Patient Death Results in FDA Hold on Pfizer Duchenne Muscular Dystrophy Gene Therapy Trial

Man with Duchenne muscular dystrophy sitting in a motorized wheelchair using power controller with degenerated hands

The Phase Ib trial assessing Pfizer’s mini-dystrophin gene therapy candidate PF-06939926 in Duchenne muscular dystrophy (DMD) was placed on hold by the FDA after the company acknowledged the death of a young male participant in the open-label study.

The study was designed to assess a single intravenous infusion of PF-06939926 in ambulatory and non-ambulatory subjects with DMD. The patient participated in the non-ambulatory cohort of the trial (NCT03362502), a first-in-human/first-in-patient, multi-center, non-randomized, ascending dose, safety and tolerability study.

“On behalf of everyone at Pfizer, we extend our sympathies to his family, friends and those closest to his care,” Pfizer stated. “At this time, we do not yet have complete information and are actively working with the trial site investigator to understand what happened.”

Pfizer said screening and dosing in the trial has been paused while the company reviews data with the study’s independent External Data Monitoring Committee.

“The safety and well-being of the patients in our clinical trial remains our top priority, and we are committed to sharing more information with the medical and patient community as soon as we can,” Pfizer promised.

PF-06939926, also known as fordadistrogene movaparvovec, is a recombinant adeno-associated virus, serotype 9 (AAV9) carrying a mini-dystrophin or truncated human dystrophin gene under the control of a muscle-specific promoter. The gene therapy is a mini-dystrophin because the human dystrophin gene is too large to fit in the AAV9 capsid.

Pfizer is among companies working to develop DMD gene therapies; others include Sarepta Therapeutics and Solid Biosciences.

“At minimum, we believe the resolution of this clinical hold will prevent Pfizer from completing enrollment of their Phase III study in 1Q22, as they have previously guided,” Brian P. Skorney, CFA, senior research analyst with Baird, wrote Monday in a research note.

Market “Sarepta’s to lose”

“Barring any larger scale fallout for AAV gene therapy, we believe the safety issues with Pfizer’s program, and the inevitable delay, make the DMD gene therapy market Sarepta’s to lose,” Skorney added.

Sarepta has long focused on DMD, bringing to FDA approval three antisense oligonucleotides for patients amenable to skipping specific exons. The three—EXONDYS 51 (eteplirsen), VYONDYS 53 (golodirsen), and AMONDYS 45 (Casimersen)—generated strong revenue during the third quarter for Sarpeta, which raised its revenue guidance for 2021 by about $70 million, to between $605 million and $615 million.

Also during Q3, Sarepta launched Part B of its MOMENTUM pivotal trial (SRP-5051-201; NCT04004065) for SRP-5051, the company’s next-generation peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) for exon 51 skip-amenable Duchenne patients; and EMBARK (SRP-9001-301; NCT05096221), a pivotal trial for SRP-9001, Sarepta’s micro-dystrophin gene therapy for Duchenne, being co-developed with Roche through an up-to-$2.85 billion collaboration.

Solid said last month it was planning to dose additional patients in the Phase I/II IGNITE DMD trial (NCT03368742) during Q4, with plans in early 2022 to report 90-day biopsy data from the first three patients dosed with SGT-001 manufactured with its improved process as well as long-term expression and functional data.

Solid reported positive 1.5-year data from IGNITE DMD in September at the World Muscle Society 2021 Virtual Congress and additional pulmonary function results from IGNITE DMD at the Child Neurology Society 50th Annual Meeting. Patients dosed with SGT-001 exhibited sustained benefit across all reported measures, the company said, over a period during which natural history has suggested a decline.

In its Phase I/II trial of PF-06939926, Pfizer dosed participants with 2×1014 vg/kg of Pfizer’s gene therapy. By contrast, the most recent death  of the four boys who died in Astellas Gene Therapies’ Phase I/II ASPIRO trial (NCT03199469) assessing its gene therapy AT132 for X-linked Myotubular Myopathy (XLMTM) received the lower dose of 1.3×1014 vg/kg—while the other three boys who died were dosed at 3.5×1014 vg/kg.

Safety concerns cited

The deaths tied to AT132 rekindled the discussion among researchers about safety concerns tied to dosing of gene therapies, particularly at higher doses.

“Recent concerns regarding immunogenic responses to high-dose intravenous administration of rAAV has highlighted the need for extensive analysis of the preparations in order to identify and catalog potentially immunogenic vector lot components,” three gene therapy experts wrote in an editorial published yesterday in Frontiers in Immunology.

The three experts were: José M. Martinez-Navio, PhD, associate scientist at University of Miami Miller School of Medicine; Nicole K. Paulk, PhD, assistant professor, University of California, San Francisco (UCSF); and Guangping Gao, PhD, Guangping Gao, PhD, the Penelope Booth Rockwell Professor in Biomedical Research at the University of Massachusetts Medical School, the director of the Horae Gene Therapy Center and Viral Vector Core, and the co-director of the Li Weibo Institute for Rare Diseases Research.

Gao is also deputy editor-in-chief, and Paulk, an editorial board member of Human Gene Therapy, a monthly peer-reviewed journal published by GEN publisher Mary Ann Liebert Inc., Publishers.

The Phase I/II trial is one of two clinical studies of PF-06939926. The other is a randomized, double-blind, placebo-controlled Phase III CIFFREO trial (NCT04281485) designed to evaluate the safety and efficacy of gene therapy in boys with DMD. Two thirds of the trial’s 99 participants will be assigned to the gene therapy, while the other one-third will be randomized to placebo until the start of the trial’s second year, when they will be able to receive treatment with the gene therapy.

In September following three “severe adverse events of muscle weakness, two of which involved myocarditis (inflammation of the heart tissue),” Pfizer amended the Phase III trial’s protocol. The company excluded individuals with mutations (exon deletion, exon duplication, insertion, or point mutation) affecting exons 9 through 13, inclusive, or a deletion that affects both exon 29 and exon 30.

“These mutations are estimated to represent less than 15% of patients with DMD,” Pfizer wrote in a September 28 letter to the DMD community.

Pfizer distributed its statement Monday as a letter to the community of DMD patients and family members—including Parent Project Muscular Dystrophy (PPMD), the nation’s nonprofit organization solely focused on DMD.

“It’s okay to rest, to take time; it’s necessary to reflect deeply and ask questions and check in with each other along the way,” Pat Furlong, PPMD’s founding president and CEO, wrote on Monday to the DMD community. “That, too, is part of the precious connection we share. To be able to lift one another while we climb so that we may continue onward together with resilience, courage, and hope. And we will move forward resolutely, thoughtfully, judiciously. We will be vigilant. We will seek answers. We will not ever give up our hope.”

“We must continue to invest in genetic therapies because of the science and possibilities, but we must do with blinders removed from our hearts and minds,” Furlong added. “We lift one another while we climb, even if we do so with heavy hearts and weary hands… we keep going forward.”

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