1b1036a5bc69803a6e1771f6c5aa&searchtype=a">JCR</a>]. <br />
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Atorvastatin (Lipitor) is marketed by Pfizer (PFE) and generated $12.4 billion in revenues in 2008 making it the top selling medication. The US patent is set to expire this summer, but PFE has reached a pay-to-delay agreement with Ranbaxy Laboratories to delay the generic launch in the US until the fall. <br />
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Rosuvastatin (Crestor) is marketed by AstraZeneca (AZN) and the patent expires in 2016. <br />
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Simvastatin was marketed by Merck (MRK) under the brand name, Zocor. The patent has expired and is widely available as a generic manufactured by Ranbaxy Laboratories, Teva Pharmaceuticals Industries (TEVA), and Dr. Reddy's Laboratories. A study led by Professor Riganti of University of Turin in Italy, targeted liposomal doxorubicin (Doxil) to LDL-R. [<a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-51726MN-1&_user=526750&_coverDate=01%2F20%2F2011&_rdoc=16&_fmt=high&_orig=browse&_origin=browse&_zone=rslt_list_item&_srch=doc-info%28%23toc%234944%232011%23998509997%232856769%23FLA%23display%23Volume%29&_cdi=4944&_sort=d&_docanchor=&_ct=17&_acct=C000023759&_version=1&_urlVersion=0&_userid=526750&md5=00ead85f0aaf3b4bd91acc52480a0f6d&searchtype=a">JCR</a>] By treating the cancer cells with simvastatin, the team was able to decrease endogenous cholesterol production. To compensate for low amounts of cholesterol, the cancer cells increased expression of LDL-R on cell membrane to bring exogenous cholesterol into the cell. The increased expression allowed the team to exploit LDL-R as targets to deliver doxorubicin to cancer cells and overcome resistance due to p-glycoprotein efflux pump. <br />
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Pravastatin (Pravachol) has been available as a generic from TEVA. A liposomal formulation of pravastatin was shown to decrease expression of pro-inflammatory and pro-angiogenesis proteins in tumor cells and theraby inhibit growth [<a href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3D-5133638-3&_user=526750&_coverDate=12%2F20%2F2010&_rdoc=7&_fmt=high&_orig=browse&_origin=browse&_zone=rslt_list_item&_srch=doc-info%28%23toc%234944%232010%23998519996%232739739%23FLA%23display%23Volume%29&_cdi=4944&_sort=d&_docanchor=&_ct=21&_acct=C000023759&_version=1&_urlVersion=0&_userid=526750&md5=8615c387d7ea19901ffb72ca040b687c&searchtype=a">Journal of Controlled Release</a>]. The free drug did not have these effects. The liposomal formulation is considered to be a new drug and a NDA can be submitted with more pre-clinical and clinical trials. The difficulty will be to find a clinical trial sponsor. <br />
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If a pharmaceutical company decides to pursue a new indication for a statin, they would have to submit pre-clinical results in animals to the FDA in order to begin testing in humans. After completing the 3 clinical trial phases, the company would submit application for approval. The company may get Orphan Drug Status and be required to continue monitoring the efficacy as the drug is used in clinical settings. The testing period can last up to 8 years and requires a lot of capital. This is the biggest deterrent against a company pursuing such a goal. If approved, the company can obtain market exclusivity for a new indication. The period can be extended if the company can obtain a patent on the new indication. To make a profit and deter physicians from prescribing generic versions, the drug will need to be a new strength or new formulation. The current data has been derived from <i>in vitro</i> experiments using liposomal formulations and statins that are available as generics. <br />
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Because of patent expirations, AstraZeneca is the only big pharmaceutical company with any incentive to pursue a new indication for statin. However, this is highly unlikely. The available data is in the preliminary stages and investors cannot get excited to capitalize. Further research will indicate how statins are to be utilize in treating cancer; either as free drugs or as liposomal formulations making them new drugs. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-84312310578108796752011-02-05T16:54:00.000-05:002011-02-05T16:54:56.163-05:00Are M&A's a Signal to Buy Stock in a Biotech Company?We all knew this would be coming as we approached the patent cliffs of 2011 and 2012. Big pharmaceutical and biotechnology companies would start buying smaller companies to access their drug and biologic candidates. Recently, we have seen Johnson & Johnson buy Crucell, and Pfizer buy Seattle Genetics. Then there is Sanofi-Aventis trying to buy Genzyme and Pfizer reaching a deal to buy Theraclone. <br />
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It is interesting to notice that all these acquisitions concern antibody technology. Antibodies have become the fad in biotech drugs making some believe that they are the silver bullets for cure of various ailments. Antibodies are proteins manufactured and secreted by the plasma cells (a type of white blood cell derived from B cells) in response to an antigen (typically an exogenous substance). Each antibody has specificity for only one antigen. The purpose of antibody-antigen binding is to destroy the antigen either directly or by recruiting other white blood cells to do the dirty work. Therefore, antibody therapy aims to either have the antibody kill the tumor or stimulate the patient's immune system to kill the tumor. <br />
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We also know that antibody therapies are expensive and can rake in huge revenues for companies especially if the antibody is for relatively common disease states such as cancers. Another advantage of pursuing antibody technology is to make generic versions difficult and expensive to design and manufacture. Small molecules are the most common forms of drugs, and they are much simpler to copy than biologics. As a result, the patent life is in essence extended and less expensive generics or biosimilars do not reach to the market as quickly. <br />
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According to a recent <i>Wall Street Journal</i> <a href="http://online.wsj.com/article/SB10001424052748703833204576113863804531534.html">article</a>, several biological drugs with $60 billion in annual sales will be off-patent by 2015. Spectrum Pharmaceuticals ($SPPI), Sandoz, and Teva Pharmaceuticals ($TEVA) have all begun designing and testing generic versions of Roche's Rituxan, which is a very complex antibody. Due to the nature in which biologics are made, generic versions are not carbon copies of the brand drug. Biologics are designed and manufactured using live cells and not following a chemical recipe that is used to make small molecule drugs. <br />
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This slight difference in chemical structure and possibly function raises issues on how the FDA will review applications for biosimilars. It would be expected that there will be a need for a modified Abbreviated New Drug Application (ANDA). <br />
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Currently, it may be worth the risk to invest in small biotechs working on biologics and with a possibility of being acquired by bigger companies. This of course requires a lot of research into the financials and scientific publications of the companies and the ability to evaluate if there will be interest in acquiring the technology. Investing in small start-ups can be lucrative for investors willing to take the risk.<br />
