Sarepta’s DMD Gene Therapy Adcomm Likely To Focus On Dystrophin As A Surrogate Endpoint
Executive Summary
Cellular, Tissue and Gene Therapies Advisory Committee will weigh whether the increase in dystrophin production seen with SRP-9001 is reasonably likely to predict clinical benefit in Duchenne muscular dystrophy, Sarepta says; agency had previously told the company a panel meeting would not be needed, but it reversed course late in the review.
A US Food and Drug Administration advisory committee review of Sarepta Therapeutics, Inc.’s SRP-9001 (delandistrogene moxeparvovec) is expected to focus on whether the increase in dystrophin production seen with the gene therapy is reasonably likely to predict clinical benefit in Duchenne muscular dystrophy, the company said.
The decision to convene the public meeting also appears to reflect the agency’s interest in exploring the use of surrogate endpoints, biomarkers and accelerated approval for gene therapies, CEO Doug Ingram said.
The meeting, a date for which has not been announced, will present another opportunity for public debate on whether changes in dystrophin levels, and particularly the magnitude of those changes, are reasonably likely to predict clinical benefit in DMD.
It also will give the patient community another opportunity to mobilize behind approval of a first-in-class treatment for a devastating neurological disease.
Adcomm Ahead Of 29 May User Fee Date
Sarepta announced on 16 March that the Center for Biologics Evaluation and Research’s Office of Therapeutic Products has decided to convene an advisory committee meeting on SRP-9001 in advance of the 29 May user fee date.
SRP-9001 delivers a micro-dystrophin-encoding gene to muscle tissue using an AAV vector, spurring targeted production of the micro-dystrophin protein. The application is under priority review for accelerated approval.
“It is our understanding that safety has not been identified as a significant issue. The primary topics of the advisory committee will be the design of the 9001 construct and the evidence supporting the conclusion that 9001 dystrophin is reasonably likely to predict clinical benefit, which is of course the standard for accelerated approval.” – Sarepta’s Doug Ingram
The company learned of this decision at a late-cycle meeting and said it represented a change from the agency’s position communicated at the mid-cycle meeting that an advisory committee review was not needed. (Also see "No AdComm Puts Sarepta On Path To Blockbuster Success With Duchenne Gene Therapy" - Scrip, 1 Mar, 2023.)
In a same-day investor call, Ingram attributed the change in position, in part, to the recent reorganization of the Office of Tissues and Advanced Therapies into a new “super office” known as OTP. (Also see "CBER’s New Home For Gene Therapies: OTAT Changes To OTP But Leadership Questions Remain" - Pink Sheet, 27 Feb, 2023.)
“It is our understanding that this change in decision results from the following: OTAT has been reorganized and the super office OTP has been established. Dr. Peter Marks, the director of CBER, has publicly confirmed CBER and OTP intend – where appropriate – to explore the innovative use of surrogate endpoints, biomarkers and the accelerated approval pathway to advance cell and gene therapies, in particular for rare, life-ending degenerative diseases,” Ingram said.
“As the 9001 application is one of the first gene therapy BLAs founded on a surrogate endpoint, CBER and OTP believe it appropriate to take expert advice in a public forum,” Ingram said. “It is our understanding that safety has not been identified as a significant issue. The primary topics of the advisory committee will be the design of the 9001 construct and the evidence supporting the conclusion that 9001 dystrophin is reasonably likely to predict clinical benefit, which is of course the standard for accelerated approval.”
Panel Input ‘Critical’ To BLA Review
It is not clear how the OTAT-to-OTP reorg, which took effect in late February, may have impacted the decision to convene an advisory committee.
A Q&A about the reorg on CBER’s website states that OTP’s goal is to maintain review teams for existing applications throughout the reorganization. “However, the responsible offices and divisions, as well as the signatory authority responsible for existing applications, may change – this will be determined by several factors, including how far along the review of the application is at the time of the reorganization.”
CBER told the Pink Sheet it is committed to making safe and effective treatments available to patients who need them, and it views gene therapies intended to treat rare diseases as an excellent opportunity to expedite the delivery of potentially life-saving therapies to patients.
“We recognize the tremendous interest in Sarepta Therapeutics’ gene therapy to treat individuals with Duchenne muscular dystrophy,” CBER said.
