Pfizer said today it will open its first U.S. sites for a global Phase III trial assessing its fordadistrogene movaparvovec (PF-06939926) in Duchenne muscular dystrophy (DMD) after the FDA lifted a clinical hold on the company’s investigational new drug (IND) application for the program, which was imposed in December 2021 after a patient died in a Phase Ib open-label study of the mini-dystrophin gene therapy candidate.

The global Phase III CIFFREO trial (NCT04281485), designed to evaluate the safety and efficacy of fordadistrogene movaparvovec in boys with DMD, has been ongoing in 11 countries. It was paused in August 2021 following three “severe adverse events of muscle weakness, two of which involved myocarditis (inflammation of the heart tissue),” Pfizer said at the time. The trial was resumed in November after a protocol amendment, before being paused again the following month after the patient death.

To date, regulators in Belgium, Canada, Spain, Taiwan, and the United Kingdom have approved the re-start of the Phase III trial, with additional global reviews ongoing. Pfizer anticipates that nearly all CIFFREO sites will open by the end of June.

“Pfizer is pleased to progress CIFFREO and is working as quickly as possible to activate trial sites as local regulatory and ethics approvals occur,” Brenda Cooperstone, Chief Development Officer, Rare Disease, Pfizer Global Product Development, said in a statement.

Shares of Pfizer inched up nearly 2% in trading today, to $50.55 from yesterday’s closing price of $49.74.

Competitive Landscape

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

On Wednesday, Solid said it concluded enrollment in its Phase I/II IGNITE DMD trial (NCT03368742) for SGT-001, and will continue monitoring dosed patients for five years post-treatment.

Solid also said Wednesday it will ramp up production of SGT-001 through a commercially scaled, transfection-based manufacturing process. Solid released positive two-year safety and efficacy data from the trials’ first three patients in the high dose (2E14 vg/kg) cohort in March showing improved motor function at two years post-infusion, as assessed by 6-Minute Walk Test (mean change from baseline of 16.0 meters) and North Star Ambulatory Assessment (mean change from baseline of -1.7 units), against expected natural history declines.

Solid added that it planned to advance SGT-003 toward an anticipated IND submission in early 2023. SGT-003 is a next generation adeno-associated virus (AAV) gene transfer therapy using a novel, internally-developed capsid with improved muscle-tropic properties. In preclinical studies, SGT-003 showed enhanced muscle tropism and microdystrophin expression.

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 a combined $612.4 million in net product revenue during 2021, up 34% year-over-year—including $178.7 million racked up during the fourth quarter, up 46% over Q4 2020.

Last year, 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.

“Given SRPT and PFE’s microdystrophin GTxs [gene therapies] are the only programs in pivotal-stage development, the lift of PFE’s clinical hold marks the start of a competitive threat to SRPT’s first-to-market opportunity,” Joseph P. Schwartz, a Senior Research Analyst at SVB Securities covering rare diseases, wrote today in a research note. “However, we believe SRPT has a good chance at maintaining their lead based on our Ph[ase] 3 timeline estimates for each program.”

“DMD GTx has been a long-time goal in the treatment landscape and we believe patient/parent enthusiasm and expectations for GTx are high,” Schwartz added. “We see first-to-market status as an important consideration for these programs given GTx is a one-time treatment.”

Schwartz projected that Sarepta would likely be first to complete Phase III enrollment this year and provide a topline readout followed by a biologics license application (BLA) filing in 2023. He laid out three possible scenarios for the timing of topline data: An optimistic or “bull” case of July 1, 2023; a middling or “base” case of August 1, 2023; and a pessimistic or “bear” case of September 1, 2023.

However, Sarepta and Pfizer will maintain timeframes that are relatively close, he predicted, adding that both companies are likely to generate topline data in the second half of 2023.

“Based on the potential proximity in timelines, we view the efficacy and safety profile of each program paramount for patient uptake and believe SRPT also has a leg up on PFE in this regard given SRP-9001 has shown fairly encouraging NSAA benefits vs. natural history and no major safety issues thus far,” Schwartz concluded.

Amended Protocol

The company first amended the Phase III protocol by excluding 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.

In December, Pfizer further amended the protocol to include a seven-day hospitalization period to enable close monitoring and management of patients following administration of gene therapy. That protocol amendment was implemented after Pfizer had acknowledged the death of a young male participant in the Phase Ib trial (NCT03362502), a first-in-human/first-in-patient, multi-center, non-randomized, ascending dose, safety and tolerability study.

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

“Like many non-ambulatory DMD patients, the participant had more advanced disease with underlying cardiac dysfunction,” Pfizer stated today.

During the clinical hold period, Pfizer said, it immediately paused screening, randomization and dosing in all studies of fordadistrogene movaparvovec as the independent external Data Monitoring Committee (eDMC) reviewed the data. Pfizer also addressed FDA questions related to the potency assay, in order to enable the trial to proceed in the U.S.

“Pfizer recognizes the significant unmet needs for new treatment options for non-ambulatory DMD patients. The company is continuing to work with the eDMC and gene therapy experts to assess potential next steps for evaluation of fordadistrogene movaparvovec in this patient population, who are more progressed in their disease,” the company stated.

Fordadistrogene movaparvovec is an investigational recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle-specific promotor. According to Pfizer, the AAV9 capsid has been chosen as the delivery mechanism because of its potential to target muscle tissue.

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