Abstract
Sarepta Therapeutics voluntarily and temporarily paused shipments of Elevidys® (delandistrogene moxeparvovec-rokl) following reports of patient deaths tied to the marketed gene therapy for Duchenne muscular dystrophy (DMD), then lifted the pause a week later when the death of a third Elevidys patient was found unrelated to treatment.
Sarepta initially refused a U.S. Food and Drug Administration (FDA) request on July 18 to pause Elevidys shipments for non-ambulant patients but reversed course 3 days later and agreed to do so voluntarily and temporarily.
“It is important for the patients we serve that Sarepta maintains a productive and positive working relationship with the FDA, and it became obvious that maintaining that productive working relationship required this temporary suspension while we address any questions that the FDA may have and complete the Elevidys label supplement process,” Sarepta CEO Douglas S. Ingram said. 1
Sarepta and the FDA have discussed in part the agency’s request that Elevidys’ label include a black box warning for acute liver failure and acute liver injury, a request that Sarepta has supported.
Shipments for non-ambulant patients have been halted since the death of a second Elevidys patient of undisclosed age, announced by Sarepta in June. Sarepta acknowledged the death of the first Elevidys patient, a 16-year-old young man, in March.
During the pause on shipments to ambulant patients, news emerged of a third and fourth patient death tied to Sarepta gene therapies. The third death was of a 51-year-old man treated not with Elevidys but with SRP-9004 (patidistrogene bexoparvovec), a gene therapy candidate, for limb-girdle muscular dystrophy (LGMD) Type 2D/R3, during the Phase I DISCOVERY trial (Study SRP-9004-102; NCT01976091).
Sarepta did not disclose the LGMD patient death on July 16 when it announced it would pause development of SRP-9004 and three of four other LGMD therapy candidates in its pipeline. The company still plans to submit a Biologics License Application in the second half of this year for its furthest-along LGMD candidate SRP-9003, a gene therapy designed to treat LGMD type 2E/R4. Sarepta disclosed the LGMD death through a statement emailed to news outlets.
The pause of LGMD therapy development was part of a restructuring of company operations that included eliminating about 500 jobs—approximately 36% of Sarepta’s workforce. Sarepta also said it would pivot much of its research and development toward therapies for five rare genetic diseases that were developed through its silent RNA platform and away from gene therapies such as Elevidys.
Sarepta’s fourth patient death emerged July 25 when the company announced that an 8-year-old boy in Brazil died in June after receiving Elevidys. The company insisted that the death was unrelated to treatment with the DMD gene therapy, citing a conclusion to that effect by Brazil’s National Health Surveillance Agency-Anvisa.
The FDA cited the finding of Brazilian authorities on July 28 when it lifted the pause on shipments of Elevidys to ambulant patients. “The patient community is an important voice, and the FDA will continue to listen to and respond to thoughts from the community impacted by DMD,” the agency stated. 2
A news report linked the agency’s about-face to support for Sarepta from conservative influencers in addition to patient advocates, who organized a petition on Change.org calling for reversal of the FDA’s pause on Elevidys shipments. The political backlash helped lead to the abrupt departure from the FDA on July 29 of Center for Biologics Evaluation and Research Director Vinayak (Vinay) Prasad, MD. 3
Elevidys is under review in Europe, where the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) on July 25 recommended against approval of the gene therapy. CHMP cited what it termed a lack of statistical significance in results from the company’s Phase III EMBARK trial (NCT05096221), where boys treated with Elevidys showed a 2.6-point improvement on the North Star Ambulatory Assessment scale 52 weeks post-treatment, versus a 1.9-point improvement in placebo patients.
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ROCKET CUTS WORKFORCE 30%, PRIORITIZES AAV CARDIOVASCULAR PROGRAMS, KRESLADI™
Rocket Pharmaceuticals said it will reduce its workforce approximately 30%—about 80 employees—through a restructuring and pipeline prioritization designed to maximize near-term value, extend its cash runway into the second quarter of 2027, and position the company for long-term growth.
Rocket said it will prioritize its adeno-associated virus (AAV) cardiovascular platform by strategically leveraging the platform to address monogenic cardiomyopathies with high unmet need. Rocket’s AAV pipeline consists of clinical programs in Danon disease, PKP2-associated arrhythmogenic cardiomyopathy (PKP2-ACM), and BAG3-associated dilated cardiomyopathy (BAG3-DCM).