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Longer term investments may be better in those companies that are acquiring these start-ups and technologies. Larger companies such as $JNJ. $MRK, and $PFE are cutting their R&D costs, decreasing their payrolls and trying to be in better financial position as many of the executives will soon be retiring and want to be compensated nicely. Investors should decide whether the companies are overpaying for drug candidates and technology. It takes around $800 million to bring a drug to market. A company is saving costs if they acquire a drug and complete clinical trials for less than that amount. An <a href="http://jco.ascopubs.org/content/21/22/4145.full">article</a> by EJ Emanuel et al. published in the <i>Journal of Clinical Oncology</i> calculated that the average cost of a phase III trial was around $6,000 per subject enrolled. It is difficult to predict the correct price for acquiring a drug. The seller will stress the potential of the candidate, which can be much higher that the $800 million average of bringing a drug to market. It is good news for investors that larger companies typically buy the smaller biotech firms and thus not only acquiring the main drug target, but other drug candidates and technologies being developed. These larger companies typically pay dividends and are safer investments (beta < 1). An investor can diversify by simply buying some shares in smaller, riskier companies, and also buying shares in larger companies. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-15874898408616764242011-01-18T13:15:00.000-05:002011-01-18T13:15:08.162-05:00Ariad and Merck Meet Primary Endpoint and to Submit for FDA ApprovalAriad Pharmaceuticals (ARIA) and Merck (MRK) are co-developing a small molecule inhibitor of the mammalian target of rapamycin (mTOR) called ridaforolimus. ARIA announced that ridaforolimus has shown to reduce the cancer progression by 28 percent and increased progression free survival by about 3 weeks. The most frequent adverse effects were mouth sores, fatigue, diarrhea and low platelets. MRK plans to submit for FDA approval this year. ARIA's stock price jumped 30% after the announcement. ARIA has no currently approved drugs. ARIA will be eligible for milestone and royalty payments. ARIA's current stock price is nearly three times higher than one year ago. <br />
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If approved, it would be the 2nd in class drug for treatment of cancer; temsiroliums (Torisel) was approved by FDA for treatment of renal cell carcinoma and is manufactured by Wyeth, now owned by Pfizer. Torisel showed slightly better results, but it was in a different type of cancer and renal cell carcinoma is known for having mTOR dysregulation. Rapamycin is another drug in this class, but is approved for prevention of transplant rejection.<br />
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mTOR is a protein that integrates signals from insulin, growth factor, and cell division pathways. It is often dysregulated in cancers and is a potential target for treatment. It interacts with othere pathways and proteins that are involved in various forms of cancer such as the Abl gene, which is translocated and fused with Bcr in chronic myelogenous leukemia. Despite the inter-connectivity with other pathways, the adverse effects are minimal and not of great concern. This can be attributed to the specificity of the drugs. ARIA and MRK are also conducting ridaforolimus clinical trials in breast, lung, prostate, pediatric, endometrial, and other solid tumors. Most of these trials are in Phase II. <br />
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There is a huge potential for ridaforolimus and can become ubiquitous in oncology as doxorubicin. With a great tolerability profile for a cancer drug and continuing good results from clinical trials, ridaforolimus can be very profitable for ARIA and MRK. Also, investors should monitor results from clinical trials of both ridaforolimus and Torisel and compare results for the same types of cancers. These trials are generally conducted in patients who have failed other therapies, so they are in the worst condition. Results from studying ridaforolimus as a first line therapy should show better results. <br />
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Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-19879809436055592062011-01-10T09:19:00.000-05:002011-01-10T09:19:15.145-05:00Avanir Pharmaceuticals Looks to Treat Uncontrollable Laughing and CryingThe FDA approved a new drug for the treatment of uncontrolled laughing and crying associated with some neurological conditions such as multiple sclerosis and Lou Gehrig's disease or amyotrophic lateral sclerosis. The medication is called Nuedexta and is a product of Avanir Pharmaceuticals (Nasdaq: AVNR). It is the first approved drugs for pseudobulbar affect, in which patient cannot control their emotion. The drug has not been shown to be safe or effective in patients with other mental disorders, such as Alzheimer's and dementia. [<a href="http://www.webmd.com/brain/news/20101102/nuedexta-treats-laughing-and-crying-outbursts">WebMD</a>] <br />
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Typically a stock's price increases when the company gets FDA approval, but the value of the company should be based upon the impact and market share the drugs will obtain. Neudexta should be on the market by March. Currently, I do not see Neudexta being a big time drug for several reasons and do not think that it will lead to appreciation of of Avanir's stock price. Neudexta is a good treatment for those who suffer from uncontrollable laughter or crying, but investors will not benefit from it's approval. <br />
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AVNR has no other drugs on the market. Abreva (10% docosanol cream) was granted to GSK to market in North America. AVNR has a drug candidate AVP-923 in Phase III clinical trials for the treatment of diabetic peripheral neuropathy. Two other candidates, a MIF inhibitor and Xenerex, were sold to other companies.<br />
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Neudexta is a combination of two drugs that are already on the market, quinidine and dextromethorphan (DXM). Quinidine is an anti-arrhythmic and is associated with a variety of side effects such ringing in the ear, thrombocytopenia (low platelets), granulomatous hepatitis, myasthenia gravis (an autoimmune disorder resulting in muscle fatigue and weakness), and torsades de pointes (type of arrhythmia). Because of these side effects, quinidine is rarely used. The drug was not approved in 2006 due to safety concerns of quinidine. Given the high prevalence of malpractice lawsuits, physicians will be reluctant to prescribe Neudexta for their patients. The approved formulation consists of a lower dose of quinidine to address the concern. DXM is a relatively safe drug and is found in OTC cough syrups. There are no studies about the effects of using DXM for prolonged time. Typically, patients take DXM for about a week to suppress their cough. Long term abuse of DXM has been associated with cognitive deterioration. [<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1188627/">Journal of Psychiatry & Neuroscience</a>] <br />
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Since these drugs are already on the market and inexpensive compared to newer chemical agents, don't expect AVNR to be able to set a high price for Neudexta. A blog on "<a href="http://seekingalpha.com/article/245611-avanir-pharmaceuticals-poised-for-a-strong-new-drug-launch?source=dashboard_stocks-sectors">Seeking Alpha</a>" reports a co-pay ranging from $60-$340 for a 90 day supply. <br />
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The market for Neudexta is not huge. Don't expect AVNR to be raking in cash. It is estimated that 20,000-30,000 people in the United States have ALS. [<a href="http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_amyotrophiclateralsclerosis.htm">NIH</a>] Of those diagnosed with ALS, approximately 50% experience pseudobulbar affect. A smaller percentage of MS patients experience pseudobulbar affect (10%). [<a href="http://journals.lww.com/neurotodayonline/Fulltext/2005/07000/New_Therapy_Targets_Pseudobulbar_Affect_in_Ms.1.aspx">Neurology Today</a>] <br />
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I just can't get excited about AVNR. Neudexta is not a blockbuster or even a drug that will generate considerable revenue. There's the risk of arrhythmia, which is very concerning. Besides AVP-923, AVNR has no other drug candidates in its pipeline. AVNR has a beta of 2.48, P/E of N/A, and a market cap of 517.46M. Investors should be cautious and think twice or maybe thrice before investing in AVNR.Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-35774536550197811092011-01-10T09:17:00.000-05:002011-01-10T09:17:51.485-05:00Sanofi-Aventis Looking to Acquire Genzyme and AlemtuzumabGenzyme (Nasdaq:GENZ) a biotechnology company known for developing therapies for rare disorders is being courted by Sanofi-Aventis (Nasdaq:SNY). An earlier offer of $69/share was considered too low by GENZ. GENZ is currently trading in the $71 range. The two companies are discussing a contigent value right (CVR) that could increase the offer to $80/share.[<a href="http://online.wsj.com/article/BT-CO-20110109-703203.html">WSJ</a>] Carl Icahn has a representative on GENZ's board and is trying to grab more seats on the board so expect GENZ to be a very tough negotiator.<br />
<br />
Sanofi's interest in acquiring Genzyme revolves around the monoclonal antibody, alemtuzumab (Campath). Alemtuzumab is currently FDA approved for B-cell chronic lymhocytic leukemia (B-CLL) [<a href="http://www.campath.com/pdfs/2009-08-Campath%20US%20PI.pdf">PI</a>] and is being investigated as a possible treatment for multiple sclerosis (MS). SNY and GENZ disagree over the potential revenue stream generated by Campath. SNY believes the annual sales could rise to $700 million, but GENZ believes the sales figures could rise to the level of $3.6 billion because of its superiority over other treatment options. The likely sales figure is somewhere in the middle, around $1.2-1.6 billion range.<br />
