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Improved Function Observed Following Mini-Dystrophin Gene Therapy in DMD

Study sponsor Pfizer recently announced the launch of a phase 3 trial in patients with Duchenne muscular dystrophy.

One-year data from an early phase clinical trial (NCT03362502) in ambulatory patients with Duchenne muscular dystrophy (DMD) showed acceptable safety and good, increasing expression of mini-dystrophin, with trends toward functional improvement following treatment with fordadistrogenemovaparvovec (Pfizer).1

The findings were presented by Russell J. Butterfield, MD, of the University of Utah School of Medicine, at the 2022 American Society of Gene and Cell Therapy Annual Meeting, taking place May 16-19, 2022 in Washington, DC.

The investigational gene replacement therapy was previously the subject of a clinical hold placed by the FDA following a fatal serious adverse event in a nonambulatory participant in December 2021. Following the event, THE FDA completed data and protocol amendment reviews and received more information from Pfizer regarding the potency assay.

The clinical hold on the investigational new drug application was lifted in late April 2022, paving the way for Pfizer to restart its global phase 3 clinical trial (CIFFREO; NCT04281485) of the treatment now with a protocol amendment that includes a 7-day hospitalization period for close monitoring following administration of the therapy.2

Among the ambulatory cohort in the phase 1b trial, 19 participants (median age, 8.8 years) with a baseline median North Star Ambulatory Assessment (NSAA) total score of 27 who were on a stable, daily corticosteroid regimen received a single intravenous infusion of fordadistrogenemovaparvovec (n=3 low-dose; n=16 high-dose).

Three treatment-related adverse events were reported: dehydration, acute kidney injury, and thrombocytopenia, all of which resolved within 15 days. Among those in the high-dose group, mean dystrophin/mini-dystrophin levels were 22% and 40% of normal at 2 and 12-month follow-up, respectively, as measured by liquid chromatography-mass spectrometry. In addition, dystrophin-positive fibers, as measured with immunofluorescence, were 39% and 62% at 2 and 12 months follow-up.

Compared with an external placebo cohort (N=66), who were matched in age, weight, baseline function, and steroid use, a trend towards functional improvement was observed at 1-year post-dosing, including a median 1-point improvement on NSAA compared with a 4-point decline in the control group (P <.005). Other functional end point observations were a median 1-point decline in the treatment group compared with a 23-point decline in the control group on 6 minute walking distance; .02 decline in 4 stair climb velocity compared with a .06 decline in controls; and a median 6-point improvement in percent predicted forced vital capacity in the treatment group compared with a 1.4-point decline in controls.

The findings support the advancement of the program into phase 3, for which Pfizer recently announced that it plans to open its US sites, in line with the go-ahead received from other regulatory authorities in the United Kingdom, Canada, Taiwan, Spain, and Belgium, with nearly all sites of the CIFFREO clinical trial open by the end of June 2022.

1. Butterfield RJ, Shieh PB, Yong F, et al. Results of One Year Follow-Up After Treatment WithFordadistrogeneMovaparvovec (PF-06939926) for Duchenne Muscular Dystrophy (DMD) in A Phase 1b, Open-label Study. Presented at: 2022 American Society of Gene and Cell Therapy Annual Meeting; May 16-19, 2022; Washington, DC. LB 8.
2. Pfizer to Open First U.S. Sites in Phase 3 Trial of Investigational Gene Therapy for Ambulatory Patients with Duchenne Muscular Dystrophy. Pfizer news release. April 28, 2022. Accessed April 28, 2022. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-open-first-us-sites-phase-3-trial-investigational