The company’s Danon disease candidate RP-A501 had been under evaluation in a pivotal Phase II trial (NCT06092034) that was placed on clinical hold by the U.S. FDA in May, after a patient died in the study. The patient, whose age has not been disclosed, suffered an unexpected serious adverse event that involved clinical complications related to a capillary leak syndrome following dosing with RP-A501.
Rocket also said it plans to submit a response to the Complete Response Letter issued by the FDA in response to the company’s Biologics License Application (BLA) for KRESLADI™ (formerly RP-L201), a gene therapy designed to treat severe leukocyte adhesion deficiency-I.
“Our prioritization reflects a commitment to the programs with the most compelling near-term opportunities for patients and to setting a foundation for Rocket’s long-term growth and success,” Rocket Pharmaceuticals CEO Gaurav Shah, MD, said. 4
Rocket has estimated it will incur approximately $3.5 million in restructuring and restructuring-related charges in the second half of 2025 in connection with the job cuts. 5
Those reductions, plus other planned cost-saving initiatives, are expected to reduce Rocket’s 12-month operating expenses by nearly 25%. Rocket also said it anticipated that its existing cash resources—excluding any potential proceeds from a Priority Review Voucher that may be granted upon FDA approval of KRESLADI—will fund company operations into the second quarter of 2027.
As a result of the restructuring, Rocket added, it anticipates delays associated with its Pyruvate Kinase Deficiency (PKD; RP-L301) and Fanconi Anemia (FA; RP-L102) programs. The company no longer expects FDA approval of RP-L102 in 2026. Rocket said it continues to evaluate strategic options and expects to offer additional information when it reports second-quarter earnings.
Rocket finished the first quarter with cash, cash equivalents, and investments of $318.164 million.
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FDA ISSUES CRL RAISING CMC ISSUES FOR ULTRAGENYX MPS IIIA CANDIDATE
The U.S. FDA has held off approving Ultragenyx Pharmaceuticals’ Biologics License Application (BLA) for UX111 (ABO-102), an AAV gene therapy being developed as a treatment for patients with Sanfilippo syndrome type A (MPS IIIA).
Instead, the agency issued a Complete Response Letter (CRL) requesting that Ultragenyx provide additional information and improvements related to specific aspects of chemistry, manufacturing, and controls (CMC) and observations from recently completed manufacturing facility inspections.
The observations related to facilities and processes were not directly related to the quality of the product. Ultragenyx said it will work with the agency to resolve them. Once resolution is achieved, Ultragenyx said, it expects to resubmit the BLA, and it anticipates up to a 6-month review period to follow the resubmission.
“We have been diligently responding to the recent CMC observations, and our priority is to resolve them so that we can resubmit the BLA as soon as possible,” said Emil D. Kakkis, MD, PhD, Ultragenyx’s CEO and president. “We believe the CMC observations are readily addressable, and many have already been addressed. While the CRL will delay the potential approval of UX111 to 2026, we are working with urgency to respond and resubmit.” 6
According to Ultragenyx, the FDA has acknowledged that the neurodevelopmental outcome data provided to date were robust and the biomarker data provided additional supportive evidence. The CRL did not note any review issues related to the clinical data package nor clinical inspections and asked that updated clinical data from current patients be included in the resubmission.
UX111 is designed to address the underlying SGSH enzyme deficiency responsible for abnormal accumulation of heparan sulfate, a glycosaminoglycan, in the brain that results in progressive cell damage and neurodegeneration. UX111 is dosed in a one-time intravenous infusion using a self-complementary AAV9 vector to deliver a functional copy of the SGSH gene to cells.
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SANGAMO FABRY DISEASE THERAPY SHOWS POSITIVE TOPLINE RESULTS IN REGISTRATIONAL TRIAL
Sangamo Therapeutics said it intends to submit a BLA in 2026 for isaralgagene civaparvovec (ST-920) after the gene therapy candidate showed positive topline results in adults with Fabry disease in the registrational Phase I/II STAAR trial (NCT04046224).
Isaralgagene civaparvovec met the trial’s primary endpoint by demonstrating a positive mean annualized estimated glomerular filtration rate (eGFR) slope at 52 weeks across all dosed patients.
After a single dose of isaralgagene civoparvovec, a positive mean annualized eGFR slope of 1.965 mL/min/1.73m2/year at 52 weeks was seen across all 32 dosed patients in the study. A mean annualized eGFR slope of 1.747 mL/min/1.73m2/year was also observed for the 19 patients who achieved 104 weeks of follow-up.
Sangamo said the data will form the basis for an anticipated BLA submission under the U.S. FDA’s Accelerated Approval pathway as early as the first quarter of 2026.
