UPDATED: FDA Panel Casts Some Doubt on DMD Drug Eteplirsen’s Accelerated Approval

UPDATE: Since this story was filed, Reuters news service is reporting that even more quickly than we had anticipated was likely, the expert panel convened by the FDA this week to review clinical trial data pertaining to Sarepta’s Duchenne Muscular Dystrophy (DMD) drug candidate Eteplirsen has denied its being granted accelerated approval. Reuters notes that only five of the 13 panelists were convinced that Sarepta had produced persuasive evidence that Eteplirsen helps increase levels of the the muscle protein dystrophin to a point likely to provide clinical benefit, and seven panelists voted that Sarepta has failed provide substantial evidence that Eteplirsen is effective for treating DMD.

A daylong, controversial meeting Monday, April 25th of a U.S. FDA advisory panel about eteplirsen, a drug candidate for Duchenne muscular dystrophy (DMD) under development by Sarepta Therapeutics, could mean the difference between accelerated approval of the drug — or not.

But the decision won’t come Monday. The FDA will weigh all the facts, and has until May 26 to make a final decision on whether to grant Sarapta’s application for accelerated approval.

Eteplirsen, the investigational drug currently in clinical trials by Cambridge, Massachusetts-based Sarepta, is designed for treatment of some mutations that cause Duchenne MD, a devastating genetic degenerative muscle disease that afflicts roughly 1 in every 3,600 boys born in the U.S.

DMD is caused by a defective gene that inhibits production of the muscle protein dystrophin that plays a key structural role in muscle fiber function. In healthy muscle, dystrophin interacts with other proteins at the cell membrane to stabilize and protect the cell during regular activity involving muscle contraction and relaxation.

Boys and young men with DMD produce little or no dystrophin in their muscles, the lack of which causes the regenerative potential of dystrophic muscle fibers to diminish over time. Without dystrophin, normal activity causes excessive damage to muscle cells, and they are ultimately replaced by fibrotic tissue and fat, leading to a progressive loss of function.

Loss of muscle mass results in most DMD patients being confined to wheelchairs by their early teenage years. They progressively lose the ability to independently perform the activities of daily living such as using the bathroom, bathing, and feeding themselves, and eventually require breathing and feeding tubes in later stages. Duchenne eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. It is currently an incurable terminal disease, with death resulting from cardiac or respiratory failure.

Although the molecular defect responsible for DMD was identified 20 years ago, there are currently no approved therapies for DMD in the U.S., with treatment generally aimed at controlling the onset of symptoms and maximizing quality of life. The outpatient cost of care is very high for boys who are non-ambulatory.

If approved by the U.S. Food and Drug Administration (FDA), eteplirsen, Sarepta’s lead product candidate, would be the first drug approved for treating DMD that addresses the disease’s genetic cause. Eteplirsen is designed to skip an exon — exon 51 — in the dystrophin pre-m RNA in order to enable synthesis of a functional shorter form of the dystrophin protein. Candidates for exon 53-skipping (SRP-4053) and for exon 45-skipping (SRP-4045) are in clinical development, with other drug candidates designed to skip exons 44, 52, 50, 43, 55, 8, and 35 in discovery and preclinical development.

Sarepta notes that about 13 percent of DMD patients may be amenable to exon 51 skipping, with available data suggesting that up to 80 percent of DMD patients have genotypes amenable to exon skipping, and it is proposed that in such patients, skipping of exon 51 might restore the reading frame of dystrophin, increase the production of dystrophin, and lead to a clinical benefit.

Sarepta began dosing in a confirmatory etoplirsen study in the third quarter of 2014; it subsequently opened additional trials in younger and older boys living with Duchenne. The main objective of  “Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI)” (ClinicalTrials.gov identifier: NCT02255552), which is currently recruiting participants, is to provide confirmatory evidence of the efficacy of Eteplirsen (AVI-4658) in Duchenne muscular dystrophy patients who are amenable to skipping exon 51.

Additional objectives include evaluation of safety, biomarkers, and the long-term effects of eteplirsen up to 96 weeks. The open-label, multi-center, non-randomized, efficacy study is being conducted at approximately 39 planned sites in the U.S.

The FDA announcement that the agency will convene a panel of independent experts this week to review Sarepta’s data on eteplirsen and advise the agency as to whether the evidence supports accelerated approval of the drug is casting some doubt as to whether FDA approval will be granted.

This news caused Sarepta’s stock to tumble late last week.

Sarepta has been in discussion with the FDA since November 2013, when the agency ruled that accelerated approval for eteplirsen was premature. Sarepta then participated in several meetings with the FDA to discuss a path forward for eteplirsen, and based on these discussions, formal guidance was outlined, with the agency ruling that with additional data to support eteplirsen’s efficacy and safety for treatment of DMD, Sarepta should be able to file a New Drug Application (NDA).

The federal regulatory agency says it provided clear guidance on an open-label, historically controlled confirmatory study of eteplirsen, as well as initial guidance on a placebo-controlled study of one or more follow-on exon-skipping compounds.

In a statement, the FDA said it recognizes the unmet medical need in Duchenne muscular dystrophy (DMD), the devastating nature of the disease for patients and their families, and the urgency to make new treatments available. The agency says it remains committed to working with companies to expedite development and approval of safe and effective drugs to treat DMD, and that over the past several years, it has worked extensively with Sarepta on the development of eteplirsen, providing guidance to the type of data and analysis necessary to determine whether it is effective, and to support the filing of an NDA.

The FDA says it understands the considerable disappointment in the Duchenne community that an initially estimated time frame for submitting the NDA for eteplirsen could not be met.