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The sales figure can rise if Campath is approved for multiple sclerosis, an autoimmune disorder that affects the central nervous system. There are about 2.5 million MS patients worldwide. [<a href="http://www.nationalmssociety.org/index.aspx">National MS Society</a>]<br />
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A phase II trial enrolled 334 MS patients to compare two different doses of alemtuzumab to high dose therapy with beta interferon 1a. Alemtuzumab was given as yearly courses (1st treatment was daily infusion for 5 days; 2nd and 3rd courses were daily infusion for 3 days; 3rd course was planned but safety concerns arose and not all patients received this course). Beta interferon 1a was administered thrice weekly by a subcutaneous injection. <br />
<br />
Patients designated to either alemtuzumab group had superior outcomes to patients in the beta interferon 1a group. At the 3 year mark,the percent of patients who had not experienced a relapse was as follows: 77% of patients in the low dose alemtuzumab; 84% of patients in the high dose alemtuzumab group; and 52% of patients assigned beta interferon 1a. Sustained disability risk was reduced by 71% in the alemtuzumab groups compared to the beta interferon 1a group. <br />
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<br />
<br />
Three percent of participants experienced low blood platelets, which may lead to increased bleeding. This condition is serious, but treatable. The phase II trial was suspended after a fatal cure of the disorder. Low platelets remains a significant concern and expect the FDA to heavily inquire safety results during review. Side effects relating to the thyroid gland were common (22.6%), but can be treated with thyroid medications. Immune suppression is another concern of alemtuzumab therapy. [<a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0802670">NEJM</a>] <br />
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<a href="http://clinicaltrials.gov/show/NCT00530348">CARE-MS1</a> and <a href="http://clinicaltrials.gov/show/NCT00548405">CARE-MS2</a> are phase III trials comparing low dose alemtuzumab and beta interferon 1 in treatment naive and patients with breakthrough disease, respectively. The results of the trials should be available sometime this or next year. [<a href="http://www.medscape.com/viewarticle/572411_7">Medscape</a>] <br />
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It should a good time to be a stockholder in GENZ especially if a merger deal is reached. Icahn has tried to force several companies to be bought by others in the past such as Yahoo! and it may be the same in this case. SNY's offer of $69 expires on Jan. 21 and is unlikely to be accepted by GENZ. A favorable price would be $75-80/share which would be about 5-13% higher than the current trading price. Even if a deal is not reached, Campath has a bright outlook to be increasingly used for B-CLL and should be approved for treatment of MS for which it can be the first line drug.Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-85438732524491807342011-01-05T18:29:00.000-05:002011-01-05T18:30:47.893-05:00The Race to Develop the Next Blockbuster: Merck and Roche Fight High Cholesterol.Cholesteryl ester transfer protein inhibitors (CETP inhibitors) are a novel class of drugs that have the potential to revolutionize treatment of high cholesterol much like the statins (Lipitor, Zocor, and Crestor). Like other drugs in their earliest stages of development, there has been some concern and adverse effects that raised red flags. In particular, Pfizer (NYSE: PFE) discontinued the development of torcetrapib after concern of increase blood pressure. Merck (NYSE: MRK) and Roche (PINK:RHHBY) have continued to develop their respective drugs, anacetrapib and dalcetrapib. With so promise in raising good cholesterol (HDL) and reducing bad cholesterol (LDL), these drugs can be blockbusters like the statins. Since this is a new class of drugs, the risks are relatively unknown and can be the deciding factor whether or not CETP inhibitors will ever thrive.<br />
<br />
<b>Dalcetrapib:</b><br />
<ul><li>It is less potent than the other two drugs and concentrations reached in clinical studies are not high enough to completely inhibit CETP. This may be a good thing.</li>
<li>It acts through a slightly different mechanism than the others and does not induce a complex between CETP and HDL. </li>
<li>In a Phase II, placebo controlled trial, it was shown to reduce LDL by 7%, increase HDL by 34% after 4 weeks at a dose of 900 mg/day. No increase in blood pressure was reported.</li>
<li>Similar results were achieved when dalcetrapib was given with pravastatin (Pravachol). Pravastatin is not widely used. A better study should have been performed using Lipitor or Crestor.</li>
<li>Current studies (dal-PLAQUE and dal-OUTCOMES) will provide a better glimpse into the potential.</li>
</ul><b> Anacetrapib:</b><br />
<ul><li>Works via the same mechanism as torcetrapib by complexing CETP with HDL. This causes researchers to be more concerned about blood pressure elevation effects. </li>
<li>It is much more potent than dalcetrapib. This is not necessarily a good thing. A higher potency may translate into higher risk of adverse effects.</li>
<li>In a Phase I trial, anacetrapib (300 mg/day) increased HDL by a whopping 129% and lowered LDL by 38% after 28 days of treatment. </li>
<li>A separate Phase I trial tested the safety of anacetrapib in helathy patients for 10 days. There was no reported increase in blood pressure. </li>
<li>A recent 8 week study evaluated anacetrapib co-administered with atorvastatin (Lipitor). The HDL increase was maintained, but the LDL was lowered by 70%. No increase in blood pressure was reported.</li>
<li>The DEFINE study is ongoing and will provide a better projection of anacetrapib's potential.</li>
</ul><b> Potential of CETP Inhibitors:</b><br />
<ul><li>High LDL and low HDL are risk factor for atherosclerosis. CETP inhibitors help in both regards.</li>
<li>Defective HDL function contributes to atherosclerosis.</li>
<li>CETP inhibitors may be the preferential drugs to increase HDL.</li>
<li>Combination therapy with statins, niacin, and fibrates lays in the future of CETP inhibitor therapy.</li>
<li>CETP inhibitors will play a big role in the treatment of common types of high cholesterol disease states, particularly patients with metabolic syndrome and type 2 diabetes.</li>
<li>Further research and investigation of CETP inhibition is needed with monotherapy and combination therapy.</li>
<li>It's still too early to tell the impact on stock prices for MRK and Roche, but this is one thing to monitor for the next two years as the Phase III trials will take approximately 18 months to complete and another couple of months for follow-up study.</li>
<li>It is interesting to see if these drugs can help MRK and Roche recuperate from the patent cliff of 2011-2012.</li>
</ul>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-15424788440658755282011-01-04T18:10:00.000-05:002011-01-04T18:10:31.259-05:00JNJ's Sensitive Cancer Test May Bear No Fruit.Healthcare giant Johnson and Johnson (NYSE: JNJ) has announced a partnership with Massachusetts General Hospital to develop a new test that is sensitive to detect a single cancer cell in a teaspoon of blood sample. The announcement has received a lot of attention simply because it involved cancer detection. To the public, the test may sound amazing and a giant leap to the cure of cancer. However, there are numerous, big hurdles it must overcome to be useful in treatment.<br />
<br />
Issues Concerning the Success of JNJ's Novel Test:<br />
<ol><li>Cost will be the primary concern for any novel treatment or diagnostics. This includes costs incurred by the hospital, doctor's office, and insurance companies and if they cover the costs of the test. Costs include a new instrument, supplies to perform the test, training that may be needed in performing and interpreting the tests, and many other things. The current CellSearch test cost a couple hundred thousand dollars. Patients may draw the shortest straw.</li>
<li>The technology is still in early stage of development. If successful, the instrument can be expected to hit the market in a few years. </li>
<li>What real clinical value lays in detecting a single cell?</li>
<ul><li>It is well known that a tumor consists of a heterogeneous cell population. Each cancer cell is different due to the high mutation rate. A single cell would not represent the tumor and metastases.</li>
