The CIFFREO trial (NCT04281485) of fordadistrogene movaparvovec, an investigational mini-dystrophin gene therapy for Duchenne muscular dystrophy (DMD) developed by Pfizer, did not meet its primary end point of motor function improvement vs placebo among boys aged 4 to 7 years, the company announced in a press release.1

Improvement in motor function among ambulatory patients, determined by change in North Star Ambulatory Assessment at 1 year post treatment, was the main end point in the study. There were also no significant improvements in key secondary end points, including 10-meter run or walk speed and time to rise from floor.

While the question of gene therapys long-term efficacy remains, it is a promising route of therapy for patients with DMD | Image credit: luchschenF - stock.adobe.com

We are extremely disappointed that these results did not demonstrate the relative improvement in motor function that we had hoped, Dan Levy, MD, PhD, development head for Duchenne muscular dystrophy at Pfizer, said in a statement. We plan to share more detailed results from the study at upcoming medical and patient advocacy meetings, with the goal of ensuring that learnings from this trial can help improve future clinical research and development of treatment options that can improve care for boys living with Duchenne muscular dystrophy. We are grateful for the boys, their families, advocates, and the investigators who have participated in this research and the continuing effort to advance treatment options for this debilitating disease.

While the overall safety profile of the treatment was largely manageable in the CIFFREO trial, the study has paused dosing in its crossover portion due to a fatal serious adverse event in the phase 2 DAYLIGHT trial (NCT05429372), a multicenter, single-arm study evaluating safety and dystrophin expression after treatment with fordadistrogene movaparvovec in boys aged 2 to less than 4 years.2 In a community letter, Pfizer announced the loss of the patient but was still working to understand the its cause at the time.3

In the CIFFREO trial, adverse events were generally mild to moderate, and serious treatment-related adverse events generally responded to clinical management.1

DMD, the most common form of muscular dystrophy in children, is characterized by muscle breakdown over time due to patients without a functional dystrophin gene.4 Patients with DMD produce little to no dystrophin, which is a crucial protein for muscle strength.

Gene therapy is a promising area of research for patients with DMD, with the goal being to stabilize the disease by inducing production of a shortened but functional version of dystrophin. Lost muscle cannot be brought back by gene therapy, so it is not a curative therapy, but gene therapies have demonstrated promise for symptom mitigation and even strength improvement among some children.

The first gene therapy for DMD was FDA approved in June 2023 for patients aged 4 through 5 years.5 Delandistrogene moxeparvovec-rokl (Elevidys) was approved through the FDAs accelerated approval pathway and remains the only approved gene therapy for this patient population. The treatment was given the green light based on data from a randomized trial establishing increased expression of micro-dystrophin protein in treated patients.

While the question of gene therapys long-term efficacy remains, it is a promising route of therapy for patients with DMD.4 Alternative approaches to delivery are also being studied, with an aim of better targeting the muscles that need dystrophin or producing versions of dystrophin that are more functional compared with current gene therapies.

References

1. Pfizer provides update on phase 3 study of investigational gene therapy for ambulatory boys with Duchenne muscular dystrophy. News release. Pfizer. June 12, 2024. Accessed June 19, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-phase-3-study-investigational-gene

2. Study of fordadistrogene movaparvovec in early stage Duchenne muscular dystrophy. ClinicalTrials.gov. Updated April 4, 2024. Accessed June 19, 2024. https://www.clinicaltrials.gov/study/NCT05429372

3. Update on Pfizers phase 2 gene therapy trial for Duchenne. Parent Project Muscular Dystrophy. May 7, 2024. Accessed June 19, 2024. https://www.parentprojectmd.org/update-on-pfizers-phase-2-gene-therapy-trial-for-duchenne/

4. Gene therapy for Duchenne muscular dystrophy. Childrens Hospital of Philadelphia. Accessed June 19, 2024. https://www.chop.edu/gene-therapy-duchenne-muscular-dystrophy

5. FDA approves first gene therapy for treatment of certain patients with Duchenne muscular dystrophy. News release. FDA. June 22, 2023. Accessed June 19, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy

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Phase 3 CIFFREO Trial of DMD Gene Therapy Misses Primary End Point - AJMC.com Managed Markets Network

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