The event of the week – some would argue the event of the year – was the release of FDA briefing documents related to BioMarin’s (BMRN) drisapersen, which faces an FDA advisory committee meeting this coming Tuesday. The drug is up for approval in Duchenne Muscular Dystrophy next month, and the upcoming committee meeting is all about FDA getting input from outside experts on the risk/benefit of approving drisapersen for DMD patients amenable to treatment by exon 51 skipping, drisapersen’s mechanism of action.
The briefing documents are the first look at FDA’s take on drisapersen. Drisapersen has a fraught data set from two phase 2 studies and a failed phase 3, encompassing more than 300 patients and run when the drug was still being developed by Prosensa Therapeutics and GlaxoSmithKline (GSK) two years ago. BioMarin picked up drisapersen when it acquired Prosensa last year, after GSK punted the asset, and the mid-size orphan drug developer has been talking up the potential for approval ever since.
The advisory committee meeting, and drisapersen’s approval or rejection, will also impact Sarepta Therapeutics (SRPT) and eteplirsen, which works by the same mechanism as drisapersen and is slated for an approval decision in February of next year, as well as PTC Therapeutics (PTCT) and its on DMD drug, ataluren. None of these three drug developers have unequivocal clinical data to support their New Drug Applications.
Here are the FDA’s briefing documents, if you haven’t already waded in, as well as BioMarin’s own documents.
Why is this such a big event? All three stocks mentioned above will move – even significantly – depending on the outcome of the meeting next week. January options for BMRN, which capture the FDA approval decision on December 24, imply a +/- move of about $20 for the $100 stock, or 20%, though Street expectations are mixed.
For Sarepta, March options, which will capture Sarepta’s approval decision, imply about the same dollar move, or $20. But for SRPT, that’s greater than a 50% move in either direction.
Again, none of these drug developers have perfectly clean data, and Friday’s briefing documents are the first glimpse at FDA’s stance on a imperfect clinical results in an unmet medical need.
A few choice excerpts from FDA’s initial summary:
A carefully planned and thorough drug development program was undertaken for drisapersen, and we believe that the sponsor and the patients and caregivers who participated in the trials should be recognized for their contributions to the understanding of the drug’s safety and efficacy. You will see in the FDA reviews enclosed, however, that it is not clear to the primary review team that substantial evidence of effectiveness has been presented for drisapersen or, consequently, that drisapersen has an acceptable risk-benefit profile.
It is greatly concerning that a number of biomarker studies suggest that, contrary to initial published reports,1 drisapersen has little effect on increasing dystrophin levels, the putative mechanism of action.
A number of post hoc subgroup analyses proposed by the sponsor were found to be highly sensitive to small differences in cutoffs for age and 6MWT and to other specific statistical manipulations, and thus lacked independent credibility.
The current thinking of the primary review team is that evidence supporting the effectiveness of drisapersen is inconsistent.
Even in the context of an invariably disabling and fatal disease such as DMD, the safety profile of drisapersen is concerning, as described briefly below.
The development program for drisapersen is extensive for a rare disease and exemplary. It is very disappointing that that both clinical and biomarker data for drisapersen are inconclusive at this time.
If nothing else, we encourage interested readers to peruse the Integrated Assessment of Effectiveness beginning on page 137 of the Clinical Efficacy Review.
To be clear, most of the FDA’s issues with drisapersen are not new to the investing community. The reviewers mention repeatedly in the briefing documents that the drisapersen development program, including the confirmatory phase 3 study, were well-designed and executed. Nevertheless, drisapersen’s initial benefit on 6 Minute Walk Test, considered a clinical outcome in DMD, failed to replicate in a larger patient population, and the drug has always had an onerous side effect profile, made more apparent than ever in the briefing documents.
Tuesday’s all-day meeting may not even provide much clarity. The FDA did not ask its expert panel to vote on drisapersen’s approval. Rather, they ask for input on the persuasiveness of data from each phase 2/3 study, and for input on the sparse dystrophin data provided by BMRN (Draft Questions). This was undoubtedly intentional. Advocates and DMD parents will be in attendance (the panel includes a 2-hour patient/parent testimony), thus the questions as they stand today allow the panel members to offer insight without putting them in the awkward position of disappointing – or infuriating – a rabid crowd.
No matter the outcome, the drisapersen advisory committee, subsequent approval decision, and impact on these three DMD players should prove an intriguing case study for healthcare investors.