<li>If the patient has a solid tumor, detection of a cancer cell in the blood would mean the cancer has metastasized. Metasized tumors are extremely difficult to treat and patients often relapse. However, this is great news if detected early and no new distant tumors have formed.</li>
<li>Tumors metastasize after growing to a certain size and being depleted of nutrients. This test will not give the earliest indication of cancer. </li>
<li>The test requires a couple of teaspoons of blood, roughly 10 milliliters (mL). An average adult has roughly 5 liters of blood. This means that for every 1 cancer cell detected by the test, there are 499 more cancer cells circulating in the blood.</li>
<li>Not all cancers metastasize via the blood. Some cancers metastasize via the lymph system such as breast cancer. The test may be of much use for these cancers. </li>
<li>The test may be better for blood cancers such as leukemia and lymphoma. It just makes more sense to tailor therapy based on blood samples when the cancer is of the blood. </li>
</ul><li>It is indirect to base therapeutic decisions on presence of cancer cells in the blood. There are many reasons why cancer cells will not be present in the blood. The tumor may be in temporary remission. Also, if the chemotherapy is very effective, it may cause tumor lysis syndrome and a lot of cellular debris may be detected in the blood resulting in a false positive.</li>
<li>This is a good shot at personalization of medicine, but does not hit the bull's eye. Each patient is going to have different tumor markers and respond to therapy in different ways. The patient's cancer is going to mutate in unique ways. The test needs to account for this fact. It is more of an art than science. The report in <a href="http://www.pnas.org/content/107/43/18392">PNAS</a> states that the antibody on the microchip was specific for epithelial cell adhesion molecule (EpCAM). I expect the final version to contain several specific antibodies for different molecular markers.</li>
</ol>Although it sounds exciting, JNJ's new test may not live up to the hype. JNJ is a good company despite recent manufacturing problems. It has made some Buffett-like acquisitions and pays a good dividend. The stock price is stable with a beta of 0.57. I don't expect a spike in the stock price because of the this test. JNJ is not a great buy for short-term investors hoping to go to bank on this news. Long-term investors should look into buying some stock because of the dividend and analysts predicting growth for large multi-nationals this year. <br />
<ol></ol>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-45113085883584298662011-01-03T10:29:00.000-05:002011-01-03T10:30:30.878-05:00Can Mannkind Avoid Repeating History with its Inhaled Insulin, Afrezza?Mannkind (Nasdaq: <a href="http://www.google.com/finance?q=mnkd">MNKD</a>) continues to wait for FDA approval of its inhaled insulin drug candidate, Afrezza. This is not the first time an inhaled insulin formulation has come up for approval. Pfizer's (<a href="http://www.google.com/finance?q=NYSE%3APFE">PFE</a>) Exubera was less than exuberant. Although winning FDA approval, it was withdrawn from the US market in late 2007 after only being on the market for a year. This led to other companies to stop their development of inhaled insulin formulations. However, MNKD has persisted to develop its own version. There have been rumors that MNKD is seeking a partnership since 2009, but nothing has materialized. MNKD is probably waiting for approval before becoming serious in negotiations. But investors must wonder if MNKD will be left hanging to dry as many big pharma companies will be reluctant to market another inhaled insulin.<br />
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Diabetic patients are a huge market and treatment is typically life long. This means that pharma/biotech companies are interested to capitalize making drugs for diabetes treatment.<br />
According to the <a href="http://www.diabetes.org/advocate/resources/cost-of-diabetes.html">American Diabetes Association</a>:<br />
<blockquote><div style="text-align: left;">"The national cost of diabetes in the U.S. in 2007 exceeds $174 billion. This estimate includes $116 billion in excess medical expenditures attributed to diabetes, as well as $58 billion in reduced national productivity. People with diagnosed diabetes, on average, have medical expenditures that are approximately 2.3 times higher than the expenditures would be in the absence of diabetes. Approximately $1 in $10 health care dollars is attributed to diabetes. Indirect costs include increased factors such as absenteeism, reduced productivity, and lost productive capacity due to early mortality." </div></blockquote><br />
Afrezza is an inhaled insulin therapy for meal time control of blood sugar in patients with diabetes based on a novel dry powder form, Technosphere Insulin. MNKD must prove to investors and potential partners that it can succeed where Pfizer failed with Exubera. MNKD must demonstrate that Afrezza:<br />
<ol><li>Superior to injectable forms of meal time insulin</li>
<li>Patients are willing to use it. Patients find their information via the internet. They will surely come across Pfizer's letter to physician reporting possible lung cancer risk with Exubera although those patients who developed lung cancer were smokers and the results were not significant. </li>
<li>Ease of use. Although it may appear that an inhaler is easy to use. Insulin is given is specific doses in international units (IU). The dose for meal time insulin depends on what is being eaten. Afrezza must make it easy for patients to calculate and obtain the correct dose. </li>
<li>Reduced risk of low blood glucose after administration.</li>
<li>Cost similar to injectable insulin formulations or the premium worth the convenience.</li>
</ol>There are many reported advantages of using the Technosphere technology over injectable insulin. Afrezza has been shown to be more rapid acting, short duration of action, and effective in controlling after meal blood sugar spikes. The figure below shows that Afrezza most closely mimics the natural insulin response. Exubera had a reported peak time of about 49 minutes. This rapid peak means that patients can take a dose when they are seated down to eat. The slow onset of conventional forms requires patients to inject before going to eat. There is a risk of hypoglycemia if the meal is delayed. The rapid action is due to the monomeric form in Afrezza compared to the hexameric form used in Exubera. The hexameric form is not active and cannot bind to insulin receptors. The hexameric form is good for slow release and is good for basal insulin. It makes sense to use the monomeric form when rapid action is needed after a meal. <br />
<br />
The There is a decreased incidence of weight gain and hypoglycemia with Afrezza. The lower risk of hypoglycemia (low blood glucose) can be attributed to the rapid decline in insulin levels. Afrezza also has a better tolerability profile than available forms of insulin. <br />
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<div class="separator" style="clear: both; text-align: center;"><img src="http://static.seekingalpha.com/uploads/2010/7/26/saupload_afrezza.png" /></div> <br />
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<a href="http://www.nature.com/nbt/journal/v25/n12/images/nbt1207-1331-I1.jpg">PFE's Exubera</a> <br />
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<div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjR3AtFngpQBDIoP8_yrETXok61QKTdbbmwPaRkUZrvUomTKznoNYiQ1KcZBx2rqRUERny33sUPjk3mGxzCu0_LFiiI33Tiq53f2rwDscqIpYCPBWee_axWCEMfjguAPdtJGxEUuNhapKA/s1600/exubera.bmp" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="200" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjR3AtFngpQBDIoP8_yrETXok61QKTdbbmwPaRkUZrvUomTKznoNYiQ1KcZBx2rqRUERny33sUPjk3mGxzCu0_LFiiI33Tiq53f2rwDscqIpYCPBWee_axWCEMfjguAPdtJGxEUuNhapKA/s200/exubera.bmp" width="129" /></a></div><br />
<b></b>Exubera's inhaler was big and clunky. Patients would look ridiculous and arouse suspicion when using it. The Exubera inhaler worked similarly to an asthma inhaler. The patient needed actuation-breath coordination when using it. This required a learning curve and pharmacists and doctors to take time to teach patients. You know the design was bad when patients rather inject themselves then simply inhale. <br />
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<a href="http://www.diabetesa1c.net/wp-content/uploads/2010/08/wpid-AFREZZA-is-the-New-and-Improved-Inhalable-Insulin-for-Diabetes.jpg">MNKD's Afrezza </a><br />