According to Sangamo, the FDA had agreed previously that positive mean annualized eGFR would serve as an intermediate clinical endpoint under the Accelerated Approval pathway, as well as its primary basis of approval for isaralgagene civoparvovec.
Sangamo said it plans to compare the annualized mean eGFR slope of isaralgagene civaparvovec with approved treatments for Fabry disease through a meta-analysis of published studies, as recommended by the FDA.
STAAR enrolled male and female patients who were either on enzyme replacement therapy (ERT), were ERT pseudo-naïve (defined as having been off ERT for 6 or more months), or were ERT-naïve. The median age of patients enrolled in the study was 42, with a median duration of follow-up of 24 months. The longest-treated patient achieved 4.5 years of follow-up.
“We are thrilled to see these compelling topline STAAR study results, including the positive mean annualized eGFR slope at both 52 and 104 weeks, alongside notable improvements in a range of secondary endpoints. Said Nathalie Dubois-Stringfellow, PhD, Sangamo’s Chief Development Officer. “Taken together these data demonstrate the potential for a single dose of ST-920 to provide meaningful clinical benefits above current standards of care and to treat the underlying pathology of Fabry disease.” 7
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33 STATES, DC, PUERTO RICO JOIN CMS ACCESS MODEL FOR GENE THERAPIES
The Centers for Medicare & Medicaid Services (CMS) said 33 states, Washington, D.C., and Puerto Rico have agreed to join the agency’s new access model designed to deliver gene therapies as well as cell therapies for people covered by Medicaid who live with sickle cell disease.
The participating states, the District of Columbia, and the commonwealth represent approximately 84% of Medicaid beneficiaries with sickle cell disease.
The model, overseen by the CMS Innovation Center, marks the first time that the federal government has negotiated outcomes-based agreements with cell and gene therapy manufacturers on behalf of state Medicaid agencies. Under the model, participating states receive guaranteed discounts and rebates from participating cell and gene therapy manufacturers if the therapies fail to deliver on promised therapeutic benefits.
“This model has the potential to improve health outcomes for patients with sickle cell disease while also ensuring state and taxpayer dollars are being used more effectively,” said Abe Sutton, Director of the Innovation Center and CMS Deputy Director. 8
The federal government offers participants optional support of up to $9.55 million to help with implementation, outreach, and data tracking. Participants have the flexibility of starting between January 2025 and January 2026.
The 33 participating states are Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Illinois, Kansas, Kentucky, Louisiana, Maine, Maryland, Michigan, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, and Wisconsin.
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FDA GRANTS RMAT STATUS TO GENASCENCE OA GENE THERAPY
The U.S. FDA has granted its Regenerative Medicine Advanced Therapy (RMAT) designation to GNSC-001, a potential first-in-class gene therapy candidate being developed by Genascence to treat knee osteoarthritis (OA) by inhibiting interleukin 1 (IL-1).
GNSC-001 is a recombinant adeno-associated viral vector expressing an optimized human interleukin-1 receptor antagonist (IL-1Ra). GNSC-001 is designed to offer long-term, sustained inhibition of IL-1 following a single intra-articular injection into the affected joint.
“The FDA RMAT designation for GNSC-001 underscores the strength of the clinical data to date, recognizing its potential to transform the treatment paradigm for OA,” said Thomas Chalberg, PhD, Genascence founder and CEO. “With the RMAT designation for GNSC-001, we look forward to working closely with the FDA as we seek to accelerate late-stage clinical development of GNSC-001 so we can bring a new treatment option to people suffering from this incapacitating, disabling disease.” 9
GNSC-001 has been studied to date in two human clinical trials. One was a first-in-human Phase I study (NCT02790723) that applied a single-center, open-label, dose-escalation design in nine participants with knee OA.
The other is the Phase Ib DONATELLO trial (NCT05835895), a double-blind, placebo-controlled dose-ranging study designed to evaluate the safety, tolerability, and pharmacodynamics of a single intra-articular injection of GNSC-001 in patients with OA of the knee. DONATELLO—which has enrolled 67 participants at 10 centers across the U.S.—was supported by a nearly $12 million award from the California Institute for Regenerative Medicine (CLIN2-14265).
The FDA granted its Fast Track designation to GNSC-001 in the fourth quarter of 2024. Earlier this year, Genascence completed a successful meeting with the FDA on the design of a Phase IIb/III trial of GNSC-001 focused on clinical efficacy. Genascence plans to initiate the Phase IIb/III trial in 2026.