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The founding members of Chimera Research Group have over 50 years of combined experience in the biotech and pharmaceutical sector. Their experience includes work at Investment Banks, Hedge Funds, Pharmaceutical Companies, top-tier Universities, and the U.S. Food and Drug Administration (FDA).... More
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  • RNAi: Is It Still Worth Investing?
     
    The New York Times published an article yesterday describing the hyperbolic trajectory of Big Pharma interest in the RNAi field. Discovered little more than a decade ago, it has already garnered Nobel prizes for two scientists credited for ilucidating its mechanism. In 2006, Merck puchased a small company focused on RNAi drug development, Sirna, for a whopping $1.1 billion; five years later, the largest independent company is valued at about half that. And as for Sirna, Merk is using its technology for laboratory studies. “Happy with its investment” says the company.

     
    It may be an understatement to say RNAi technology was overhyped. The technology is quite amazing, to be sure. Much more potent and longer lasting than antisense, RNAi quickly became the tool of choice in scientific laboratories. It seemed only a short leap from the benchtop to the countertop. “Undruggable” targets were now within reach.

     
    Not surprisingly, RNAi drug development has been considerably slower than previously imagined. After about 20 years, only now are antisense drugs beginning to gain traction in the clinic. It has required significant work improving the molecules. RNAi drug development should not have been expected to be much faster.

     
    Now that research budgets are being cut, large pharmaceutical companies have followed each other in lock-step, dropping their RNAi programs one after the other. High profile cases include Roche and Novartis both ending large research projects. Pfizer shut down a 100 person RNAi unit.

     
    A bit of a surprise on Roche's part seeing how it was one of the early movers in antibody technology. But pharma never seemed too fond of RNA technology to begin with due to the lack of progress. This leaves biotechs once again to lead the way in the development of new technologies, with pharma certain to play catch-up in the near future. The story never changes.

     
    Abandoned, RNAi has lost some luster. Still, work continues and the products are improving. Progess is even being made on the crucial drug delivery stage. Commentators have noted RNAi is beautiful in concept; I believe it is only a matter of time before we will see the beauty of its design.
    Feb 09 3:18 AM | Link | Comment!
  • Vivus- Last One Standing
     
    Only a year ago, three companies were in a tight race to be the first to bring a novel anti-obesity drug to market in years. Each one, Arena, Orexigen, Vivus, had claims of superiority, whether it be safety, novelty, or efficacy. And each one was valid. It appeared possible all three could be approved, but we know that case is now highly unlikely. For now, there is only one still standing, however wobbly.

     
    Arena was sent packing early when the FDA identified higher incidences of cancer in Lorcasarin preclinical studies. What many had thought was the best bet for safety was turned completely upside down. Vivus too, was dismissed- this time due to concern over cardiovascular and birth defect risks. In a surprise to obsesrvers, Orexigen's Contrave won majority backing of the FDA advisory panel, only to be rejected by the FDA, asking for a new trial seeking cardiovascular safety data; this will add many years and hundreds of millions of dollars to the drug's development.

     
    There are analysts who have written off all three drugs; the FDA is in safety mode and wants to preempt the possibility of future recalls. Mathew Harper of Forbes has opined that the entire obesity drug field is essentially dead as a result of the Contrave rejection. He is wrong.

     
    Both Lorcasarin and Contrave were only marginally effective in clinical trials of weight loss. They passed the FDA requirements for only one measure of efficacy; this made it easy for the FDA to make a negative decision based on the poor benefit to risk ratio. Even though Lorcasarin had two full years of data on thousands of patients, its true activity would never be known until use became widespread. The FDA simply was not willing to take any risks on a drug with such modest benefits.

     
    Vivus' Qnexa stands out with a highly effective drug tested at three different doses. Results surpassed all FDA benchmarks for efficacy for the high and mid-doses. Even at the lowest dose, one benchmark was passed, making it as effective as either of the other two drugs.

     
    Obviously, there is room for concern: FDA analysts pointed out that a higher percentage of patients in the studies discontinued the drug due to anxiety, sleep, and depression-related adverse events. Adverse effects on memory, attention, and language was noted along with concerns regarding increased heart rates. This may sound like a scary list, but these are known side-effects of topiramate and phentermine- the components of Qnexa.