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<div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiPCfMCqij1_oGrQp_5yoSMhZE66DanyMJybsFAo102XS9V2e2BgRntQ0zn3H5ZE9l7dfhXwDcdcRyRgi6rsAoPYfmy2suFAqzndEKXxQJOQrsLiM9XeMV5xXdpfaalfYKdXAxl_oq8JjQ/s1600/afrezza.jpg" imageanchor="1" style="clear: left; float: left; margin-bottom: 1em; margin-right: 1em;"><img border="0" height="150" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiPCfMCqij1_oGrQp_5yoSMhZE66DanyMJybsFAo102XS9V2e2BgRntQ0zn3H5ZE9l7dfhXwDcdcRyRgi6rsAoPYfmy2suFAqzndEKXxQJOQrsLiM9XeMV5xXdpfaalfYKdXAxl_oq8JjQ/s200/afrezza.jpg" width="200" /></a></div><br />
<b></b>Afrezza's inhaler is a big upgrade over Exubera's. The Afreeza inhaler is small and discreet. Patients can easily carry it in a pocket or purse. The inhaler is breath actuated thereby getting rid of a large chunk of the learning curve and improving the precision and accuracy of dose delivery. <br />
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<br />
<br />
<b><span style="font-weight: normal;">Afrezza's blockbuster potential lies in its costs. A report by <a href="http://www.ncbi.nlm.nih.gov/pubmed/17767897">Black et al.</a> stated that Exubera's efficacy did not justify the extra cost. To be competitive, Afrezza must be similarly priced to injected forms of insulin or a price that justifies the convenience. Up to a 20% premium seems to be the consensus and if MNKD decides a higher price, expect insurers to not cover Afrezza and MNKD not to find a marketing partner or someone to buy it outright. </span></b><br />
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<b><span style="font-weight: normal;">There was recent pullback in the stock price. The stock was trading at $8.17 at the time of writing. A FDA approval would definitely help the price. I believe the increase would be slight as investors are likely to worry about a possible bust and how big a market share it can grab onto. The major increase will follow a partnership announcement with a big pharma to help market and distribute Afrezza. This would happen a couple of weeks after FDA approval. The market potential for an inhaled insulin is huge and MNKD's marketcap will go through the roof. </span></b><br />
<br />
<b><span style="font-weight: normal;">If MNKD fails to win approval or is issued a Complete Response Letter, the price will begin to tank. The bottom will depend on what the FDA wants from MNKD; additional studies on safety or efficacy. MNKD at this point has nothing to fall back on. It's other drug candidates are in earlier stages of clinical trials or in the pre-clinical setting.</span></b>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com3tag:blogger.com,1999:blog-4599326694255740220.post-65146212138524689422010-12-30T17:00:00.000-05:002010-12-30T17:03:34.310-05:00CytRx is an Up and Coming Biopharma Company with 3 Promising Candidates.<div align="justify" class="plain"><b></b><br />
CytRx Corporation (NASDAQ: CYTR) is a biopharma R&D company that specializes in oncology therapeutics. The pipeline has 3 drug candidates for various cancers, which have caught my attention. I think that CYTR is an interesting company and their products have the potential to be widely used for treatment of cancers. What is more impressive is that the company's 3 candidates have different mechanisms of actions and are being studied for a wide range of cancers unlike a lot of small cap companies that put all their eggs in one basket. It will still be a few years before the candidates will hit the market. Here's a brief overview:<br />
<ul><li>Initiation of Phase 2b clinical trials of its drug candidate bafetinib in patients with high-risk B-cell chronic lymphocytic leukemia and advanced prostate cancer, and a pharmacokinetic clinical trial in patients with brain cancer. </li>
<li>Phase 2 trials with its oncology candidate INNO-206 for soft tissue sarcomas and pancreatic cancer. </li>
<li>Tamibarotene for non-small-cell lung cancer (Phase 2b), and acute promyelocytic leukemia (APL). </li>
<li>Seeking a potential partnership of molecular chaperone technology. </li>
<li>17% equity interest in RXi Pharmaceuticals Corporation, or RXi (NASDAQ: RXII). There has been speculation for a long time about RXII being acquired by a big pharma. Nothing has come to fruition. </li>
</ul>CYTR is currently trading at $1.00 after sliding from a high of $1.11 from just a couple of weeks ago. The price began falling after a site reported that a uptrend was spotted for CYTR. Guess they got to the party when it was already over. I began following the stock when it was trading at $0.74 during the summer. I have studied papers of each of their candidates and think the company is onto something. The market cap is $109 million, which is lower than similar biotech/pharma companies. Perhaps the company is undervalued. If you did not pounce on the stock during the uptrend, this is the perhaps the best time to join in on the action. When CYTR begins Phase 3 trials, the price is surely to go up. Phase 3 trials may begin in mid to late 2011 if everything goes as planned. <br />
<br />
I would like to just briefly explain the specifics of INNO-206 and its potential as it is similar to a project that I have worked on and many researchers around the world have studied. </div><div align="justify" class="plain"><br />
</div><div align="justify" class="plain">INNO-206 (formerly DOXO-EMCH) is a pro-drug of doxorubicin., a very commonly used drug in oncology. Doxorubicin is used for a wide variety of cancers and has a liposomal nanotechnology formulation called Doxil, which has effectively replaced doxorubicin. CYTR has the worldwide rights to INNO-206. The design of the drug is similar to another nanotechnology formulated drug called Abraxane by Abarix Bioscience. Whereas Abraxane is manufactured with paclitaxel attached to a blood protein called albumin, INNO-206 is doxorubicin modified with a chemical linker that binds with albumin when injected. The linker breaks down when it enters the tumor environment which is acidic. Abraxane and Doxil have been spectacular in reducing adverse effects of the original drugs. I believe that INNO-206 can do better than these. Doxil is the main competition for INNO-206; it would be interesting to see Phase 3 trials comparing the two formulations.<br />
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There are several issues that INNO-206 must address for wide acceptance by oncologists and pharmacists:<br />
<ol><li>Doxorubicin has a cumulative lifetime dose maximum. This means a person can only receive a certain amount of it throughout their life. It is unknown if this also applies to Doxil. </li>
<li>This relates to the previous issue. Doxorubicin is known to be cardiotoxic and that is why it has a limit. CYTR must demonstrate that there is no toxicity issues with the heart if they want a blockbuster oncology drug. </li>
<li>This relates to the previous two posts. Patients with heart problems such as heart failure are exempt from taking doxorubicin. By demonstrating that INNO-206 has no toxic effects on the heart, a greater number of patients can qualify for therapy.</li>
<li>Doxil has a side effect known as Hand-Foot Syndrome. This is another issue that INNO-206 must overcome.</li>
<li>Doxorubicin can cause serious damage to the skin and blood vessels when being given to the patients. By avoiding this, INNO-206 will gain favor with patients.</li>
<li>The technology used in INNO-206 needs to demonstrate higher accumulation in the tumors. </li>
<li>CYTR must also evaluate if cancer develops resistance to INNO-206. Resistance is a big drawback to effective doxorubicin treatment.</li>
<li>Doxorubicin is used for many types of cancer. Can INNO-206 be applied to these cancers? Is CYTR willing to test 5+ types of cancer? Probably not off the back.</li>
</ol>This may seem like an overwhelming list but this is what companies have to consider when bringing new drugs to the market. </div><div class="plain"><br />
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</div>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-84423835649114541832010-12-29T17:08:00.000-05:002011-12-20T08:29:14.989-05:00Mucus Producing Proteins: The Key to Curing Cancer? Minerva Biotech Bets on It.Over the past fours years, I have done research on designing nanotechnology based drug delivery systems to target and kill cancer cells. I have decided to target a particular protein that it over-expressed on many cancer cells. While there are thousands of labs targeting receptors like epithelial growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEFGR), which control growth and blood vasculature. I went another direction and targeted mucus producing proteins called mucin, specifically MUC-1. One study I read stated that over 90% of late stage ovarian cancer cells over-expressed the mucin receptor. Another stated that nearly 75% of epithelial cancers over-express mucin proteins. What does a mucus producing protein have to do with cancer? And why aren't more companies interested in exploiting mucins?<br />
