It usually takes a successful Phase 3 trial for a new drug to get approved. The FDA may consider granting accelerated approval with just two phases of testing, if the drug addresses a significant unmet medical need and shows promise in treating life-threatening conditions.
On April 15 Sarepta (NASDAQ:SRPT) announced that the FDA will consider accelerated approval for eteplirsen, its experimental drug for Duchenne muscular dystrophy, after further review of data on dystrophin and clinical outcomes. The FDA may accept dystrophin as a surrogate endpoint that would reasonably predict clinical benefit in DMD patients and may accept the eteplirsen safety database for accelerated approval filing.
Sarepta will submit details of the methodologies used to analyze dystrophin in the studies and supportive data suggesting that the dystrophin produced is functional. Also, Sarepta will continue to collect long-term safety data from the ongoing eteplirsen extension study for a potential submission.
The FDA would also review safety data coming from the first few months of the planned Phase 3 study. Sarepta intends to begin dosing patients in a confirmatory study in the first quarter of 2014. All eteplirsen related manufacturing and clinical development activities by Sarepta will go ahead as planned.
Duchenne muscular dystrophy
In Duchenne muscular dystrophy (DMD) the patients are unable to produce the essential protein dystrophin and because of this lack of dystrophin they end up on a progressive track toward losing the ability to walk by their pre-teen years, having a life expectancy into their 20s, and rarely living beyond the age of 30.
The essential protein dystrophin is the shock absorber of the muscles that allows all of us to maintain good muscle function throughout our life. The drug eteplirsen is a chemical which in essence repairs the RNA mutation and restores the production of the protein.
To achieve this, Sarepta uses exon-skipping technology. Exon-skipping is an innovative disease-modifying treatment designed to skip an exon in the dystrophin gene, thereby enabling the repair of specific genetic mutations and the production of a functional, but shorter, form of dystrophin.
Sarepta currently has four exon-skipping programs in DMD addressing patients with genotypes amenable to skipping of exons 51, 45, 50 and 53. Eteplirsen is focusing on exon 51.
In the Phase 2b 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. (2 more patients discontinued the trial)
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 were excellent and their biomarker data mimics the standard outcome measure, the 6 minute walk test.
The small number of patients in the trial is no doubt problematic for the approval chances. However, the FDA may consider that Duchenne MD is an ultra-rare disease making it difficult to find patients, especially during the beginning of the rapid declining phase which is the only time suitable to determine in a statistically feasible way if a drug is working.
Also, there are many subtypes of Duchenne MD which means that the developers must study subgroups of an already ultra rare condition. 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.
It is difficult for a company to justify spending millions of dollars on preclinical and numerous clinical trials for almost the same drug. Especially, given the small number of patients. So Sarepta is seeking a simplified approval process from the FDA and it may get it.
Sarepta's eteplirsen is no cure, but it is the best news to come to DMD sufferers for a long, long time.
The study met its primary endpoint of increased novel dystrophin at week 48 as shown by muscle biopsy. The other measure is the six-minute walking test, which measures how far an individual can walk in six minutes time.
After 74 weeks the 6 boys who were treated with eteplirsen, still walked well and demonstrated less than 5 percent decline (13.4 meters) from their baseline in walking ability. During the whole trial the 6 boys showed a statistically significant treatment benefit of 65.2 meters when compared to the 4 boys who were on placebo.
The 4 boys on placebo in the first 24 weeks showed substantial declines on the 6-minute walk test. After 24 weeks, when they were switched over to the treatment group, their walking ability stabilized. In weeks 36 through 74, the period in which meaningful levels of dystrophin were likely produced in their body, they have declined less than 10 meters from their baseline.
Eteplirsen seeks to enable dystrophin production in DMD patients with a deletion in exon 51 by skipping exon 51 and restoring the reading frame. An exon-51 deletion is thought to be the most common deletion in DMD, afflicting approximately 13 percent of those who suffer from the genetic muscle wasting disease.
Eteplirsen is delivered systemically through IV infusion weekly. The drug has a short plasma half life, but once it gets into the cell and produces the protein, the protein has a longer half life. It's cleared through the kidney intact, no metabolites can be detected, so it's a very hearty compound that's cleared very efficiently.
The company is in a race with the rival DMD therapy drisapersen from the British giant GlaxoSmithKline (NYSE:GSK), which uses the same basic idea of exon-skipping. The drug has shown side effects: some DMD patients treated with drisapersen have been hospitalized due to kidney toxicity and low platelet counts.
Glaxo has larger number of patients in trials. A six-month, Phase 2 study of 54 patients is complete. A one-year, Phase 3 study of 180 patients is expected to have results ready for release in the fourth quarter of 2013. Due to side effects and efficacy, at this time, eteplirsen is considered to have an edge.
According to a recent article in Barron's, Sarepta's swelling stock price will either pop up or instantly deflate depending on the FDA's next move. The FDA may go for accelerated approval or demand a larger Phase 3 trial, and the difference between the two decisions: a stock price of $50 or the $20s.
DMD afflicts approximately 8,000 males in the US. Barron's is projecting a potential $500 million market in the US alone for Sarepta's drug, which would justify the investor's enthusiasm who have bid up the little company's shares by 281 percent over the past year.
Sarepta is headquartered in Cambridge, Massachusetts, and has about 120 employees. It is well capitalized, at the end of 2012 it had about $187 million in cash.
It has money coming in from the US government for two separate programs in the infectious disease arena: One is the Marburg hemorrhagic fever virus program for biodefense and the other is the Influenza program, funded by the Department of Defense and the National Institute of Health respectively.
Sareptas' DMD technology originally comes from the University of Western Australia (UWA). They have recently renewed their agreement granting Sarepta rights to UWA's patent portfolio in DMD and enabling the Company to build out its exon-skipping pipeline with new candidates based on the proprietary PMO (phosphorodiamidate morpholino oligomer) technology.
The current deal is an extension of the agreement first signed in 2008. The university is eligible to receive up to $7.1 million upfront and milestone payments, as well as low single-digit royalties on future sales.
Glaxo has licensed drisapersen from the privately held Dutch firm Prosensa.
Sareptas' new technologies now have a compelling proof of concept, both with the Duchenne program but also in the infectious disease programs. For example, primates were treated with Sarepta's drug for the Marburg hemorrhagic fever virus after four days of infection and showed a 100 percent survival at the end of treatment and 83 percent survival at the end of 40-day follow-up.
The company has a variety of new chemistries, established a strong patent protection around them and now looking for aggressive strategies to lock up the morpholino segment because it thinks it is the best available in the emerging RNA technology field.
In the past 52 week the share price ranged between $2.60 and $45.00. Technically speaking, SRPT has broken out of an uptrending channel, and appears to have little resistance up to $45.00. Some analysts warn however that the stock is approaching overbought territory.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.