     
    What may have Vivus over a barrel is topiramate's teratogenic effects. A study of 178 babies born to women taking topiramate showed 16 had cleft lip or genital defects- an eleven-fold higher incidence. Thirteen babies born to women in taking Qnexa in the clinical trial had no signs of birth defects, but the sample size is very small. Vivus is now gathering additional data on topiramate and its affect on birth defects to present to the FDA.

     
    The worry is that Qnexa will be used long term in women of child-bearing age, leading to a serious risk of increased birth defects. Vivus will certainly need to design a Risk Evaluation and Mitigation Strategy (REMS) satisfatory to the FDA. Keep in mind that even with its inherent risks, topiramate is approved and used by women as a preventative for migraines, a serious disorder, but surely less so than seizures.

     
    Qnexa is not a weight-loss cure-all, but a drug that can shave 10% off the weight of a seriously obese individual is of real benefit.
    Feb 08 8:20 PM | Link | Comment!
  • Celgene: Is It Time To Buy?
    Celgene has been hit again with issues of secondary malignancies arising from prolonged treatment with its key drug, Revlimid. Shares have crumbled in the past month from $60/sh early this year to as low as $49 on February 4. It has now bounced back above $50.
     
    News of secondary malignancies has bedeviled the company since data from two key trials was release at ASH in early December 2010. Data from two clinical trials showed that, while helping stave off multiple myeloma, the treatment regimens that included Revlimid were associated with a numerical increase in the number of secondary malignancies in patients who previously received a stem cell
    transplant.
     
    In a trial known as CALGB, patients were either given high dose melphalan followed by stem cell transplant, then Revlimid, or were given melphalan, stem cell transplant and placebo. Patients in the Revlimid group had a 60 percent reduction in the risk of their disease progressing after four years. However, about 15 patients in the Revlimid arm developed a secondary cancer compared to 10 patients in the placebo group.
    Patients in a second trial, IFM, received consolidation therapy with Revlimid, and then were randomized to receive long-term Revlimid maintenance therapy or a placebo. Patients in the Revlimid arm had a 50 percent reduction in the risk of their disease progressing after four years. Seven patients in the Revlimid arm developed a non-blood cancer secondary malignancy compared with one in the placebo group. Ten patients in the Revlimid arm developed a secondary blood cancer, compared with two in the placebo group.
     
    These were critical trials for Celgene; much of Revlimid’s future growth depended on increasing the duration of treatment, approval for maintenance therapy would go far in accomplishing that goal. Management reassured investors that the observed increase in secondary malignancies was not unusual, but caused by the uneven follow-up of Revlimid treated patients compared to placebo.
     
    The hammer fell last week when Celgene said it had suspended dosing in one of its three pivotal maintenance therapy trials, known as IFM 2005-02, due to a higher rate of secondary malignancies. There were suggestions by investigators that that the duration of Revlimid maintenance should be limited to 12, 18 or 24 months.
     
    This was a hit not only to potential drug sales but management’s credibility; the company had assured analysts of Revlimid’s safety only days ago during its quarterly earnings call.
     
    Over time, I believe this will all blow over. The overwhelming efficacy and tolerability of Revlimid will likely garner it approval in the maintenance setting. Even if limited to 24 months of use, there is plenty of growth left considering the average duration of treatment is approximately 12 months in the US and around 8 months in Europe. Along with increasing time on treatment is geographic expansion. Only now is Revlimid becoming available in Japan and Russia. It will soon be launched in China. Pivotal trials are also ongoing in additional cancer indications including CLL, NHL, and even a couple solid tumors.
     
    Celgene has been slow to develop its own pipeline, but has done well with acquisitions. It has picked up companies with approved, complimentary products for decent prices, and ramped up their sales with an enviable sales force. If this can be repeated with breast cancer drug Abraxane, from its most recent purchase of Abraxis, it may well have a blockbuster.
     
    The company’s pipeline is finally beginning to bare fruit. Several compounds are in Phase III trials: Pomalidomide in Myelofibrois, Apremilast in Psoriatic Arthritis and Psoriasis, and Amrubicin in SCLC. Sales potential for these three if successful could be quite significant.
     


    Disclosure: I am long CELG.
    Feb 07 10:45 PM | Link | Comment!
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