Pfizer Reports Positive Results from Phase 3 Hemophilia B Gene Therapy Study

Pfizer Inc. (NYSE: PFE) announced in late December, positive top-line results from the Phase 3 BENEGENE-2 study (NCT03861273) evaluating fidanacogene elaparvovec. Fidanacogene elaparvovec is a novel investigational gene therapy, for the treatment of adult males with moderately severe to severe genetic bleeding disorder hemophilia B.

Hemophilia, also known as factor IX (FIX) deficiency or Christmas disease, causes the blood to take a long time to clot because of a deficiency in one of several blood clotting factors, and is almost exclusively found in males. Fidanacogene elaparvovec is an investigational vector that contains a bio-engineered adeno-associated virus (AAV) capsid (protein shell) and a high-activity human coagulation FIX gene. The aim of this gene therapy for people living with hemophilia B, once treated, is that they will be able to produce FIX via this one-time treatment rather than having to regularly receive exogenous FIX.

In this Phase 3 trial, eligible study participants (n=45) completed a minimum six months of routine exogeneous FIX prophylaxis therapy during the lead-in study (NCT03587116) and then received one intravenous dose of fidanacogene elaparvovec at a dose of 5e11 vg/kg.

Participants in the BENEGENE-2 study were screened with a validated assay designed to identify individuals who test negative for neutralizing antibodies to the gene therapy vector. Clinical trial participants will be evaluated as part of a long-term study over the course of 15 years.

The BENEGENE-2 study met its primary endpoint

The BENEGENE-2 study met its primary endpoint of non-inferiority and superiority in the annualized bleeding rate (ABR) of total bleeds post-fidanacogene elaparvovec infusion versus prophylaxis regimen with Factor IX (FIX), administered as part of usual care. The results demonstrated superiority with a mean ABR for all bleeds of 1.3 for the 12 months from week 12 to month 15 compared to an ABR of 4.43 during the lead-in pre-treatment period of at least six months, resulting in a 71% reduction in ABR (p<0.0001) after a single dose of 5e11 vg/kg of fidanacogene elaparvovec. Key secondary endpoints demonstrated a 78% reduction in treated ABR (p=0.0001) and a 92% reduction in annualized infusion rate (p<0.0001). Mean FIX activity was 27% at 15 months by one-stage SynthASil assay and 25% at 24 months. The mean steady-state FIX:C was significantly higher than the pre-specified threshold of 5% (p<0.0001).

Fidanacogene elaparvovec was generally well-tolerated, with a safety profile consistent with Phase 1/2 results. Fourteen serious adverse events (SAEs) were reported in seven (16%) patients, with two assessed as related to treatment, a duodenal ulcer hemorrhage occurring in the setting of corticosteroid use, and an immune-mediated elevation of liver aminotransferase levels. No fatalities, SAEs associated with infusion reactions, thrombotic events, or FIX inhibitors were reported.

Advancing the latest innovation for people living with hemophilia B

Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology and Rare Disease, Pfizer Global Product Development stated:

“Pfizer has more than 30 years of experience in developing and commercializing therapies for hematological disorders, and a deep understanding of the significant challenges that people living with hemophilia continually face. We are proud to advance the latest innovation for people living with hemophilia B and are encouraged by the potential of this investigational gene therapy.

“We are extremely appreciative of those who are participating in the trial and to the investigators contributing to this innovative research as we work to unlock the full potential of gene therapies for people living with hemophilia.”

Three Phase 3 programs are currently underway at Pfizer, investigating gene therapy in populations where there is a high unmet need: hemophilia B, hemophilia A, and Duchenne muscular dystrophy. A Phase 3 trial is also ongoing investigating marstacimab, a potential novel subcutaneous therapy option being studied for the treatment of people with hemophilia A and B with and without inhibitors.

Adam Cuker, M.D., M.S., Director, Penn Comprehensive and Hemophilia Thrombosis Program said:

“The burden people living with hemophilia B face is significant, with many receiving routine infusions or injections which can interfere with their ability to take part in day-to-day activities that many take for granted.”

“The BENEGENE-2 data demonstrate the promise of this gene therapy candidate as a potential one-time option for people living with hemophilia B as a means of reducing the clinical and treatment burden over the long term.”

Fidanacogene elaparvovec has been granted breakthrough, regenerative medicines advance therapy (RMAT), and orphan drug designations from the US FDA, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency. Pfizer intends to discuss these data with regulatory authorities in early 2023.

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