On December 29, Vall d'Hebron became the first center in the world to include a patient (a 5-year-old boy) in the Pfizer phase 3 gene therapy clinical trial for Duchenne muscular dystrophy. The CIFFREO study will evaluate the efficacy and safety of PF-06939926 (the aforementioned gene therapy) in children with Duchenne muscular dystrophy. CIFFREO is a global, multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial. It is planned to recruit 99 male pediatric patients aged 4 to 7 years, in 55 centers in 15 countries.
Duchenne muscular dystrophy is a disease caused by mutations in the DMD gene, located on the X chromosome, which encodes the dystrophin protein, necessary for muscle membrane stability. Due to the lack of dystrophin, children present a muscle degeneration that progressively worsens with age to the point of requiring wheelchair and non-invasive ventilation in the second decade of life. The disease also affects the heart and, unfortunately, life expectancy is greatly reduced due to respiratory and cardiac complications. It is estimated that there are approximately 140,000 children affected by Duchenne muscular dystrophy worldwide and approximately 30,000 in the United States and Europe.
As explained by Dra. Francina Munell, of the Pediatric Neurology Service and coordinator of the Pediatric Neuromuscular Diseases Unit of Vall d'Hebron and researcher of the Pediatric Neurology Group of the Vall d'Hebron Research Institute (VHIR), “although the disease has been known since many years ago and significant progress has been made in care to improve the quality of life of patients, the clearly significant impact on the evolution of the disease occurs with the emergence of therapies that manage to significantly increase the amount of dystrophin in the muscle".
How is the study conducted?
The main objective of this study is to measure changes in motor function in children with Duchenne muscular dystrophy over one year from baseline. The NorthStar Ambulatory Assessment (NSAA) test is used for this. The NSAA is a 17-element test that measures gross motor function in children with Duchenne muscular dystrophy. Regardless of the assigned group (placebo or therapy), it is planned that participants will receive gene therapy in research, either at the start of the study or after one year of placebo treatment.
Participants will be randomly assigned to cohort 1 or cohort 2 (placebo or therapy). Treatment will consist of two intravenous infusions, one of PF-06939926 and one of placebo. Approximately two-thirds will be in cohort 1 and will receive gene therapy PF-06,939,926 at the start of the study and placebo after one year. Cohort 2, the remaining third, will receive placebo at the start of the study and gene therapy after one year, if they remain fit. All participants will have a 5-year follow-up period after treatment with gene therapy.
Preliminary results obtained in phase 1b of the Pfizer study showed a sustained increase in minidistrophin levels in muscle and improved motor function. Some patients experienced significant side effects after administration, which they were able to resolve with medication within two weeks. For this reason, patients receiving the infusion are thoroughly monitored for the first few weeks and then the controls are spaced out.
As explained by Dra. Francina Munell, to administer therapy and monitor patients "requires the participation of multiple specialists, from pharmacists to the various members of the Pediatric Neuromuscular Diseases Unit, such as neuropediatricians, nurses, rehabilitative physicians, physiotherapists, cardiologists and pulmonologists. They are all well aware of the evolution of the disease to assess changes after administration and can act immediately in the case of any adverse event, with the help of specialists in nephrology, emergencies and the Intensive Pediatric Care Unit".
PF-06939926 is a gene therapy in development, based on the administration of a vector with a recombinant capsule of serotype 9 adeno-associated virus (rAAV9) that carries inside a shortened version of the human dystrophin gene (mini -dystrophin) under the control of a specific muscle promoter. The rAAV9 capsule was chosen as a vector for its potential to target muscle tissue. PF-06939926 received the Fast Track Designation from the United States Food and Drug Administration (FDA) in October 2020, as well as the Orphan Medication and the Rare Pediatric Diseases Designations in the United States in May 2017. The pharmaceutical treatment is manufactured at Pfizer’s gene therapy production plant in Sanford, North Carolina.
“The start of Phase 3 Pfizer’s clinical trial for Duchenne muscular dystrophy, with screening of several patients and infusion of the first participant, is an important milestone for the patient community because currently there are no treatment options that modify the disease, available for this pathology ", points out Núria Mir, medical director of the Rare Diseases Unit of Pfizer in Spain. “If our gene therapy candidate is successful in phase 3 and gets authorized, it has the potential to significantly improve the progression pathway of Duchenne muscular dystrophy,” adds Núria Mir.
"Duchenne muscular dystrophy is a progressive disorder, and patients and parents are looking forward to treatment options", says Sílvia Ávila, president of Duchenne Parent Project Spain. "The start of this study is an important step forward for the community with Duchenne muscular dystrophy. It is hoped that one day we will have treatment options for children with this disease".