Pfizer Reports Positive Top-Line Results from Phase 3 Study of Hemophilia B Gene Therapy Candidate

Pfizer reported positive top-line results from the phase 3 BENEGENE-2 study evaluating its experimental gene therapy fidanacogene elaparvovec for the treatment of adult males with moderately severe to severe hemophilia B, which met both primary and secondary endpoints.

Photo: Chris Boshoff, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development

Hemophilia B is a rare, genetic life-threatening degenerative disease. People with the condition are particularly vulnerable to bleeds in their joints, muscles, and internal organs, leading to pain, swelling, and joint damage. Current treatment includes life-long prophylactic infusions of factor IX (FIX) to temporarily replace or supplement low levels of the blood-clotting factor.

Gene therapy has the potential to make more normal clotting ability possible in hemophilia B. In November, the U.S. Food and Drug Administration approved Hemgenix, the first gene therapy for adults with hemophilia B from CSL Behring and UniQure, which carries a $3.5 million price tag.

Pfizer’s experimental gene therapy, fidanacogene elaparvovec, experimental vector that contains a bio-engineered adeno-associated virus (AAV) protein shell and a high-activity human coagulation FIX gene. The goal 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 completed a minimum six months of routine exogeneous FIX prophylaxis therapy during the lead-in study p 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 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 percent reduction in ABR after a single dose of 5e11 vg/kg of fidanacogene elaparvovec. Key secondary endpoints demonstrated a 78 percent reduction in treated ABR (and a 92 percent reduction in annualized infusion rate). Mean FIX activity was 27 percent at 15 months by one-stage SynthASil assay and 25 percent at 24 months. The mean steady-state FIX:C was significantly higher than the pre-specified threshold of 5 percent.

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 patients (16 percent), 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 deaths, SAEs associated with infusion reactions, thrombotic events, or FIX inhibitors were reported.

“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,” said Chris Boshoff, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development.

Pfizer currently has three phase 3 programs 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.

“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,” said Adam Cuker, director of the Penn Comprehensive and Hemophilia Thrombosis Program. “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 FDA, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency. Pfizer will discuss these data with regulatory authorities in early 2023. Additional key data will be presented at a scientific conference in early 2023 as well.

Pfizer licensed SPK-9001 (fidanacogene elaparvovec), from Spark Therapeutics pursuant to a December 2014 agreement under which Spark Therapeutics was responsible for conducting all phase 1/2 studies for the investigational gene therapy while Pfizer assumed responsibility for pivotal studies, any regulatory activities, and potential global commercialization.

Author: Rare Daily Staff