Patients with moderate to severe hemophilia B can now take Pfizer’s BEQVEZ (fidanacogene elaparvovec-dzkt) with the approval of the FDA. Hemophilia B is an inherited bleeding disorder that affects more than 38,000 people globally and is caused by impaired blood clotting due to a factor IX (FIX) deficiency.

The current gold standard for FIX replacement therapy prevention is infusions given once weekly or monthly. These infusions supplement or temporarily replace low blood clotting factor levels. Despite receiving prophylaxis and regular intravenous infusions, people with moderate to severe hemophilia B may still experience spontaneous bleeding episodes. Additionally, the current standard of care places a burden on healthcare systems’ budgets and resource allocation.

BEQVEZ is an adeno-associated virus (AAV)-based gene therapy developed to help people with hemophilia B produce more FIX on their own by inserting a working copy of the FIX gene that codes for a high-activity FIX variant.

This authorization is only available to patients with hemophilia B who meet two criteria. Their medical history must include either a life-threatening hemorrhage or multiple episodes of severe spontaneous bleeding, and they must be taking the FIX prophylaxis medication at present. Additionally, they need negative results from an FDA-approved test for AAV serotype Rh74var (AAVRh74var) capsid-neutralizing antibodies.

The BENEGENE-2 study

The FDA’s approval is based on the outcomes of the groundbreaking BENEGENE-2 study, a Phase III open-label, single-arm study that assessed the safety and efficacy of BEQVEZ in adult male patients with moderately severe to severe hemophilia B (defined as FIX circulating activity of 2% or lower), who were aged 18 to 65. This study aims to compare the annualized bleeding rate (ABR) of two groups: one that received gene therapy treatment and another that received a FIX prophylaxis replacement regimen as part of their standard care.

In the first phase of the study, 45 participants willingly agreed to undergo a minimum of six months of continuous FIX prophylaxis treatment (NCT03587116). These individuals were then given a single intravenous infusion of BEQVEZ.

The primary goal of BENEGENE-2, which was to compare the incidence of total bleeding following BEQVEZ infusion to a prophylactic regimen using FIX that was given as part of routine care, was effectively accomplished. Patients who received BEQVEZ had an average ABR of 2.5 during the efficacy evaluation period, which ran from week 12 to the data cutoff (with a median follow-up of 1.8 years). This is significantly lower than the average ABR of 4.5 observed during the six-month lead-in period before treatment (with a median follow-up of 1.2 years). Just 29% of patients in the prophylaxis group experienced a decrease in bleeding, whereas 60% experienced a reduction. The median ABR for the efficacy evaluation period was 0 (ranging from 0 to 19), whereas for the prophylaxis arm, it was 1.3 (ranging from 0 to 53.9).

Patients generally tolerated BEQVEZ well. The most common adverse reaction observed in Phase III and I/II clinical trials was a significant increase in transaminase levels, with an incidence rate of more than 5%. There were no reports of death, serious adverse events related to the treatment or infusion reactions, thrombotic events, or FIX inhibitors.

To learn about BEQVEZ’s long-term safety and efficacy, participants in the clinical trials will be followed for a maximum of fifteen years. This includes six years in the BENEGENE-2 study and an additional nine years in a separate Phase III study (NCT05568719). In addition to the Phase III trial, a Phase I/IIa study and its associated Phase IIa long-term follow-up study have monitored patients receiving BEQVEZ for up to six years. 

Pfizer’s gene therapy programs

Spark Therapeutics originally created BEQVEZ, which Pfizer licensed in December 2014. The parties agreed that Pfizer would be responsible for the gene therapy’s pivotal studies, regulatory actions, and possible worldwide commercialization. BEQVEZ is under review by the European Medicines Agency (EMA), and Canadian regulators have just approved the medication.

Not only does Pfizer have BEQVEZ in its Phase III trials, but it also has two other gene therapy programs looking into high-unmet-need populations: hemophilia A (giroctocogene fitelparvovec) and Duchenne muscular dystrophy (fordadistrogene movaparvovec).

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