Fidanacogene Elaparvovec Bests Standard of Care in Phase 3 Hemophilia B Study

Treatment with a single infusion of fidanacogene elaparvovec (PF-06838435) demonstrated non-inferiority and even superiority in annualized bleeding rates (ABR) compared with factor IX (FIX) treatment for patients with moderately severe to severe hemophilia B, according to findings from the phase 3 BENEGENE-2 study (NCT03861273) announced by Pfizer, the company developing the gene therapy.

Prior to administration of fidanacogene elaparvovec in the single-arm BENEGENE-2 study, ABR with FIX therapy were assessed during a lead in period that lasted 6 months or longer. This lead-in was completed in a separate trial (NCT03587116). In the lead-in period, the ABR with standard of care FIX was 4.43 compared with an ABR of 1.3 from week 12 through 15 months with fidanacogene elaparvovec. This was equivalent to a 71% reduction in ABR, which was significantly superior to standard FIX therapy (P <.0001).

“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,” Adam Cuker, MD, MS, director, Penn Comprehensive and Hemophilia Thrombosis Program, said in a statement. “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.”

The phase 3 BENEGENE-2 study included 45 male participants with moderately severe to severe hemophilia B, defined as a FIX coagulation activity of 2% of less. All patients completed lead-in therapy with FIX prophylaxis therapy, which was stopped after administration of the gene therapy. Fidanacogene elaparvovec was administrated as a single intravenous infusion at a dose of 5e11 vg/kg. All patients tested negative for neutralizing antibodies prior to treatment with the agent.

In addition to improvement in the primary end point of ABR, there were improvements seen across several key secondary end points, Pfizer announced. Compared with the lead-in period, fidanacogene elaparvovec led to a 78% reduction in ABR for treated bleeds (P = .0001). Moreover, there was a 92% reduction in the annualized infusion rate of exogenous FIX following infusion with fidanacogene elaparvovec (P <.0001).

The activity seen with the gene therapy remained durable with additional follow up, which will continue for 15 years for patients enrolled in the study. The steady-state vector-derived FIX coagulation activity was consistently higher than the pre-specified 5% threshold required for significance (P <.0001). At the 15-month mark, by one-stage SynthASiL assay, the FIX activity was 27%. At 24 months, the FIX activity was 25%.

The safety profile with fidanacogene elaparvovec was consistent with prior reports from the phase 1/2 studies, Pfizer noted. Overall, there were 14 serious adverse events (SAEs) observed in 7 patients (16%), none of which were related to infusion reactions, thrombotic events, or FIX inhibitors. Of the 14 SAEs, 2 were deemed to be related to treatment: duodenal ulcer hemorrhage occurring in the setting of corticosteroid use and an immune-mediated elevation of liver aminotransferase levels. There were no deaths during the study.

Pfizer announced plans to submit additional findings from the study for presentation at a medical conference in early 2023. Other secondary end points included the percentage of patients without bleeds, joint health and joint bleeds, patient reported outcomes, and additional outcome measures.

“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,” Chris Boshoff, MD, PhD, chief development officer, Oncology and Rare Disease, Pfizer Global Product Development, said in a statement.

“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.”

Fidanacogene elaparvovec, which has received breakthrough, regenerative medicines advance therapy (RMAT), and orphan drug designations, transfers a human coagulation FIX gene using a bio-engineered adeno-associated virus capsid, which was developed by Spark Therapeutics. Under a research collaboration, Spark completed phase 1/2 studies while Pfizer completed pivotal studies and subsequent regulatory discussions and commercialization, if applicable. Pfizer plans to discuss the findings from BENEGENE-2 with regulatory agencies in early 2023.