Monday, February 7, 2011

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.    

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