Sarepta Therapeutics, Inc. , a biopharmaceutical company focused on developing innovative RNA-based therapeutics, has announced a pre-New Drug Application (NDA) meeting with the U.S. Food and Drug Administration (FDA) pertaining to its lead product candidate eteplirsen — a Duchenne muscular dystrophy (DMD) treatment. Sarepta and the agency are agreed on Sarepta’s initiation of a rolling NDA submission for eteplirsen (AKA AVI-4658) and the company is to submit the non-clinical and CMC components of the NDA by the end of this week. As previously announced, Sarepta is currently primarily focused on rapidly advancing the development of its potentially disease-modifying DMD drug candidates, including eteplirsen, the final NDA component of which will be submitted by mid-year 2015.
“We will initiate a rolling NDA submission to facilitate the regulatory review of the NDA,” said Edward Kaye, M.D., Sarepta’s interim chief executive officer and chief medical officer in a release. “The initiation of our NDA submission for eteplirsen marks a significant milestone for the Duchenne community and we look forward to completing the submission by the middle of the year and to continuing to work with the Agency towards the goal of providing treatments to patients as quickly as possible.”
Eteplirsen/AVI-4658, currently in clinical trials, is designed for treatment of some mutations that cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease that afflicts roughly 1 in every 3,600 boys born in the United States.
Persons afflicted will usually experience progressively more severe muscle weakness which will eventually confine them to a wheelchair in early adolescence and lead ultimately to full paralysis. The disorder is caused by mutated dystrophin genes, which encode the dystrophin protein whose function is to connect muscle fibers to surrounding external matrixes thereby preventing injury. Duchenne muscular dystrophy sufferers are nearly always boys because of the dystrophin gene’s being located on the X chromosome. A girl would need to inherit two faulty dystrophin gene copies, highly improbable because male carriers often die in early adulthood.
Sarepta has been in discussion with the regulatory agency since November 2013 when the FDA ruled that accelerated approval for eteplirsen was premature. Since the end of last year, Sarepta participated in several meetings with the FDA to discuss the 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 of for treatment of DMD, an NDA should be fileable. Furthermore, the regulatory agency 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.
Sarepta Therapeutics began dosing in the confirmatory eteplirsen study in the third quarter of 2014; and has been opening additional trials in younger and older boys living with Duchenne.
The main objective of “The 48-Week Study With a Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy“ confirmatory study in DMD Patients (PROMOVI – ClinicalTrials.gov identifier: NCT02255552) is to provide confirmatory evidence of efficacy of eteplirsen (AVI-4658) in Duchenne muscular dystrophy (DMD) patients that are amenable to skipping exon 51. Additional objectives include evaluation of safety and biomarkers.
The open-label, multi-center, non-randomized, efficacy study to evaluate the efficacy and safety of eteplirsen in patients with genotypically confirmed Duchenne muscular dystrophy (DMD) is being conducted at approximately 39 planned sites in the U.S. Sites will vary in the following functions:
• Local Site (N=39) – Enrolls patients and is the primary contact point for their patients. Sites will perform all protocol activities (including dosing and laboratory assessments), except for functional assessments and biopsies.
• Hub Site (N=14) – Performs functional (physical) assessments at specified times per protocol.
• Surgical Site (N=2) – Performs muscle biopsies for the Treated group.
Eligible for participation in the study are males aged seven years to 16 years, diagnosed with DMD, genotypically confirmed and on a stable dose of corticosteroids for at least six months with intact right and left alternative upper muscle groups and a mean 6MWT greater than 300m (primary analysis on 300 to 450 meters), stable pulmonary and cardiac function: and predicted FVC equal to or greater than 50% and LVEF of greater than 50%
Exclusion Criteria include previous treatment with drisapersen within the last 6 months, participation in any other DMD interventional clinical study within 12 weeks, major surgery within three months, presence of other clinically significant illness, and major change in the physical therapy regime within three months.
Estimated Enrollment will be 160 subjects with an Estimated Study Completion Date of August 2016, and an Estimated Primary Completion Date of May 2016 (Final data collection date for primary outcome measure).
Primary outcome measures are change in 6-Minute Walk Test (6MWT) distance from baseline [ Time Frame: Baseline, Weeks 12, 24, 36, 48 ] [ Designated as safety issue: No ]; and secondary outcome measures are the percentage of dystrophin-positive fibers [ Time Frame: Baseline, Weeks 24/48/TBD ] [ Designated as safety issue: No ], and Maximum inspiratory/expiratory pressure percent predicted (MIP/MEP % predicted) [ Time Frame: Baseline, Weeks 12, 24, 36, 48 ] [ Designated as safety issue: No ]
Patients in the treated group will receive once weekly intravenous (IV) infusions of 30 mg/kg Eteplirsen. Patients in the untreated group will not receive treatment.
Clinical efficacy will be assessed at regularly scheduled study visits, including functional tests such as the six minute walk test. Patients in the treated group will undergo a muscle biopsy at Baseline and a second muscle biopsy over the course of the study. Patients in the untreated group will not undergo muscle biopsy.
Safety, including adverse event monitoring and routine laboratory assessments, will be continuously monitored for all patients.
In a statement, the FDA says 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 all companies to expedite development and approval of safe and effective drugs to treat this disease, and that over the past several years, the FDA has worked extensively with Sarepta on development of eteplirsen, and provided guidance with respect to the data that would be necessary to determine whether it is effective and support filing of an NDA.
The FDA says it has been working intensively to help Sarepta provide the additional data and analyses needed to support an NDA, and that the agency understands the considerable disappointment in the Duchenne community following Sarepta’s October 27, 2014 announcement that the previous 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 the muscle protein dystrophin. (eteplirsen’s proposed mechanism of action is through increasing production of this muscle protein), and that 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 that 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. Thus, FDA provided Sarepta with detailed recommendations on how to improve these dystrophin analyses.
The FDA states that it has also 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, and 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 Administration has expressed willingness to conduct a rolling review of Sarepta’s NDA. Under a rolling review, companies can submit, and FDA can review, portions of an application as they are completed. Once submission of all components is complete, the review clock begins, the FDA expects the NDA for eteplirsen will qualify for a priority review.
Presenting the NDA for eteplirsen to a public advisory committee meeting before making a decision on approval will afford FDA the ability to gain advice from outside experts and interested stakeholders on the adequacy of the data to support approval, including the possibility of accelerated approval a mechanism to approve drugs in particular situations prior to the availability of definitive evidence of effectiveness.
The FDA says it understands the dire urgency of the situation, that the importance of the agency’s actions to the DMD community, and it will continue to work with Sarepta in their efforts to provide the data it considers critical to FDA’s ability to review the NDA and reach a decision on approvability.
On March 31, 2015 Sarepta Therapeutics announced the appointment of Edward Kaye, M.D., the company’s Chief Medical Officer (CMO), as interim Chief Executive Officer (CEO) effective immediately, replacing Christopher Garabedian, who resigned as President and Chief Executive Officer and as a member of the Board, also effective immediately. Dr. Kaye will continue in a dual capacity as CEO and CMO while the company conducts a search for a new full-time CEO, and will focus his efforts on heading the regulatory and clinical process for getting eteplirsen approved.
Sarepta Therapeutics, Inc.
U.S. Food and Drug Administration