Graham R. writes, "Sarepta Therapeutics has acted badly since the FDA [advisory committee] dates were straightened out. Why is this perceived to be bad news for Sarepta?"
I'll give you the "new" Sarepta bear thesis to explain why the stock is sinking, but let me first set the stage based on what we learned Wednesday.
Biomarin Pharmaceuticals (BMRN) will bring drisapersen in front of an FDA advisory panel on Nov. 24. The FDA's approval decision deadline for drisapersen is Dec. 27. Sarepta believes FDA will convene a second advisory panel for its drug eteplirsen on Jan. 22, 2016. [That date is currently tentative.] The FDA approval decision deadline for eteplirsen is Feb. 26, 2016.
Under this timeline and assuming all goes well for Biomarin, drisapersen will be approved before Sarepta's advisory panel. Therefore, the FDA -- theoretically -- will have less urgency to approve eteplirsen.
This is the new Sarepta risk factor now that we know the two drugs won't be reviewed at FDA advisory panels on consecutive days in November, as previously expected.
The bright side of the current timeline: Sarepta has a greater opportunity to learn and react to whatever happens during the earlier Biomarin advisory panel.
In case you're interested, I've previously predicted how FDA will rule on the Biomarin and Sarepta drugs, and I've taken a closer look at the Sarepta investment bear case. I also wrote about the new analysis of eteplirsen conducted by Sarepta.
Update: On Friday morning, after this column was written, Zafgen announced that the FDA had placed a partial clinical hold on all beloranib clinical trials. Zafgen confirmed that the patient who died was being treated with beloranib. The cause of death is still unknown but Zafgen's statement Friday suggests a thrombolic (blood clotting) adverse event was involved.
The death of a patient in a clinical trial is always a big deal, particularly when the cause of death -- and the role an experimental drug may have played -- is not known. Zafgen is taking the Prader-Willi Syndrome patient deathreported in the beloranib study very seriously, as it should. Unfortunately, the company handled the disclosure of the material event to investors very poorly.
Given the lack of information available Friday, it's difficult to assess the impact of the patient death on the future clinical development of beloranib. Zafgen shares rebounded Wednesday and Thursday because the worst-case scenario -- the shutdown of all beloranib clinical trials due to a catastrophic safety problem -- didn't materialize. But in no way is all risk off the table.
Some unanswered questions:
Was the Prader-Willi patient in the study taking beloranib when he (or she) died?
The study randomized patients equally to beloranib (a low or high dose) or a placebo. As of Thursday, Zafgen says it does not know if the deceased patient was on drug or a placebo. I have no reason to doubt the company, which rightfully must be blinded to the ongoing conduct of the study. However, the data-safety monitoring board overseeing the study almost certainly has this information and shared it with FDA. It seems highly unlikely for Zafgen to be engaged in ongoing discussions with FDA if the Prader-Willi patient had been on placebo.
Why did the Prader-Willi patient die?
Results from the autopsy have not been disclosed. This is important information for obvious reasons, particularly if the patient was taking beloranib at the time of death. The cause of death may or may not help determine if beloranib played a role. Keep in mind that Prader-Willi is a rare genetic disease which causes insatiable appetite. Patients have a compulsive need to eat, leading to severe and life-threatening obesity and related health problems. The annual death rate for Prader-Willi patients is approximately 3%. It will be important to learn if the patient's death was caused by morbidities associated with Prader-Willi or something different.
Are there any known safety risks related to beloranib which could contribute to a patient's death?
Possibly, yes. Zagfen describes beloranib as belonging to a class of drugs which block an enzyme, MetAP2, believed to play a role in metabolism, hence the interest in obesity and related illnesses. MetAP2 inhibitors are also anti-microbials and have a blocking effect on angiogenesis, or the growth of new blood vessels, which has led to some of the drugs in the class to be studied in cancer.
Zafgen reported two serious thrombotic (blood clotting) adverse events in a previous, phase II study, but neither were attributable to beloranib, according to study investigators. Still, given the anti-angiogenic qualities of MetAP2 inhibitors, thrombosis might be a worrisome safety signal for beloranib, especially for patients treated at higher doses and longer exposure. [Avastin, an anti-angiogenesis drug, has prominent safety warnings in its label describing arterial and thrombotic adverse events.]
"Sleep disturbances" and "abnormal dreams" attributed to beloranib, some bad enough to cause treatment discontinuation, are the most common adverse events reported by Zafgen in its clinical trials. References to neuropsychiatric toxicity, including sleep disturbances, are also found in published studies of other MetAP2 inhibitors. Zafgen says central nervous system-related side effects have been manageable, so it's not clear if they're serious enough to cause serious harm or even death.
Gastrointestinal side effects -- nausea, vomiting, diarrhea -- have also been reported by patients treated with beloranib.
What happens if the FDA concludes beloranib contributed to the patient's death?
The FDA could do nothing and allow the Zafgen study to continue as is because the potential benefits outweigh the risks for Prader-Willi patients. The FDA could also place beloranib trials on clinical hold until Zafgen can better characterize the safety risks tied to the drug. A middle option might have FDA allowing Zafgen to continue the study but with changes or restrictions to better ensure patient safety.
Rick K. writes, "Bluebird Bio continues to drop. I know you can't predict what will happen but is there something you can say about what it will take for the stock to move higher again?"
In the past, Bluebird's stock price has reacted well to strong data from the ongoing gene therapy studies in beta-thalassemia and sickle cell disease. Luckily, the next update -- and a big one -- from these Bluebird studies is just weeks away. [I wrote about a Bluebird competitor emerging in sickle cell disease, Global Blood Therapeutics (GBT) , last month.]
Circle Nov. 5 on your calendar. This is when the American Society for Hematology will make public the research abstracts for its annual meeting held in December. Bluebird has submitted research abstracts covering three studies of its gene therapy Lentiglobin in beta-thalassemia and sickle cell disease -- HGB-204, HGB-205 and HGB-206.
The Bluebird abstracts for the ASH meeting were submitted in July, so they contain limited data which will be further updated at the actual meeting in December, said Manisha Pai, Bluebird's head of investor relations. Given the volatility (mostly down) in Bluebird's stock price, I expect you'll see a reaction to the preliminary information contained in the abstracts.
The last presentation of data from the HGB-204 study (spectacular, if you recall) was at the December 2014 ASH meeting, so the update in the Nov. 5 research abstract will contain a good amount of new information. This beta-thalassemia study is now fully enrolled but Bluebird has not said how much data (number patients, treatment duration) will be included in the abstract or at the ASH meeting.
Bluebird last presented results from the HGB-205 study (beta-thalassemia and sickle cell) at a European medical meeting held in June. [Again, the data were very positive.] The Nov. 5 ASH meeting abstract will not contain significant, new information because the submission deadline was in July. At the ASH meeting in December, Bluebird will have updated results from the HGB-205 study representing 5-6 months of patient follow-up from last June's presentation.
The first sickle cell disease patient to be infused with the Lentiglobin gene therapy as part of the HGB-206 study occurred in June, so the ASH abstract available Nov. 5 will only be a placeholder. Bluebird has not specified how much data from this study will be available to present at the ASH meeting in December, although it will update progress on patient enrollment.
Gene therapy is very cool. Owning the stocks of companies developing gene therapies used to be very cool too, but not so much lately. No one knows that better than long-time holders of Bluebird stock, which is down almost 60% since May. Another showing of strong results from the Lentiglobin studies is the best fuel for a Bluebird rally.