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Sarepta Wants to Change the Way We Do Business with the FDA
At The World Orphan Drug Congress USA, CEO Chris Garabedian of Sarepta Therapeutics gave the audience want they wanted – a bold talk about shaking up the way the pharmaceutical industry works with the FDA. And the audience loved it.
In his presentation “Leveraging a personalized medicine platform to treat genetic sub-groups”, Mr. Garabedian noted that his company is using exon skipping technology to treat genetic subgroups of Duchenne muscular dystrophy (MD). Duchenne MD is caused by mutation of the dystrophin gene that prevents the production of dystrophin protein that eventually weakens their muscles. At present, the company is waiting to complete their phase 2 study with their drug eteplirsen but they have been very open to sharing the data with the public. In the study, 6 patients with Duchenne MD were treated with eteplirsen for 62 week and compared to 4 patients who were originally given placebo for 24 weeks then switched to eteplirsen for 38 weeks. The 6 patients given continuous eteplirsen treatment showed stabilization throughout the 62 weeks while the 4 patients in the placebo/delayed-treatment cohort showed decline in their 6 minute walking test that only stabilized after they were later given eteplirsen. Muscle biopsies confirmed a significant increase in dystrophin levels which is believed to be what the exon skipping eteplirsen is allowing these children to synthesize. In summary – the results are excellent and their biomarker data mimics the standard outcome measure - the 6 minute walk test. Soon, the company will finalize the phase 2 study and begin a phase 3 study. So what is the problem?
The problem is that Duchenne MD has three things going against it that can have drug easily approved for it. First, it has a rapid onset between the ages of 9-15 and once that occurs, the boys will quickly lose muscle strength and eventually die. Therefore, there is a strong desire by many to push these drugs through. Second, Duchenne MD is an ultra rare disease making it difficult to find patients, especially during the beginning of the rapid declining phase when it is the only time that they can statistically determine if a drug is working in a clinical trial. Third, there are many subtypes of Duchenne MD which means that companies now must study subgroups of an already ultra rare condition. As a result, it is likely unfeasible for companies to test for many of the smaller subgroups. At present, Sarepta is focused on its eteplirsen which skips exon 51 but it also has drugs for skipping other exons that can be used for other subgroups of Duchenne MD. What bothers Mr. Garabediean is the idea that Sarepta is using the same basic technology (exon skipping) to treat different subpopulations of the same disease and that makes it difficult for the company to justify spending the millions of dollars on preclinical and numerous clinical trials for almost the same drug. Especially, given the small number of patients. And that is why Sarepta wants to change the way they do business with the FDA.
To do this, Sarepta has a 3 step process.
Step 1. Build a strong foundation with eteplirsen and establish dystrophin as a surrogate marker.
They have done this. Dystrophin levels are a good biomarker and may be as reliable than the 6 minute walk test.
Step 2. Demonstrate comparable safety and efficacy with similar exon skipping products.
They are showing this with three other exon skipping agents (exon 45, exon 50, exon 53 PMO)
Sarepta believes that if they can show similar PK/PD and safety profiles etc, Sarepta thinks they should be allowed to get approval. Mr. Garabedian noted that the company will be very transparent with all the data to ensure the drugs are safe and effective but he warned that as soon as someone starts asking for different doses or dosing schedules or more animal model studies etc. the whole program will quickly become undoable.
Step 3. Apply standardized manufacturing process and dose to collect long-term
post marketing evidence.
Sarepta wants to replace the long drawn out process of phase 1, 2, and 3 clinical trials with data that will be collected long term after the drugs are approved (ie, post marketing data). This long term data can then be used to adjust dose or test safety etc.
Sarepta believes that this innovative regulatory science is the only way to achieve the goal of reaching all of the subtypes of Duchenne MD. Since the number of patients is so small for many of these subgroups, Sarepta believes it is time for drug companies to talk with the FDA about different ways to approve drugs in certain circumstances. And based on what many leaders in the FDA have said recently, they may be open to new ways to conduct business.