November 6, 2012 10:23 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Sarepta Therapeutics’ (NASDAQ:SRPT) eteplirsen faces low prospects of attaining accelerated US approval in Duchenne’s muscular dystrophy (DMD) based on a mid-stage trial, experts and patient advocacy leaders told BioPharm Insight. Despite encouraging results, a larger trial is necessary to fully determine its therapeutic benefit, they explained.
Some experts noted the drug’s benign safety profile may be convincing enough for regulators to grant approval on a conditional basis in light of poor therapeutic options for DMD patients.
DMD afflicts approximately 8,000 males in the US. Because it is caused by a mutation on the X-chromosome, males are more likely than females to exhibit symptoms, which include muscle weakening and degeneration. Females can be “carriers” of the disease. Symptoms can manifest in boys between three to five years, with many requiring a wheelchair by age seven to 12.
The absence of the protein dystrophin, which plays a role in keeping muscle cells intact, results in DMD symptoms. Dystrophin is absent in these patients because sequences of DNA, known as an exons, are deleted, preventing the dystrophin gene from being read and the protein being produced.
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% of those who suffer from the genetic muscle wasting disease.
The FDA would consider granting accelerated approval without the requisite large-scale Phase III trial when a drug treating serious, life-threatening conditions shows great promise in earlier testing.
Accelerated approval for eteplirsen could be granted based on data showing the drug effectively produced dystrophin protein in the Phase IIb trial, according to Sarepta CEO Chris Garabedian. Several experts countered the key factor for accelerated approval would be how well patients faired on the six-minute walk test (6MWT), which measures how far an individual can walk in six minutes time.
Sarepta plans to meet with the US Food and Drug Administration (FDA) early next year to discuss eteplirsen’s fastest approval pathway, said Garabedian. The company will decide whether to file for approval before conducting a Phase III program after the FDA meeting, the CEO added. The company is not suggesting it is currently pushing hard for accelerated approval, he reiterated.
Small sample size problematic
On 3 October, the company announced eteplirsen 50mg/kg, given to four patients, yielded an increase from baseline at the end of a 48-week treatment period of 21 meters in distance walked on the 6MWT, while the two patients in the 30mg/kg cohort demonstrated a loss of 31.5 meters from baseline. Additionally, four patients received placebo for 24 weeks, with two patients then getting 50mg/kg for 24 weeks and the other two receiving 30mg/kg for 24 weeks; these individuals demonstrated a 68.4 meter decline from baseline over the 48 weeks.
The 48-week data is seen as difficult to interpret considering the small patient cohort coupled with the high variation in both the 6MWT and muscle biopsy data, experts added. Phase IIb is preliminary and only establishes proof-of-principle, said Marita Pohlschmidt, director of research, Muscular Dystrophy Campaign, London. A larger Phase III trial with a true placebo group is needed to demonstrate clinical efficacy, she added.
Pohlschmidt would be surprised if accelerated or conditional approval is granted based on the Phase IIb data considering the small sample size. She pointed to GlaxoSmithKline (NYSE:GSK) and Prosensa’s 180-patient placebo-controlled Phase III trial with their DMD drug candidate, drisapersen (GSK2402968/PRO051).
Sarepta is currently planning to begin enrollment late 2013 and dosing early 2014 for a confirmatory trial, Garabedian said.
While the small cohort size is a problem, the stabilization effect seen in the Phase IIb results is “so compelling,” said Steve Wilton, professor, Centre for Neuromuscular and Neurological Disorders, University of Western Australia. He is optimistic for accelerated approval as boys with DMD get progressively sicker at substantial rates.
Eteplirsen demonstrated disease stabilization, which is as good as what one could have hoped for, agreed Dr Sanjay Bidichandani, vice president, research, Muscular Dystrophy Association (MDA), a nonprofit health agency. However, the 21.0 meter improvement could have been a “blip” considering the variability of the 6MWT, he added.
Pohlschmidt added while the pooled Phase IIb results are encouraging, individual data is important because each boy responds to the therapy differently. Without this individual data, it creates false hope to patients, she said. Sarepta previously guided it does not plan to release individual data.
Accelerated or conditional approval is likely to be a challenge, indicated Bidichandani. The small trial size is likely to be met with skepticism, he said.
Dystrophin not seen as sufficient for accelerated approval
In terms of using dystrophin production to judge how well the drug is doing, Bidichandani said the FDA is likely to consider the complimentary relationship between dystrophin-positive fiber response and 6MWT. The former by itself would not be enough and the latter alone would have required some explaining, he said.
The 50mg/kg eteplirsen demonstrated a 41.7% mean change from baseline in percent of dystrophin-positive fibers, while 30mg/kg demonstrated a 52.1% change, according to a company press release.
Phase II Principal Investigator Dr Jerry Mendell, Nationwide Children’s Hospital, Columbus, Ohio, agreed that from his experience, functional data like 6MWT is critical for accelerated approval, not biomarker data like dystrophin production alone. He declined to provide an opinion on whether accelerated approval is warranted or not.
Humanitarian access on a conditional basis is typically granted for therapeutics that treat ailments that afflict only 10 to 20 patients in the world, which is not the case with DMD, Bidichandani said . Such approval is also granted for rapidly progressing conditions that result in death in one to two years, but DMD is not as drastic, he added.
Additionally, the dystrophin data is unreliable as a muscle biopsy is only a small snapshot of a single muscle, not representative of the whole, Pohlschmidt said.
Matthew Wood, professor of Neuroscience, University of Oxford, said he would be astonished if eteplirsen is granted accelerated approval based on the Phase IIb data. If approval is granted, he noted, it would be on the basis of poor therapeutic options and because eteplirsen appears largely safe.
Sharon Hesterlee, senior director of Research, Parent Project Muscular Dystrophy, added the FDA is cognizant that there is no good therapeutic intervention for DMD, therefore a drug as safe as eteplirsen would be worthwhile.
Corticosteroids such as prednisone serve as the only currently available therapeutic option for DMD.
Sarepta’s current market cap is USD 540.7m.
For more information or to inquire about a trial please email firstname.lastname@example.org or call Americas: +1 212-500-1384 or Europe: 44 (0)20 7059 6202
Copyright The Financial Times Limited 2017. You may share using our article tools.
Please don't cut articles from FT.com and redistribute by email or post to the web.