The FDA explains that in its advice to Sarepta, the agency has consistently stated it would be necessary to include data in its NDA demonstrating that eteplirsen increases production of dystrophin — the missing protein that lubricates muscles in DMD patients. Also, the need for additional data and analyses to support the NDA was reinforced by an FDA inspection of the clinical site where dystrophin analyses had been conducted.

The FDA adds it is important to note that the agency did not find any evidence of fraud at this site, as has been perceived by some, but was concerned that methods used to measure dystrophin were not adequately robust to support an NDA submission.

As a result, FDA provided Sarepta with detailed recommendations on how to improve these dystrophin analyses, and said it has been consistent in its guidance to Sarepta that it would be necessary to submit data from the ongoing open-label trial of eteplirsen (Study 202) in an NDA, along with data from natural history studies that could show that patients treated with eteplirsen experienced slower decline in physical function.

The FDA says it has worked closely with Sarepta in efforts to obtain these natural history data from investigators, consistently advising Sarepta that data from additional patients, beyond the patients included in Study 202, would be critical to the agency’s assessment of the safety and efficacy of eteplirsen.

The FDA briefing notes that the Advisory Committee meeting was initially scheduled to take place on Jan. 22, but had to be rescheduled due to a weather emergency, and that since the initial FDA briefing materials were released, Sarepta has submitted additional information about clinical outcomes of patients in Study 201/202, and also made public an addendum to its briefing materials — where Sarepta describes what it calls “key inaccuracies” in the briefing document FDA released in advance of the original January meeting of the Advisory Committee.

In its original briefing document, “Peripheral and Central Nervous System Drugs Advisory Committee Meeting released January 22, 2016,“ the FDA explains that in order to support marketing approval, safety of a drug must be supported by an adequate number and duration of patient exposures to characterize any potential risks, although drugs shown to provide an important benefit would generally need less safety data to provide adequate assurance that risks are commensurate with benefits.

The agency says it recognizes that persons affected by life-threatening and severely disabling illnesses with unmet medical needs are generally willing to accept greater risks and greater uncertainty about risks. Consequently, a single highly persuasive positive trial combined with independent findings that substantiate efficacy might support approval, but the FDA adds that it is critical that the possibility of an incorrect outcome be considered and that all available data be examined for the potential to either support or undercut reliance on a single trial, and the characteristics of a single adequate and well-controlled study could support an effectiveness claim.

In the case of eteplirsen, factors should be considered in assessing whether Study 201/202 as a single study could be sufficient to support approval.

The FDA reiterates that Duchenne MD is a rare and serious disease without approved treatments, and says it has long stressed that it is appropriate to exercise the broadest flexibility in applying the statutory standards to drugs for such diseases, while preserving appropriate guarantees for effectiveness and safety. It notes that the accelerated approval program is designed to treat a serious or life-threatening disease if it is found that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit — or on a clinical endpoint that that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. This would take into account the severity, rarity, or prevalence of the condition and the lack of alternative treatments.

The document goes on to explain that two potential pathways to accelerated approval were discussed with Sarepta during the eteplirsen development program:

One would be using clinical data from Study 201/202 on six-minute walk distance as an intermediate clinical endpoint that could have the potential to support accelerated approval. The FDA says under that approach, basis for accelerated approval would be a conclusion that Eteplirsen reduced the rate of decline of walking performance to an extent that is reasonably likely to predict a long-term beneficial effect on irreversible morbidity or mortality.

However, they say Study 201 “clearly failed to show an advantage of eteplirsen over placebo on 6-minute walk distance in the placebo-controlled trial, noting that the specific finding proposed by Sarepta as supporting accelerated approval is the comparison of 6-minute walk distance between the 12 patients in Study 201/202 and historical controls, where the control patients were selected post hoc.”

The FDA explains there are significant concerns regarding the ability to draw valid conclusions from this historically controlled comparison, and that comparisons between patients in Study 201/202 and patients in a related development program who had received placebo suggest that the change in 6-minute walk distance with eteplirsen was consistent with the natural history of the disease.

An alternate route to accelerated approval would be using dystrophin data as a surrogate endpoint to support accelerated approval. The FDA indicated in its DMD guidance that biomarkers that reliably reflect the health and amount of skeletal muscle may, if supported by sufficient scientific evidence, be used as surrogate endpoints to support accelerated approval of a new DMD drug.

While the FDA says it is prepared to be flexible with respect to a devastating illness with no treatment options, it cannot approve drugs for which substantial evidence of effectiveness has not been established, and that it does not agree with Sarepta’s characterization of inaccuracies in the initial FDA briefing document. The FDA explains that eteplirsen’s intended mechanism of action is the removal of exon 51 of the premessenger ribonucleic acid (RNA), thereby restoring the messenger RNA reading frame — a shift that would enable production of a truncated form of the dystrophin protein, and by increasing the quantity of an abnormal but potentially functional dystrophin protein, the objective is to slow or prevent the progression of DMD.

However, the FDA observes that the clinical course of eteplirsen patients over more than three years of treatment has been generally similar to the expected natural history of patients provided with intensive supportive care, and that NSAA results, potentially representing a more direct measure of strength, suggest that differences in DMD progression between eteplirsen patients and Sarepta’s natural history controls were too small and variable.

Regarding future efficacy studies, any beneficial effects of eteplirsen are unlikely to be large enough to be detectable outside of a placebo-controlled trial, FDA said, although dose-limiting toxicity was not observed, so higher doses of eteplirsen, with potentially greater likelihood of efficacy, could be studied in the future.

None of which looks like a likely speedy approval for eteplirsen. An official decision by the FDA is scheduled on or before May 26.