During the FDA’s evaluation of the SRP-9001 BLA, “a determination was made late in the review process that input from the agency’s Cellular, Tissue and Gene Therapies Advisory Committee would be critical to this evaluation,” CBER said. “We have therefore worked expeditiously to schedule an advisory committee meeting, which will be announced in the Federal Register in the near future, in order to facilitate the evaluation of the safety and effectiveness of the product in a timely manner.”
Emotional Eteplirsen Adcomm
While this will be the second advisory committee review of an application for a Sarepta DMD treatment, the forthcoming meeting seems likely to present a different dynamic than the April 2016 meeting on the antisense oligonucleotide Exondys 51 (eteplirsen), which became the first FDA-approved treatment for DMD in a highly controversial regulatory action.
However, as with the eteplirsen meeting, the patient community can be expected to make a strong stand in favor of SRP-9001’s approval, although the emotional impact may be considerably less if the meeting is virtual, rather than in-person. The agency has yet to schedule an in-person advisory committee meeting since the COVID-19 pandemic was declared in March 2020.
The Peripheral and Central Nervous System Drugs Advisory Committee voted 7-6 that there was not substantial evidence from adequate and well-controlled studies that eteplirsen induces dystrophin production to a level that is reasonably likely to predict clinical benefit. The panel also voted 7-3, with three abstentions, that there was not substantial evidence that eteplirsen is effective as a Duchenne treatment.
The highly engaged DMD patient community mobilized for the advisory committee review. Hundreds of patients, parents and advocates were present at the Hyattsville, MD, conference center, so many that an overflow room was reserved for those who could not find seats. Cable TV and other national mainstream media outlets covered the event, which was unusual.
Dozens of people testified during the public hearing portion of the meeting, which lasted more than 2.5 hours. Most favored approval, which committee members admitted influenced their decision. The audience hissed when one person suggested the eteplirsen study was poorly designed and should not be the basis for clearance. And when the committee did not give a favorable recommendation that the evidence suggested efficacy, some shouted at the panel in disgust. (Also see "Patients Can't Rescue Sarepta's Eteplirsen" - Pink Sheet, 25 Apr, 2016.)
The meeting also was thought to be the first time a patient group was allowed to speak during the sponsor’s presentation. (Also see "Duchenne Group's Presentation Is Milestone For Patient Involvement" - Pink Sheet, 2 May, 2016.)
Advocates also seemed to run afoul of advisory committee protocol and common decency in pushing for the drug’s approval. Some sent advisory committee members information considered germane to the proceedings before the meeting, which was not allowed. Many agency staffers also received what were termed “vulgar” and abusive correspondence. (Also see "Eteplirsen Review Offers Lessons For FDA, Advocacy Groups, Industry" - Pink Sheet, 21 Sep, 2016.)
The eteplirsen advocacy campaign troubled the FDA and at the time could have damaged the agency’s relationship with patients. (Also see "Patient Advocacy With FDA Review Staff Will Be Tougher Post-Sarepta" - Pink Sheet, 23 Sep, 2016.)
Despite the negative advisory committee recommendation, eteplirsen was granted accelerated approval in September 2016 by Janet Woodcock, who at the time was the director of the Center for Drug Evaluation and Research. Woodcock overruled the views of the clinical review team and other center personnel in concluding that accelerated approval was warranted on the basis of a small but significant increase in dystrophin production. (Also see "Sarepta's Eteplirsen Approved After Contentious Internal FDA Debate" - Pink Sheet, 19 Sep, 2016.)
Interactions between Sarepta and Woodcock during eteplirsen’s review also stirred controversy, with the company asserting its financial health depended upon the drug’s approval. (Also see "Sarepta Complained To Woodcock About Exondys 51 Review Early And Often" - Pink Sheet, 6 Sep, 2017.)
Clinical Benefit Still Not Verified
Eteplirsen’s accelerated approval opened the door for three other drugs to reach market on basis of the same surrogate endpoint: Sarepta’s Vyondys 53 (golodirsen) and Amondys 45 (casimersen) and NS Pharma, Inc.’s Viltepso (viltolarsen).
However, clinical benefit has yet to be demonstrated for any of the four approved antisense oligonucleotides.
