Pfizer, a prominent pharmaceutical company, has significantly invested in gene therapy, recognizing its potential to reshape the treatment landscape for inherited diseases. This innovative approach aims to address the root genetic causes of conditions, offering a different way to manage illnesses traditionally treated with ongoing medications. The company’s commitment reflects a broader industry movement towards specialized, one-time therapeutic interventions.
The Underlying Technology
Pfizer’s gene therapy efforts largely depend on a delivery system known as the adeno-associated virus (AAV) vector. Imagine this vector as a harmless delivery vehicle that transports a functional copy of a gene into the body’s cells. This specific type of virus is chosen because it does not cause illness in humans and can effectively enter various cell types.
To ensure safety and prevent the virus from replicating or causing disease, the original viral genes are carefully removed from the AAV vector. What remains is the protein shell, or capsid, which encases the new, therapeutic gene. Once inside the target cells, often in organs like the liver, the delivered gene can then instruct the cell to produce a missing or non-functional protein, thereby correcting the genetic defect.
Targeted Diseases and Programs
Pfizer’s gene therapy pipeline has focused on several genetic diseases, with particular emphasis on conditions affecting muscle and blood clotting. One significant area of study has been Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder primarily affecting boys, caused by a genetic alteration that prevents the body from making dystrophin, a protein needed for healthy muscle function. The company acquired Bamboo Therapeutics in 2016 to advance its gene therapy programs, including a preclinical candidate for DMD.
Another major focus for Pfizer has been hemophilia, a group of inherited bleeding disorders where the blood does not clot properly due to a lack of specific clotting factors. For hemophilia A, characterized by insufficient Factor VIII, Pfizer has been developing giroctocogene fitelparvovec. Similarly, for hemophilia B, which involves a deficiency in Factor IX, the company has pursued fidanacogene elaparvovec. Beyond these, Pfizer also secured an option in 2019 to acquire Vivet Therapeutics, a company specializing in gene therapies for liver disorders, including a program for Wilson disease.
Clinical Trial Progress and Hurdles
Pfizer’s journey in gene therapy clinical trials has encountered both promising results and considerable obstacles. For Duchenne muscular dystrophy, the investigational gene therapy fordadistrogene movaparvovec was evaluated in both the Phase 2 DAYLIGHT study for boys aged 2 to 4 and the Phase 3 CIFFREO study for boys aged 4 to 7. In May 2024, a patient participating in the DAYLIGHT study died from cardiac arrest, leading Pfizer to pause dosing in the crossover portion of the CIFFREO trial while investigating the event. This setback followed a previous temporary hold by the FDA in 2021 due to other safety concerns and a prior patient death in an earlier study.
Further challenges emerged in June 2024 when the Phase 3 CIFFREO study failed to achieve its primary goal of improving motor function over one year compared to placebo. Key secondary endpoints also did not show a significant difference. Following these results, Pfizer announced the discontinuation of the Duchenne muscular dystrophy gene therapy program. Despite these outcomes, the overall safety profile observed in the Phase 3 trial was generally manageable, with most adverse events being mild to moderate.
In contrast, Pfizer has seen more favorable outcomes in its hemophilia gene therapy programs. The Phase 3 AFFINE study for hemophilia A, investigating giroctocogene fitelparvovec, met its primary and secondary objectives, demonstrating a notable reduction in annualized bleeding rates compared to prophylactic treatments. This study had faced a clinical hold from the FDA in November 2021, but the trial resumed in 2022 after protocol updates. For hemophilia B, the fidanacogene elaparvovec candidate successfully met its primary endpoint in the Phase 3 BENEGENE-2 study, leading to its approval in the United States in April 2024 and in Canada in January 2024.
Manufacturing and Commercialization Strategy
Developing and producing gene therapies presents significant manufacturing complexities and high costs. Pfizer has made substantial investments to build its in-house manufacturing capabilities, establishing three specialized facilities in North Carolina. These facilities collectively provide significant manufacturing space. The facilities support both early-stage clinical manufacturing and late-stage commercial production.
The company’s approach to manufacturing is part of a “build-buy-partner” strategy, which includes collaborating with other biotechnology firms to produce their gene therapy candidates. This strategy aims to ensure that if therapies receive regulatory approval, Pfizer possesses the infrastructure to scale up production to meet potential patient demand. The manufacturing process utilizes advanced single-use technology, allowing for flexible and scalable expansion.