Ariad: Leading the Pack to Introduce a New Generation of TKIs

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.1

Ponatinib (AP24534) and Tyrosine Kinase Inhibitors


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.

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.

BCR-ABL fusion gene allows for escape from growth regulation à activated as functional oncogene à increased kinase activity à cell proliferation, inhibition of apoptosis, and malignant clones.

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)2 and nilotinib (Tasigna, Novartis; NYSE: NVS)3, 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. 

ENESTnd Study- Nilotinib showed superior results compared to imatinib in terms of CCyR and MMR at 12 months for newly diagnosed patients 4

DASISION Study- Dasatinib showed superior results compared to imatinib in terms of CCyR and MMR at 12 months for newly diagnosed patients 5

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.

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.


Background on Leukemias (ALL and CML)

• Leukemias are malignancies of hematopoietic cells in the bone marrow and blood
• They occur in either the myeloid lineage (basophils, eosinophils, neutrophils, monocytes, platelets, erythrocytes) or lymphoid lineage (T lymphocytes and B lymphocytes)
• Type of leukemia reflect maturity of hematopoietic stem cells from which it developed
• Acute Leukemias- early cells in the myeloid (AML) or lymphoid (ALL) lineage
• Chronic Leukemias- genetic abnormalities occur in later stages of white blood cell development 
• Acute Lymboblastic Leukemia 
• Incidence: 5,760 in 2009
• Deaths: 1,400 in 2009
• Patients typically attain remission, but it is difficult to keep them in remission
• Poor prognostic factors: L2 or L3 (based on French American British System, 70% of adult ALL); Ph+ (30% of adult ALL); 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.
• Goal: Achieve complete remission and continue therapy. CR achieved in 65-85%; relapse is common. Gleevec is added to the regimen if cancer is Ph+.

• Relapsed/ Refractory ALL
• 60-70% of ALL patients relapse 
• If Ph+, add dastinib or nilotinib
• High relapse rate increases potential need for ponatinib

• Chronic Myelogenous Leukemia
• Incidence and Deaths (2009): 5,050 and 470
• Median age at Dx: 67 years of age (Most studies report 45-55 years)
• Male: Female = 1.5:1
• 95-100% of patients have BCR-ABL fusion protein

• Treatment Responses
• Hematologic response: normalization of peripheral blood counts
• Cytogenetic response: % of cells positive for Ph in bone marrow
• Complete- elimination of Ph
• Major- <35% Ph+ cells
• Molecular response: most sensitive; uses PCR for quantitative number of bcr-abl transcripts

• 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.
• Median age at T315I mutation detection: 54 years
• 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). 
• After T315I mutation detection, dasatinib and nilotinib were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%.
• 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
• 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

ASH 2011

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 

• 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).
• Secondary Objective: Clinical and molecular responses; molecular genetic status of patients; safety
• 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).
• About 30% patients in chronic (64/207) or accelerated (19/60) phase CML cohorts with T315I mutation
• 46 of 48 patients in blast phase and Ph+ ALL cohort had T315I mutation
• F317L was also a common mutation
• 47% of patients in chronic phase CML cohort reached primary endpoint
• 67% of patients in accelerated CML and 37% of blast phase CML+ Ph+ ALL reached primary endpoint
• Responses for all cohorts were better than responses to most recent dasatinib or nilotinib therapy (25% CP-CML, 33% AP-CML, 25% BP-CML + Ph+ ALL).
• 67% (301/449) patients remained on study. 
• Only 22% (21/94) in BP-CML + Ph+ ALL remain on study.  Remember that these patients have the worse prognosis
• 4 on-study deaths were treatment related, but no evidence of ponatinib specific findings

ASH 2011 Abstracts

Analysis of the Potential Effect of Ponatinib on the QTc Interval in Patients with Refractory Hematologic Malignancies

• No effect on cardiac repolarization measured by lack of significant change in QTcF at all doses

Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

• 81 patients (54% male) received ponatinib. 43 pts had CP-CML. 
• Best responses: MCyR in 31/43 (72%), 27 (63%) CCyR.  
• Complete Hematologic Response in 42/43 patients.  
• Major molecular response in 19/43 (44%).  
• The median time to MCyR was 12 (3-104) weeks. 

ATP Dependent Efflux Transporters ABCB1 and ABCG2 are Unlikely to Impact the Efficacy, or Mediate Resistance to the Tyrosine Kinase Inhibitor, Ponatinib.

• Ponatinib is the least susceptible TKI as a substrate for efflux pumps.  Nilotinib and dasatinib are the most susceptible.