In addition to the internal agency disagreement on the adequacy of efficacy evidence for eteplirsen, the drug’s accelerated approval remains controversial because the confirmatory trial had not even been designed at the time of approval, and that study was many years delayed in getting off the ground.
The original projected completion date for the eteplirsen trial was May 2021. The study did not even start until July 2020, and the estimated completion date currently is November 2024, according to ClinicalTrials.gov.
The original projected completion date for the ESSENCE trial, which is to serve as confirmatory evidence for Vyondys and Amondys, was October 2024. That study appears to be running behind, with the estimated primary completion date listed as October 2025 in ClinicalTrials.gov.
The clinical trials database lists a primary completion date of November 2024 for the Viltepso confirmatory study, which is in-line with the original milestone target date for completion.
Fully Enrolled Confirmatory Trial
Sarepta appears to be coming into the SRP-9001 advisory committee much better positioned with regard to strength of the efficacy and biomarker data and the status of its confirmatory trial.
The BLA includes efficacy and safety data from three Phase I and II studies, as well as an integrated analysis across studies comparing functional results to a propensity-score-matched external control. Quantification of the SRP-9001-protein expression is measured by western blot and supported by immunofluorescence, and efficacy is further supported by biomarker and clinical functional benefit as measured by the North Star Ambulatory Assessment (NSAA) and secondary timed tests, Sarepta said.
Sarepta proposed the fully enrolled EMBARK study as the confirmatory trial. EMBARK is a global, randomized, double-blind, placebo-controlled clinical trial, and the primary endpoint is assessment of the change in NSAA total score from baseline to week 52. The trial is expected to read out in fall 2023.
Relitigating Dystrophin As ‘Reasonably Likely’
It is possible that CBER, which regulates gene therapy products, may hold a different view than CDER on whether dystrophin changes are reasonably likely to predict clinical benefit, or the magnitude of such changes to reach the reasonably likely threshold.
Leaders of both CBER and CDER previously have acknowledged there may be scientific disagreements or inconsistencies in advice between the two centers, especially in the rare disease setting, due to differences in the types of therapies that each regulates. (Also see "Product Differences Necessitate Some US FDA Inconsistency In Rare Diseases, Center Directors Say" - Pink Sheet, 8 Jul, 2022.)
“SRP-9001 leads to far more robust expression of similarly shortened dystrophin, although with a different genetic sequence. In addition, functional benefit was observed in patients across Sarepta's clinical development program.” – Needham’s Gil Blum
Nevertheless, challenges that eteplirsen raised with regard to quantum of evidence, robustness of effect and lack of a confirmatory trial plan may have helped smooth the path for SRP-9001.
Needham Co. analyst Gil Blum said that throughout Sarepta’s clinical program for SRP-9001, there has been a debate on the expected relationship between the biomarker micro-dystrophin and functional clinical benefit.
“It is worth remembering that exon-skipping drugs (Exondys, Vyondys, Amondys) do not result in full-length expression of dystrophin but in a truncated protein that includes key functional components. All three were approved based on surrogate endpoint of in vivo dystrophin expression,” Blum said. “SRP-9001 leads to far more robust expression of similarly shortened dystrophin, although with a different genetic sequence. In addition, functional benefit was observed in patients across Sarepta's clinical development program, despite noise in dosing.”
Furthermore, the clinical experience to date with Sarepta's commercial drugs “better supports the hypothesis of shortened dystrophin contributing to functional improvement than the data that was available in the original advisory committee for Exondys,” Blum said.
The advisory committee meeting on SRP-9001 is the second, high-profile panel review announced for the coming months that will involve issues of surrogate endpoints and unmet need in a devastating neurological disease.
The agency also is expected to convene the Peripheral and Central Nervous System Drugs Advisory Committee to consider Eisai Co., Ltd. and Biogen, Inc.’s application for regular approval of the Alzheimer’s drug Leqembi (lecanemab-irmb), which has a 6 July user fee date. The anti-amyloid antibody received accelerated approval in January on the basis of amyloid plaque reduction. (Also see "Transparency In Alzheimer’s: AdComm Expected On Regular Approval For Eisai/Biogen’s Leqembi" - Pink Sheet, 6 Mar, 2023.)