High-Cost Therapy Profile

May 15, 2024

Detailed information about Fidanacogene elaparvovec-dzkt Intravenous (IV)

High-Cost Therapy Profile

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

CATEGORY PROCEDURE CODES
Hemophilia B (congenital FIX deficiency) ICD-10: D67
FIX replacement therapy HCPCS: J7193, J7194, J7195, J7200, J7201, J7202, J7203, J7213
History of inhibitor to FIX HCPCS: J7198, J7189, J7212
Significant liver disease ICD-10: K70.40, K70.41, K72.00, K72.01, K72.10, K72.11, K72.90, K72.91, K7030, K70.31, K71.7, K74.3, K74.4, K74.5, K74.60, K74.69, P78.81
Active hepatitis B or hepatitis C ICD-10: B17.10, B17.11, B16.0, B16.1, B16.2, B16.9, B19.10, B19.11, B19.20, B19.21
HIV-1 or HIV-2 ICD-10: B20, B97.35
Heparin-induced thrombocytopenia ICD-10: D75.82
Hepatitis B or hepatitis C antiviral treatments HCPCS: S0145

GPI10: 1235306010, 1235208320, 1235201510, 1235990240, 1235990380, 1235990230, 235306005, 1235990460, 1235205000, 1235203000, 235990235, 1235308000, 1235990265, 1235307000

Blood products HCPCS: P9010-P940, P9043, P9044, P9048-P9099

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)

NAME MANUFACTURER ROUTE OF ADMINISTRATION MECHANISM OF ACTION PROPOSED/STUDIED INDICATION STATUS
AskBio009 Baxalta/Shire IV AAV8-based FIX Padua gene therapy Hemophilia B Phase 2
Verbrinacogene Setparvovec

(FLT180a)

Freeline IV Liver-directed AAV gene therapy Hemophilia B Phase 2
References
  1. Annual review of factor replacement products. Oklahoma Health Care Authority Review Board. Updated April 2016. https://oklahoma.gov/ohca.html. Accessed April 1, 2022.
  2. Burke T, Asghar S, O’Hara J. et al.Clinical, humanistic, and economic burden of severe hemophilia B in the United States: Results from the CHESS US and CHESS US+ population surveys. Orphanet J Rare Dis 2021; 16(1): 143. DOI: 10.1186/s13023-021-01774-9.
  3. Clinicaltrials.gov. An open-label, non-investigational product, multi-center, lead-in study to evaluate prospective efficacy and safety data of factor IX 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. Available at: https://clinicaltrials.gov/search?intr=NCT03587116. Accessed March 20, 2024.
  4. Clinicaltrials.gov. 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). Available at: https://clinicaltrials.gov/study/NCT03861273. Accessed March 20, 2024.
  5. Clinicaltrials.gov. GOLD-B: Gene therapy, open-label, dose-escalation study of fidanacogene eleparvovec [AAV vector with human FIX gene] in subjects with hemophilia B. Available at: https://clinicaltrials.gov/study/NCT02484092?intr=NCT02484092&rank=1. Accessed March 20, 2024.
  6. Clinicaltrials.gov. 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 in participants with hemophilia A or hemophilia B, respectively. Available at: https://clinicaltrials.gov/study/NCT05568719?intr=Fidanacogene&rank=2. Accessed March 20, 2024.
  7. Croteau SE, Neufeld EJ. Transition considerations for extended half-life factor products. Haemophilia. 2015; 21(3): 285-288. DOI: 10.1111/hae.12683. Accessed April 1, 2024.
  8. Data & Statistics on Hemophilia. Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/ncbddd/hemophilia/data.html. Accessed March 20, 2024.
  9. FDA accepts Pfizer’s application for hemophilia B gene therapy fidanacogene elaparvovec. June 27, 2023. Available: https://www.pfizer.com/news/press-release/press-release-detail/fda-accepts-pfizers-application-hemophilia-b-gene-therapy. Accessed April 19, 2024.
  10. Graham A and Jaworski K. Pharmacokinetic analysis of anti-hemophilic factor in the obese patient. Haemophilia. 2014; 20(2): 226-9. DOI: 10.1111/hae.12300. Accessed April 1, 2024.
  11. Guidelines for the Management of Hemophilia. 3rd World Federation of Hemophilia 2020. Available at: https://www1.wfh.org/publications/files/pdf-1863.pdf. Accessed April 1, 2024.
  12. Hemophilia Federation of America. Available at: https://www.hemophiliafed.org/disease_type/inhibitors/#:~:text=Approximately%202-3%25%20of%20people%20with%20hemophilia%20B%20develop,to%20infused%20factor%20IX%2C%20which%20can%20be%20life-threatening. Accessed April 11, 2024.
  13. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. National Hemophilia Foundation. MASAC Document #263; August 2020. Available at: http://www.hemophilia.org. Accessed April 1, 2024.
  14. MASAC recommendations concerning prophylaxis. 2016 National Hemophilia Foundation. MASAC Document #241; February 2016. Available at: http://www.hemophilia.org. Accessed April 1, 2022.
  15. Mingot-Castellano, et al. Application of pharmacokinetics programs in optimization of haemostatic treatment in severe hemophilia A patients: changes in consumption, clinical outcomes and quality of life. Blood. 2014; 124(21): 1502.
  16. National Bleeding Disorders Foundation. Hemophilia B. Available at: https://www.hemophilia.org/bleeding-disorders-a-z/types/hemophilia-b. Accessed March 20, 2024.
  17. Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012; 10 (4): 615‐ DOI: 10.1111/j.1538-7836.2012.04653.x. Accessed April 1, 2024.
  18. Rayment R, Chalmers E, Forsyth K, et al. Guidelines on the use of prophylactic factor replacement for children and adults with Haemophilia A and B. B J Haem 2020; 190(5); 684-695. DOI: 10.1111/bjh.16704. Accessed April 1, 2024.
  19. Shapiro AD. Hemophilia B. Updated September 20, 2023. National Organization for Rare Disorders (NORD). Available at: https://rarediseases.org/rare-diseases/hemophilia-b/#affected. Accessed March 20, 2024.
Disclaimer

The information provided has been developed based on available information as of April 26, 2024. This therapy is FDA approved, and content may change as more information becomes available. Caution should be used when developing formulary and utilization management strategies. The trademarked drug name is the property of its respective manufacturer.

By receipt of this report, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced or distributed to or disclosed to others at any time without the prior written consent of Magellan Rx Management, a Prime Therapeutics company. The information contained in this report is intended for educational purposes only and is not intended to define a standard of care or exclusive course of treatment, nor be a substitute for treatment.

Drug names are the property of their respective owners.

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