At the beginning of the month, we included BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) and its development stage candidate drisapersen as one of our drugs to watch before the end of the year. The treatment is up for review on December 26, 2015, and the review date will mark the end of a long road to approval for BioMarin; that is, of course, if the drug gets the green light. When we covered the drug briefly a few weeks ago, we promised we’d come back and take a closer look at it ahead of decision day – so, with this promise made, here goes.
We covered the science in a little detail last time, but let’s recap in a little more detail. Drisapersen is a Duchenne muscular dystrophy (DMD) candidate, and is part of a class of drugs known as 2′-O-methyl phosphorothioate oligonucleotides. Dystrophin is a protein that is responsible for providing structural stability in muscle tissue, coded by its eponymous gene, dystrophin. Patients with DMD have a mutation in their dystrophin gene, and this mutation means that higher than normal calcium deposits penetrate cell membranes. Higher calcium levels disrupt signaling pathways, and water builds up in the mitochondria of muscle tissue cells. Mitochondria (you may remember this from school) are the power houses of cells – they produce the energy needed for replication. When water enters mitochondria, the mitochondria bursts, and the cell dies. This creates a gradual, but persistent, degeneration in muscle tissue in DMD patients, which in turn causes the classic symptoms – awkward mobility, fatigue, falls, skeletal deformities, etc.
Drisapersen targets the dystrophin gene at its RNA phase, and alters it to stimulate the production of a partially functional dystrophin protein. In doing so, BioMarin hopes it can reverse, and improve going forward, the severity of the disease in DMD patients.
So what’s the issue? Well, the drug failed to meet its primary endpoint in the phase III on which BioMarin hoped to base its NDA. Further, in an FDA advisory review, the drug got severely criticized. A number (the majority, in fact) of the review panel refused to accept any benefit over placebo, and argued that the progress in the treatment arm (as measured by the distance a patient can walk in six minutes) fell in line with the standard progression of the disease. Additionally, a number of the panel pointed to the drug’s toxicity as reason enough to discourage approval.
However, in a presentation to the FDA, BioMarin presented pooled results from three separate trials that suggested efficacy. Further, we got a number of guest appearances at this presentation from parents of children involved in the trial. Two of these sets of parents represented children that had discontinued treatment. The first assumption before the presentation was that they would rather submit to the degenerative nature of the disease, than force their child to suffer the AEs associated with drisapersen. In reality, however, these parents merely switched to a alternative dev stage treatment, etiplirsen, which is up for review in January following an NDA submission by Sarepta Therapeutics, Inc. (NASDAQ:SRPT) earlier this year. We also got anecdotal evidence from parents whose children are part of the trial, suggesting that the drug is effective, and has a negligible AE profile – one for which the benefits vastly outweigh the costs.
So what is likely to happen come the 26th? Well, there are plenty of arguments against approval, not least of all the panel review, which pretty much flat out stated the FDA shouldn’t even consider approval. The FDA doesn’t have to listen to the panel, however, and we’ve got to remember this is a serious condition for which – at present – there is no real effective therapy that addresses the underlying cause of the disease. Anecdotal evidence from trial participants can be effective in swaying the FDA’s decisions, and this may come in to play when the agency comes to a conclusion. As a prediction, the FDA will approve the treatment, with the necessity for follow up data going forward. It will also approve Sarepta’s candidate, and let the open market decide which safety vs efficacy profile it prefers to accept.
All said, this is a real interesting one, and is likely to be one of the biggest market moving decisions of the year in the biotech space. Risk averse investors might want to avoid the DMD space outright over the next six weeks. For those with a little speculative capital they can afford to lose, however, there is plenty of reward on the table for the right call. Bring on the 26th.