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Studies have discerned functions of the mucin proteins ranging from controlling the environment surrounding the cells, preventing drugs from entering the cells, participating in metastasis and growth, intracellular signalling, and recent studies showed that it may interact with EGFR. All these steps are important to the initiation, growth, and metastasis of cancer. Mucin appears to be the untapped gold mine for cancer research. I believe that many big pharma companies are working on mucins but not substantially investing in it because of the relative recent studies. They're probably waiting for more research to come out before pouring money into projects. Of course investing millions of dollars into research of mucins is filled with risk, but the reward is immense. It is also noteworthy that the current accepted test for monitoring ovarian cancer is the CA-125, which is a mucin protein.<br />
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There is a private biotech company in Waltham, MA named Minerva Biotechnologies. They have produced some amazing results concerning the functions of mucins and how to exploit them for treating cancers. They discovered that the mucin proteins are not only overexpressed on cancer cells, they are expressed as a different form. The scientists at Minerva discovered that in cancer cells, a large chunk of the mucin protein breaks off and thus initiates the processes involved in cancer progression. While there are a lot of academic researchers targeting mucins, based on Minerva's findings, they are targeting the chunk of the receptor that breaks off. This broken off piece does play a role in cancer, acting like a ligand and activating the mucin receptor. Minerva has worked on targeting the piece of the receptor that remains on the cell, the piece on the outside is about 45 amino acids in length.<br />
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Minerva Biotechnologies is perhaps the leader of targeting mucin receptors and has the possibility of changing the landscape in cancer treatment. Investors cannot benefit form the results because Minerva Biotech is currently a private company. I will be very interested when Minerva IPO is available and believe that investors will greatly benefit by investing into the company. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-23788498179151012422010-12-28T16:29:00.000-05:002010-12-28T16:29:22.455-05:00Can a Monoclonal Antibody Take Over Cheaper Drugs?Amgen's (AMGN) denosumab (Xgeva/ Prolia) is a fully human monoclonal antibody that is FDA approved for the treatment of osteoporosis and prevention of skeletal-related events in patients with bone metastasis (a fancy way of saying that it helps to prevent cancer cells from spreading into bones and prevent fractures and pain caused by cancer cells).<br />
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A drug class called bisphophonates are typically used to treat these conditions. An example is Boniva, which had Sally Fields as a spokeswomen. Compared to denosumab, these drugs are much cheaper , but have some serious adverse effects such as degradation of the jaw bone (osteonecrosis of the jaw).<br />
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<u><b>Denosumab (Prolia) for Treatment of Osteoporosi</b><b>s</b></u><br />
<span style="font-family: "Times New Roman","serif"; font-size: 10pt;">Cummings SR, Martin JS, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361:756-65. </span><br />
<ul><li>Compared to placebo, denosumab reduced the risk of vertebral fracture (2.3% denosumab, 7.2% placebo)</li>
<li>Denosumab reduced the risk of hip fracture (0.7% denosumab, 1.2% placebo)</li>
<li>Reduced non-vertebral fracture in denosumab group (6.5% denosumab, 8.0% placebo)</li>
<li>No increased risk of cancer, infection, heart disease, slow fracture healing, injection site reactions, and<u> no reports of osteonecrosis.</u></li>
<li>Patients typically develop immune reactions to monoclonal antibodies (auto-antibodies) and the treatment becomes ineffective. There have been no such reports in osteoporosis trials of denosumab, which is a good sign.</li>
<ul><li>It should be kept in mind that the trials were only a couple of years in duration and osteoporosis treatment would be lifelong. This increases chances of immune tolerance. </li>
</ul><li>Bisphosphonates are taken usually taken weekly or monthly (Reclast is taken once a year). the side effects are intolerable and the patient has to stand or sit up for 30-60 min after taking the dose. Denosumab is taken twice a year. This is a convenience factor and patients prefer the most convenient form.</li>
<li>Further studies are needed comparing denosumab to bisphosphonates. Denosumab acts through a different mechanism to prevent bone loss and may be more effective than bisphosphonates.</li>
<li>Denosumab costs around <a href="http://www.thestreet.com/story/10771798/amgen-proposes-premium-price-for-prolia.html">$1,650 yearly</a>. This price should decrease as it will continue to compete with bisphosphonates. I believe that Reclast, the once yearly bisphosphonate cost about the same. However, Reclast requires an infusion, given over a hour or more, and Prolia is a subcutaneous injection like an insulin injection. The cost of treatment for Prolia end up being less than Reclast. Compound that with ease of administration and less injection reactions, expect Prolia to become the favorites among physicians and patients.</li>
</ul><u><b>Denosumab (XGEVA) for Treatment and Prevention of Bone Metastasis </b></u> <br />
<ul><li>Denosumab and Zometa were studied in castrate-refractory prostate cancer.</li>
<li>Bone metastases occur in 1.5 million patients with cancer worldwide. Most of these patients are debilitated by skeletal issues such as fractures and pain.</li>
<li>Patients with bone metastases have higher medical costs. Treating these skeletal issues can significantly reduce costs.</li>
<li>The most common cancers associated with bone metastases are those of the prostate, lung, and breast.</li>
<li>Patients receiving XGEVA developed bone metastases about 8 months later than those taking Zometa</li>
<li>Adverse effects, jaw bone degradation (osteonecrosis), overall survival, and cancer progression were similar in both groups.</li>
<li>The fact that treating skeletal issues drastically reduces costs means that hospitals are acively seeking ways to treat the issue and lower their costs.</li>
<li>To compete with Zometa cost wise, Amgen has begun the XGEVA FIRST STEP Coupon Program, the 1st of its kind for onocology commercial co-pay program and it does not have any income eligibility requirement.</li>
<ul><li>Patients will not have to pay out of pocket for the initial injection and only $25 for subsequent injections.</li>
<li>XGEVA may become the preferred treatment for prevention of bone metastasis for similar reasons as those for osteoporosis.</li>
</ul></ul><u><b>Is Denosumab a Game Changer</b></u><br />
<br />
<ul><li>Denosumab is a novel way to treat osteoporosis and prevent bone metastases</li>
<li>The costs are competitive vs. bisphosphonates</li>
<li>Denosumab has a slightly better adverse effect profile and may be preferred by patients and physicians</li>
<li>Denosumab has a high probability of being a game changer and becoming the standard of care for the approved conditions</li>
<li>Further studies will need to examine adverse effects and immune tolerance</li>
<li>Amgen has been trading in the $52-58 range over the past 6 months. This can really give a boost to the stagnant stock price. </li>
</ul>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com1tag:blogger.com,1999:blog-4599326694255740220.post-19175836350659766642010-12-27T21:42:00.000-05:002010-12-27T21:42:05.842-05:00Otsuka Holdings OutlookOtsuka Holdings recently held its IPO on the Tokyo Stock Market priced at $2.4 billion, the largest IPO in Japanese history. Otsuka was offered at the lower end of its range because there are concerns about future drug products that it will be a successor after Abilify (aripiprazole) is off patent in 2015. The company is based on two business segments: pharmaceuticals and consumer products similar structure to Pfizer. <br />
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Otsuka has several drugs in their <a href="http://www.otsuka.co.jp/en/research/pipeline/pdf/pipeline_en_101112.pdf">pipelines</a> which include drug candidates for depression, schizophrenia, ADHD, low blood sodium, cancer, tuberculosis, Crohn's disease, dry eyes, and COPD. These agents range from Phase I to Phase III. Otsuka does have one other drug on the market that has the potential to alter treatment standard: tolvaptan.<br />