AACR 2011

Ponatinib (AP24534), a potent pan-FGFR inhibitor with activity in multiple FGFR-driven cancer models with distinct mechanisms of activation

• In vitro and in vivo inhibition of FGFR of ponatinib versus other TKIs in clinical development
• Ponatinib was more potent than other TKIs and potent against different forms of FGFR
• Inhibition levels may be achieved in humans

ASH 2010

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

• 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
• Primary objective: Maximum tolerated dose or recommended dose
• Secondary objectives: safety; anti-tumor efficacy; pK/PD; pharmacogenomics
• Intra-patient dose escalation using capsules or tablets
• Patients with any stage CML (60 of 74 patients), AML, ALL, MDS, MM, or CLL
• 60 patients were Ph+ 
• 95% resistant to at least 2 TKIs
• Prior Treatment with imatinib (97%), dasatinib (90%), nilotinib (57%), dasatinib + nilotinib (52%)
• 28% had T315I mutant at entry; 11% with F317L mutation
• Hematologic dyscrasias most common Grade 3 AEs. Expected based on mechanism of ponatinib
• Pancreatic DLTs at 60 mg
• CP-CML: 66% MCyR, 53% CCyR, 42% MMR
• CP-CML with T315I: 100% MCyR, 89% CCyR, 78% MMR

Summary

• Ponatinib a "3rd Generation" TKI has shown great promise in terms of efficacy and safety for the treatment of CML and Ph+ ALL
• Due to long-term therapy and high rate of resistance of ALL and CML patients, ponatinib will easily find a place in therapy.
• Activity against T315I provides a solution for an unmet clinical need
• Ponatinib is the most advanced TKI in clinical development that is active against the T315I mutation
• It is encouraging that ponatinib is not likely to be a substrate for efflux pumps
• Superior results of nilotinib and dasatinib compared to imatinib in newly diagnosed patients may allow ponatinib to play a greater role in patient therapy
• 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
• Activity versus other receptors (FGFR and VEGFR) may lead to indications for solid tumors
• Long term efficacy and safety data still need to be collected and analyzed
• Ariad Pharmaceuticals has become an investor favorite and should continue to see great growth due to ridaforolimus and especially due to ponatinib
• 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. 

Sources (not listed in-text)

DiPiro J et al. Pharmacotherapy: A Pathophysiologic Approach.
Presentations of clinical data are available from Ariad Pharmaceutical's website.
CML Guideline available from National Comprehensive Cancer Network (NCCN)
O'Hare T et al. Clin. Cancer Res. 2011; 17: 212-221.
Gruber FX et al. Leukemia advance online publication, 5 August 2011; doi:10.1038/leu.2011.187



  

Intrexon and Ziopharm's "Synthetic Biology" Platform More Abstract than Picasso's Art

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.  

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.

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.  

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.

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. 

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.      

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.   

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. 

Summary

• Palifosfamide is a slight improvement over ifosfamide, but there is not a large market for the drug and higher cost will hinder clinical adoption.
• Darinaparsin is a substitute for arsenic compounds.  As with palifosfamide, it is a "me-too" drug and will likely not be a clinical success.
• 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. 

All of the Pieces of the Puzzle Coming Together for BSD Medical

I 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.

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. 

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.

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.

The company also noted a study published in the prestigious scientific journal PNAS demonstrating the power of hyperthermia therapy.  The study was reviewed in science magazine, The Scientist.  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.

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.   

Chart Analysis: Teva and Mylan Stock Prices Mirror Images

I 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.

 

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? 

What's Teva Getting Out of the Cephalon Buyout

Teva 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. 

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. 

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.

Currently Approved Products from Cephalon:

1. 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.
2. Provigil (modafinil)- Accounts of 41% of revenues for Cephalon. 
3. 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.
4. Amrix (cyclobenzaprine)- treatment of muscle spasms. This is an extended release formulation; Teva markets an immediate release formulation.
5. Fentora (fentanyl buccal tablet)- Teva has a similar oral transmucousal lozenge.
6. Actiq (oral transmucousal fentanyl citrate)- Since Teva has a generic version already, Actiq may go away
7. Trisenox (arsenic trioxide)- indicated for inducing remission in patients with acute promyelocytic leukemia
8. Gabitril (tiagabine)- treatment of partial seizures

Drugs in the Pipeline:

CNS Disorders

1. Nuvigil- Phase III trial for bipolar depression.
2. 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

Inflammatory Diseases

1. 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.
2. Lupuzor (forigerimod)- Phase II. CD4 T cell modulator for treatment of Systemic Lupus Erythematous
3. CEP-37248- Phase I. Humanized antibody targeting interleukins 12 and 23.  Multiple autoimmune disorder indications are possible.

