Detailed information about Fidanacogene elaparvovec-dzkt Intravenous (IV)

Gene therapy/Hematology

Fidanacogene elaparvovec-dzkt Intravenous (IV)

Pfizer/Spark Therapeutics

Proposed indications

Hemophilia B in adults

U.S. Food and Drug Administration (FDA) approval timeline

Approved April 26, 2024

• Breakthrough Therapy
• Orphan Drug
• Regenerative Medicine Advanced Therapy (RMAT)

Place in therapy

Fidanacogene elaparvovec-dzkt is a gene therapy that contains a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX (FIX) Padua (R338L) transgene. Treatment with fidanacogene elaparvovec-dzkt may enable patients with hemophilia B to produce adequate levels of FIX to avoid bleeds without regular infusions of exogenous FIX.

• Fidanacogene elaparvovec-dzkt (Beqvez™) is the second gene therapy for adults with hemophilia B and will compete with etranacogene dezaparvovec-drlb (Hemgenix^®).
• Both gene therapies utilize the AAV vector to deliver a FIX Padua transgene and are intended to be given as a single dose in a patient’s lifetime.
• Durability of response to etranacogene dezaparvovec-drlb has been demonstrated for up to three years after the dose (94% of patients were free from continuous FIX prophylaxis), however, duration of response longer than 15 months is not yet available for fidanacogene elaparvovec-dzkt.
• Fidanacogene elaparvovec-dzkt demonstrated noninferiority and superiority to the standard of care (FIX replacement regimen) with respect to annuallized bleeding rates.

Understanding your data

Fidanacogene elaparvovec-dzkt is an AAV-based gene therapy that is engeneered to replace the faulty or missing FIX protein in patients with hemophilia B. It delivers a highly functional copy of the Padua FIX gene to the cells in the liver resulting in production of clotting factors. After receiving a one-time infusion of gene therapy, patients with moderately severe to severe hemophilia no longer needed regular preventative infusions of FIX. There are several ongoing clinical trials that include:

• NCT03861273 BENEGENE-2: Phase 3, open-label, single-arm study to evaluate efficacy and safety of FIX gene transfer with PF-06838435 (rAAV-Spark100-hFIX-R338L) in adult male participants with moderately severe to severe hemophilia B (FIX:C ≤2%) (BeneGene-2).
• NCT03587116: An open-label, non-investigational product, multi-center, lead-in study to evaluate prospective efficacy and safety data of FIX or factor VIII prophylaxis replacement therapy in the usual care setting of moderately severe to severe adult hemophilia B subjects (FIX:C≤2%) who are negative for neutralizing nAb to AAV vector spark100 and moderately severe to severe hemophilia A adult subjects (FVIII:C≤1%) who are negative for nAb to AAV vector SB-525 capsid (AAV6), prior to the respective therapeutic PH 3 gene therapy studies.
• NCT02484092 GOLD-B: Gene therapy, open-label, dose-escalation study of fidanacogene eleparvovec-dzkt [AAV vector with human FIX gene] in subjects with hemophilia B.
• NCT05568719: A phase 3, non-investigational product, multi country cohort study to describe the long-term safety and effectiveness of a prior single-dose treatment with investigative giroctocogene fitelparvovec or fidanacogene elaparvovec-dzkt in participants with hemophilia A or hemophilia B, respectively.

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

• Age ≥ 18 years
• Male
• Moderately severe to severe hemophilia B (congenital FIX deficiency).
• Completed six months of FIX prophylaxis therapy prior to receiving therapy.

Common measurable exclusion criteria:

• History of inhibitor to FIX
• History of any of the following conditions:
  • Significant liver disease
  • Active hepatitis B or hepatitis C; hepatitis B surface antigen, hepatitis B virus deoxyribonucleic acid positivity or hepatitis C virus ribonucleic acid positivity
  • HIV-1 or HIV-2
  • Heparin-induced thrombocytopenia
• Currently on antiviral therapy for hepatitis B or hepatitis C
• Use of blood products

Appendix

Clinical deep dive

Disease state overview

Hemophilia B is an X-linked bleeding disorder caused by mutations in the FIX gene. The majority of cases are found in men. However, women who carry the gene may exhibit symptoms that are usually mild. Hemophilia B severity is dependent on the FIX levels. FIX levels between 5% and 40% of normal are indicative of mild disease, FIX levels between 1% to 5% of normal indicate moderate disease, and FIX levels < 1% of normal are associated with severe disease. Patients with moderate to severe hemophilia B experience recurrent painful spontaneous bleeding into joint space and muscles. GI, kidney and CNS bleeding may also occur. Long-term damage, including arthropathy, muscle weakness, permanent neurologic damage and/or death may occur if left untreated.

Epidemiology

Hemophilia is a rare disease with an estimated 33,000 men affected with the disorder in the U.S. While hemophilia A occurs in about 1 in every 5,000 male births, hemophilia B is less prevalent and occurs in about 1 in 25,000 male births. Hemophilia B comprises about 20% of all hemophilia cases affecting about 6,000 persons. About 3% of patients with hemophilia B will develop neutralizing antibodies, or inhibitors to factor products.

Treatment

The standard of care for hemophilia B is exogenous FIX infused IV as on-demand treatment for an acute bleeding episode and infused 1 to 3 times per week to prevent bleeding. Several FIX products are available; due to a lower risk of pathogen transmission, recombinant products are preferred over products derived from human plasma. The plasma derived activated prothrombin complex (Feiba^®) is also indicated for control and prevention of bleeding associated with hemophilia B with inhibitors. It is administered IV every other day for routine prophylaxis and on-demand for acute treatment. In addition, the gene therapy, Hemgenix was U.S. Food and Drug Administration (FDA) approved in 2022 for use in select adults with severe congenital hemophilia B.

Drug and clinical trial overview

The ongoing, open-label, single-arm, phase 3, BENEGENE-2 study is evaluating fidanacogene elaparvovec-dzkt in adult men with moderately severe to severe hemophilia B, defined as having ≤ 2% of normal FIX activity. Enrollees completed ≥ 6 months of routine FIX prophylaxis during the trial’s lead-in period. Fidanacogene elaparvovec-dzkt was administered via IV infusion as a single dose of 5×10¹¹ vector genomes per kilogram of body weight (vg/kg). Interim analysis of data from 45 men demonstrated superiority of fidanacogene elaparvovec-dzkt compared to prophylactic exogenous FIX, based on the primary endpoint of annualized bleeding rate (ABR). Fidanacogene elaparvovec-dzkt led to a 71% reduction in ABR, measured from 12 weeks to 15 months after the dose compared to the ABR reported during the lead-in pre-treatment period (ABR, 1.3 versus 4.43, respectively; p<0.0001). In addition, key secondary endpoints revealed a 78% reduction in treated ABR (p=0.0001) and a 92% reduction in annualized infusion rate (p<0.0001). Moreover, the mean FIX activity was 27% at 15 months and 25% at 24 months. No deaths were reported. Two serious treatment emergent adverse events (TEAEs) were reported, a duodenal ulcer hemorrhage in a patient receiving corticosteroids, and an immune-mediated liver aminotransferase elevation. No serious infusion reactions, thrombotic events, or FIX inhibitors were reported.

In the ongoing, open-label, phase 1/2 GOLD-B trial, all 15 patients who received fidanacogene elaparvovec-dzkt discontinued routine infusions of FIX concentrates at a cumulative follow-up of over 18 patient years of observation (5 to 121 weeks). No participant experienced a serious adverse event or thrombotic event. In addition, FIX inhibitors were not detected.

Pipeline (late-stage development)