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The drug Samsca (tolvaptan) is a FDA approved oral agent for the treatment of hyponatremia (low sodium in the blood). The main competitor is Vaprisol (conivaptan) marketed by Astellas. It's not fully clear which is the the superior drug, but theere probably are ongoing clinical trials evaluating them. Other therapeutic options for low blood sodium are sodium rich fluids, fluid restriction, and treating the cause of the low sodium (this is usually not clear). These are quite ineffective and the need for new options was great; leading to the disocveries of conivaptan and tolvaptan. <br />
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The SALT-1 and SALT-2 Phase III trials evaluated tolvaptan in patients with low sodium. Patients receiving tolvaptan reached normal sodium levels and maintain these levels while on tolvaptan. Unfortunately, the sodium levels dropped upon discontinuation of therapy. <br />
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Tolvaptan would have been a gem if positive results were obtained in the EVEREST trial. Tolvaptan showed modest improvement in difficulty of breathing, but no significant improvement in improving morbidity and mortality in patients with heart failure.<br />
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<b><u>TOLVAPTAN SAVINGS POTENTIAL</u></b> <br />
Tolvaptan can have a huge impact of saving on hospital budgets. Boscoe et al. estimated that direct cost of treating low sodium to be $1.6-3.6 billion annually.(<span style="font-size: small;"><span style="font-family: Constantia;">Boscoe A, Paramore c, Verbalis JG. Cost of illness of hyponatremia in the United States. Cost Effectiveness and Resource Allocation. 2006;4:10 doi: 10.1186/1478-7547-4-10). Another study showed that low sodium accounts for a 47.1% increase in treatment cost at 1 year (</span></span><span style="font-size: small;"><span style="font-family: Constantia;">Shea AM, Hammill BG, Curtis LH, Szczech LA, Schulman KA. Medical costs of abnormal serum sodium levels. J </span><span style="font-family: Constantia;">Am Soc Nephrol. 2008;19:764-770). </span></span><br />
<u><b><span style="font-size: small;"><span style="font-family: Constantia;"> </span></span></b></u><br />
<u><b><span style="font-size: small;"><span style="font-family: Constantia;">TOLVAPTAN VS. CONIVAPTAN COSTS </span></span></b></u><br />
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<div class="O"> <div><span style="font-family: Constantia; font-size: 78%;"><span style="color: #0bd0d9; font-size: 95%; left: -5.27%; position: absolute; top: 0.04em;">1.</span></span><span style="font-size: small;"><span style="font-family: Constantia;">MacDonald E. New drug bulletin: Tolvaptan (Samsca- Otsuka America). University of Utah Hospitals & Clinics. </span></span><span style="font-family: Constantia; font-size: 14pt;"><span style="font-size: small;">Sept. 2009.</span> </span></div><div><span style="font-family: Constantia; font-size: 78%; visibility: hidden;"><span style="color: #0bd0d9; font-size: 95%; left: -6.25%; position: absolute;">2.</span></span><span style="font-family: Constantia; font-size: 14pt;"> </span></div></div><u><b><span style="font-size: small;"><span style="font-family: Constantia;"></span></span></b></u><br />
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<tr> <td height="47" style="border-color: black; border-style: solid; border-width: 2px 1px 1px 2px;" width="107"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">Medication</span></span></div></td> <td height="47" style="border-color: black; border-style: solid; border-width: 2px 1px 1px;" width="167"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">Dosage forms</span></span></div></td> <td height="47" style="border-color: black; border-style: solid; border-width: 2px 1px 1px;" width="126"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">Dosage </span><span style="font-family: Constantia;">Regimen</span></span></div></td> <td height="47" style="border-color: black; border-style: solid; border-width: 2px 2px 1px 1px;" width="102"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">AWP cost </span><span style="font-family: Constantia;">per day</span></span></div></td> </tr>
<tr> <td height="61" style="border-color: black; border-style: solid; border-width: 1px 1px 1px 2px;" width="107"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">Conivaptan</span></span></div></td> <td height="61" style="border: 1px solid black;" width="167"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">20 mg/mL in D5W</span></span></div></td> <td height="61" style="border: 1px solid black;" width="126"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">20 mg LD, then </span><span style="font-family: Constantia;">20 mg/d IV</span></span></div></td> <td height="61" style="border-color: black; border-style: solid; border-width: 1px 2px 1px 1px;" width="102"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">$573</span></span></div></td> </tr>
<tr> <td height="75" style="border-color: black; border-style: solid; border-width: 1px 1px 2px 2px;" width="107"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">Tolvaptan</span></span></div></td> <td height="75" style="border-color: black; border-style: solid; border-width: 1px 1px 2px;" width="167"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">15 mg or 30 mg blister </span><span style="font-family: Constantia;">pack of 10 tab</span></span></div></td> <td height="75" style="border-color: black; border-style: solid; border-width: 1px 1px 2px;" width="126"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">15 mg/d po – </span></span></div><div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">30 mg/d po</span></span></div></td> <td height="75" style="border-color: black; border-style: solid; border-width: 1px 2px 2px 1px;" width="102"> <div style="text-align: center;"><span style="font-size: x-small;"><span style="font-family: Constantia;">$300</span></span></div></td> </tr>
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<div class="O"> </div> <br />
<ul><li>Tolvaptan is less costly than conivaptan and this will be a deciding factor for hospital's to choose tolvaptan over conivaptan unless conivaptan is proven to be far superior</li>
<li>Tolvaptan is an oral agent. It is preferred by patients, easy to administer, and much cheaper to administer. </li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">Patients do not have to be in the hospital to take tolvaptan: additional costs savings.</span></span><span style="font-size: small;"><span style="font-family: Constantia;"> </span></span></li>
</ul><u><b><span style="font-size: small;"><span style="font-family: Constantia;">OUTLOOK</span></span></b></u><ul><li><span style="font-size: small;"><span style="font-family: Constantia;">Tolvaptan should become the standard treatment for low blood sodium</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">Otsuke expects profits to grow 18% by March 2011 (http://www.reuters.com/article/idUSTRE6B515920101206)</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">IPO offering at the low range means there is more room for Otsuka to grow and investors to cash in.</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">The stagnant Japanese economy is not encouraging.</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">Otsuka trades at about 15 times future earnings compared to Takeda which trades at about 13 times future earnings.</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">56.7 million shares will be traded outside of Japan</span></span></li>
<li><span style="font-size: small;"><span style="font-family: Constantia;">Although analysts may worry about Otsuka after 2015, I believe that it will be a good position which tolvaptan having a large clinical role and other candidates will reach the market if successful. The consumer market should increase if the Japanese economy grows and Otsuka begins more heavy marketing of consumer products overseas.</span></span></li>
</ul><span style="font-size: small;"><span style="font-family: Constantia;"> </span></span><br />
<span style="font-size: small;"><span style="font-family: Constantia;"> </span></span>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-77410554085103958002010-12-27T12:22:00.000-05:002010-12-27T12:30:56.396-05:00King Pharma Re-submits NDA for RemoxyKing Pharma (NYSE: KG) is resubmitting its NDA for Remoxy to the FDA. The NDA was submitted berfore, but the FDA wanted more information about the deterrence technology used in Remoxy and its effectiveness. If Remoxy is approved, it's main competitor will by OxyContin manufactured by Purdue Pharma. Because the high abuse of Oxycontin, it may be given that a drug with abuse deterrence will trump the use of one without such technology. King Pharma has taken a leading role in developing drug deterrence technology and may get a large market share in narcotic medications.<br />