Oncology:

1. 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.
2. CEP-18770- Phase II. It's a proteasome inhibitor for treatment of multiple myeloma.  
• Bortezomib (Velcade) by Millennium Pharmaceuticals is already approved.  
• Ritonavir, a protease inhibitor developed for AIDS, has some proteasome inhibitory activity and may have potential for treating glioma.
3. Mesenchymal Precursor Cells (with Mesoblast Limited)- Phase II for bone marrow transplantation
4. 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.  
• Iniparib from Sanofi is in Phase III.  FDA has fast tracked it for triple-negative breast cancer
5. CEP-11981- Phase I for treating solid tumors.
6. 3 others in pre-clinical stages

Pain:

1. 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.
2. 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.
3. CEP-37247 (anti-tumor necrosis factor)- Phase II for treatment of sciatica

 Cardiology:

1. Revascor (collaboration with Mesoblast Limited)- Phase II for congestive heart failure and myocardial infarction

Big 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.

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?

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. 

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.    

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.

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.

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.
 
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.

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.  

 

BSD Medical's MicroThermX System Used to Treat Lung Cancer

BSD 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.   

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.     

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.     

Is 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.

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.  

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.

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.

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.

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.

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.   

Will 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.
There are several things investors have to love about Teva:

1. 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. 
2. 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.
3. 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.
4. 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.
5. 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.
6. A wide variety of drugs are manufactured, marketed, or sold by Teva.  This will ensure a revenue stream for many years to come.    

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.

Will 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.

A recently published study 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.  

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 [JCR]. 

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. 

Rosuvastatin (Crestor) is marketed by AstraZeneca (AZN) and the patent expires in 2016.

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. [JCR]  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. 

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 [Journal of Controlled Release].  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. 

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 in vitro experiments using liposomal formulations and statins that are available as generics.

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.    

Are 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.  

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. 

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.

According to a recent Wall Street Journal article, 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. 

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). 

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.

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 article by EJ Emanuel et al. published in the Journal of Clinical Oncology 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.      

Ariad and Merck Meet Primary Endpoint and to Submit for FDA Approval

Ariad 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. 

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.

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.  

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.   

     

Avanir Pharmaceuticals Looks to Treat Uncontrollable Laughing and Crying

The 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. [WebMD]  


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.

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.
  
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. [Journal of Psychiatry & Neuroscience] 


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 "Seeking Alpha" reports a co-pay ranging from $60-$340 for a 90 day supply. 

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. [NIH]  Of those diagnosed with ALS, approximately 50% experience pseudobulbar affect.  A smaller percentage of MS patients experience pseudobulbar affect (10%). [Neurology Today] 

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.

Sanofi-Aventis Looking to Acquire Genzyme and Alemtuzumab

Genzyme (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.[WSJ] 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.

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) [PI] 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.

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. [National MS Society]

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. 

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.



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. [NEJM]



CARE-MS1 and CARE-MS2 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.  [Medscape]


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.

The 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.

Dalcetrapib:

• 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.
• It acts through a slightly different mechanism than the others and does not induce a complex between CETP and HDL. 
• 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.
• 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.
• Current studies (dal-PLAQUE and dal-OUTCOMES) will provide a better glimpse into the potential.

 Anacetrapib:

• Works via the same mechanism as torcetrapib by complexing CETP with HDL.  This causes researchers to be more concerned about blood pressure elevation effects.    
• 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.
• 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.  
• A separate Phase I trial tested the safety of anacetrapib in helathy patients for 10 days.  There was no reported increase in blood pressure.  
• 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.
• The DEFINE study is ongoing and will provide a better projection of anacetrapib's potential.

 Potential of CETP Inhibitors:

• High LDL and low HDL are risk factor for atherosclerosis.  CETP inhibitors help in both regards.
• Defective HDL function contributes to atherosclerosis.
• CETP inhibitors may be the preferential drugs to increase HDL.
• Combination therapy with statins, niacin, and fibrates lays in the future of CETP inhibitor therapy.
• 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.
• Further research and investigation of CETP inhibition is needed with monotherapy and combination therapy.
• 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.
• It is interesting to see if these drugs can help MRK and Roche recuperate from the patent cliff of 2011-2012.

JNJ'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.

Issues Concerning the Success of JNJ's Novel Test:

1. 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.
2. The technology is still in early stage of development.  If successful, the instrument can be expected to hit the market in a few years. 
3. What real clinical value lays in detecting a single cell?
• 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.
• 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.
• Tumors metastasize after growing to a certain size and being depleted of nutrients.  This test will not give the earliest indication of cancer.
• 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.
• 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.
• 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.
4. 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.
5. 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 PNAS 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.

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.   

Can Mannkind Avoid Repeating History with its Inhaled Insulin, Afrezza?

Mannkind (Nasdaq: MNKD) 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 (PFE) 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.

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.
According to the American Diabetes Association:

"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."

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:

1. Superior to injectable forms of meal time insulin
2. 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. 
3. 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.
4. Reduced risk of low blood glucose after administration.
5. Cost similar to injectable insulin formulations or the premium worth the convenience.

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. 

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. 

 

PFE's Exubera                                                    

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.





MNKD's Afrezza

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.    



Afrezza's blockbuster potential lies in its costs.  A report by Black et al. 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. 

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.   

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.