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Remoxy is a novel formulation of the pain killer oxycodone, which has high addictive and abuse potential. Purdue's OxyContin is a delay-release formulation, which means that the drug is slowly release and the patient does not get the "high" feeling. However, drug abusers have found ways to extract the oxycodone from the formulation for recreational use. Remoxy is a high viscosity (think thick) liquid in a hard gelatin capsule (physical barrier). Freezing, dissolving in ethanol, and manipulation are made difficult. The fraction of oxycodone released is a fraction compared to OxyContin. <br />
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There are two other formulations that fall in the same cateogry as Remoxy: Embeda by Alpharma which was bought by King Pharma and Acurox by Acura Pharma and King Pharma. Embeda has been approved by the FDA while Acurox was rejected in April.<br />
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Both technologies are great in fighting against abuse of narcotics. Personally, I believe Embeda's drug deterrence technology is better than Remoxy. Embeda is a combination of morphine and naltrexone, which opposes the effects of morphine. When swallowed, naltrexone is digested by the stomach and has no counter-effect. When injected, naltrexone is active and prevents effects of morphine. Separating naltrexone from the formulation is difficult without degrading morphine. Remoxy's deterrence technology may be easier to "hack." There might be higher prescribing of Embeda than Remoxy but it may be too early to tell.<br />
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Since both formulations are under license of King Pharma, it is a win-win situation potentially (not to mention Acurox is also developed by King Pharma). It will be interesting to see if KG stock price increases in response to submission of the Remoxy NDA. The price may simply increase because of FDA approval. The sales figures from the two drugs are difficult to predict and the fact that they may compete against each other may cancel any great benefit for investors. Both drugs are used for moderate-to-severe pain. Think of GM when it had numerous brands and each brand had models that competed against each other. Embeda is restricted to use in opioid-tolerant patients; those who no longer respond to lower potency drugs. KG may decide to try to market them in different ways to increase prescribing. It would be wise of King Pharma to promote Remoxy and if the patient becomes tolerant (unresponsive) to it, the patient could be placed on Embeda. Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-4271706957199459012010-12-27T10:34:00.000-05:002010-12-27T10:38:59.506-05:00Time to Buy InterMune (ITMN)?<span id="ctl00_PageCenterContent__newsStory1_FormView1_ContentLabel">Gilead Sciences Inc. (Nasdaq: GILD) just announced that it is halting it's Phase III clinical trial of ambrisentan dubbed <a href="http://www.biospace.com/news_story.aspx?StoryID=206044&full=1">ARTEMIS-IPF</a>. Ambrisentan was a drug candidate for the treatment of idiopathic pulmonary fibrosis (IPF). GILD cited lack of efficacy as the reason for stopping the trial. </span><br />
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IPF is a condition that results in thickening and scarring of lung tissue. There is actually a change in the type of tissue of the lung. This causes less oxygen and gases to be transferred within the lungs. Therefore, the body receives less oxygen, especially the brain. The cause of IPF is unknown (idiopathic means that the cause is unknown). IPF affects nearly 200,000 patients in the US. Currently, there are no drugs that effectively treat or cure IPF. Physicians prescribe drugs that treat the symptoms or stabilize the disease. Source: <a href="http://www.pulmonaryfibrosis.org/ipf">Pulmonary Fibrosis Foundation</a><br />
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The FDA recently approved InterMune's (Nasdaq: ITMN) Esbriet (pirfenidone) for the treatment of IPF. The drug was also approved in the EU. This is the first drug that effectively treats IPF. It is likely that pirfenidone will become the standard of care for IPF as other treatment options are not ideal. <span style="color: red;">ITMN recently surged on news of positive results and should get another boost on the bad news from GILD as this eliminates some serious competition. </span>Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0tag:blogger.com,1999:blog-4599326694255740220.post-71152112641367126772010-12-26T15:24:00.000-05:002010-12-26T15:24:55.512-05:00Hyperthermia, Radiofrequency, and Microwaves: The Future of Cancer TherapeuticsRecently I heard about a forward thinking biotech company called <a href="http://www.bsdmedical.com/index.php">BSD Medical (BSDM)</a>. The company designs systems that deliver radiofrequency or microwave energy to precise targets within the body, primarily tumors located near the surface of the skin. They also have systems to reach deeper tumors. I was excited researching this company as I have worked on some projects involving hyperthermia therapy for cancer treatment. Unlike BSDM, I worked with superoxide iron nanoparticles and carbon nanotubes. Our plan was to use MRI or some other form of external rotating magnet field to help target and then heat up and destroy cancer cells. We hypothesized that we could heat and destroy tumors while leaving normal surrounding tissue unharmed. <br />
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The BSDM website explains that their hyperthermia technology treat cancer with heat and boost the efficacy of radiation therapy. BSDM's website explains that the immediate environment surrounding tumors (acidic and low amount of oxygen) causes radiation to be ineffective while microwave therapy is enhanced in this environment. Since cancer patients are usually treated with multiple forms of therapy: drugs (chemotherapy), surgery, and radiation, BSDM's system can easily be added onto standard treatment protocols to increase effectiveness. The microwave therapy is utilized in tumor ablation therapies in which soft tissue is vaporized.<br />
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Reasons that I AM excited about BSDM:<br />
<ol><li>Novel form of therapy. Expect BSD Medical to maintain a large share of the market for several years.</li>
<li> The technology can be combined with other conventional forms. As briefly mentioned before, cancer patients are routinely treated with different forms of treatment. Microwave technology can be used as a primary form of treatment, used before surgery to reduce the size of the tumor so surgeons can more easily remove it, or it can be used after surgery to kill any remaining cancer cells.</li>
<li>Drug resistance is a ever-present concern when treating cancer. There is less concern of resistance to microwave and radiofrequency therapies, but this must be kept in mind.</li>
<li>BSDM is also beginning to supply its systems for worldwide distribution. This is very exciting because physicians and healthcare practitioners overseas tend to be more welcoming to novel forms of cancer therapy than their counterparts in the USA. An example is the I-SPY clinical trials for breast cancer therapies. It was a novel way of performing clinical trials and has a novel paradigm of treating breast cancer. It was only recently started in the USA. </li>
</ol>Reasons that I AM NOT excited about BSDM:<br />
<ol><li>The adoption of therapy may be slow. Physicians, especially older ones, are reluctant to try new agents let alone novel forms of therapy. When dealing with cancer, you can bet that a new form of therapy will be met with some resistance. BSDM does hold training events and their success will be do in part to educating physicians about their technology.</li>
<li>The technology is new and it will take several years to better understand the mechanisms. In addition, we do not know of all side effects and long term detrimental effects. </li>
<li>In addition to convincing physicians to use their technology, BSDM will need to convince patients to use microwave or radiofrequency treatments. Patients are now involved more in their treatments than ever before. BSDM will need to focus on patient education. The website does a decent job providing patient information.</li>
<li>Insurance companies will need to cover the expense of treatment. They are the more difficult to convince.</li>
</ol><br />
Recommendation: <span style="color: red;">BSDM is buy-strong buy.</span> I love where the company is heading. This is not some biotech company that is focused on treating rare conditions that only effects a thousand or so patients and design drugs that have prohibitive costs and that insurance companies will not even consider covering. There is a very high ceiling and this is the best time to buy BSDM. <br />
Ronak Savlahttp://www.blogger.com/profile/16068437679427623681noreply@blogger.com0