Hemgenix - Drug Monograph

Introduction

Hemgenix (etranacogene dezaparvovec-drlb) is a groundbreaking gene therapy approved by the FDA in November 2022 for the treatment of hemophilia B. It represents the first gene therapy for this inherited bleeding disorder and offers the potential for long-term factor IX expression, potentially reducing or eliminating the need for routine factor replacement therapy.

Mechanism of Action

Hemgenix is an adeno-associated virus (AAV5)-based gene therapy containing a codon-optimized human factor IX (FIX) Padua variant gene. The AAV5 vector delivers the FIX gene to hepatocytes, where it becomes episomal and enables endogenous production of functional FIX protein. The Padua variant (FIX-R338L) demonstrates approximately 8-fold higher specific activity compared to wild-type FIX, allowing for improved hemostatic protection at lower circulating levels.

Indications

Hemgenix is indicated for the treatment of adults with hemophilia B who:

• Currently use factor IX prophylaxis therapy
• Have recurrent serious spontaneous bleeding episodes
• Have a history of life-threatening hemorrhage

Dosage and Administration

• Dosage: 2 × 10¹³ genome copies per kilogram of body weight
• Route: Single intravenous infusion administered at a rate of approximately 4 mL per minute
• Administration: Pre-treatment with corticosteroids (prednisone 0.5 mg/kg or equivalent) is recommended starting 3 days prior to infusion and continuing for at least 14 days post-infusion
• Special populations: Not studied in patients with hepatic impairment, pre-existing AAV5 antibodies, or children

Pharmacokinetics

• Absorption: Administered directly into systemic circulation via IV infusion
• Distribution: Primarily targets hepatocytes via AAV5 receptor-mediated uptake
• Metabolism: Degraded by cellular mechanisms; not metabolized by cytochrome P450 enzymes
• Elimination: Vector DNA persists episomally in transduced hepatocytes
• Onset of action: Factor IX activity increases gradually over several weeks post-infusion

Contraindications

• Hypersensitivity to any component of Hemgenix or its formulation
• Patients with known hypersensitivity to corticosteroids (pre-medication requirement)

Warnings and Precautions

• Liver enzyme elevations: Transaminase elevations may occur, requiring corticosteroid management
• Thromboembolic events: Monitor for thrombotic events due to supraphysiological FIX levels
• Vector shedding: Patients may shed vector in semen; advise use of condoms for 6 months post-infusion
• AAV5 antibodies: Pre-existing immunity may reduce efficacy
• Malignancy potential: Theoretical risk of insertional mutagenesis; long-term monitoring recommended
• Coagulation monitoring: Regular FIX activity monitoring essential during first year

Drug Interactions

• No formal drug interaction studies conducted
• Theoretical interactions with immunosuppressive agents that might affect gene therapy efficacy
• Concurrent anticoagulant or antiplatelet therapy may require adjustment based on FIX levels

Adverse Effects

• Elevated liver enzymes (AST/ALT)
• Headache
• Influenza-like illness
• Fatigue
• nausea
• Feeling unwell

• Hepatotoxicity
• Thromboembolic events
• Infusion-related reactions

Monitoring Parameters

• Factor IX activity levels: Weekly for first 4 weeks, then monthly for first year, then annually
• Liver function tests: Weekly for first 4 weeks, then as clinically indicated
• Complete blood count: Baseline and as clinically indicated
• Coagulation parameters: Regular monitoring, especially during first year
• Signs of thrombosis: Clinical monitoring for thrombotic events
• Vector shedding: Semen testing for vector DNA if appropriate

Patient Education

• Hemgenix is a one-time treatment that may provide long-term factor IX production
• Regular monitoring of factor IX levels is essential for safety
• Report any signs of liver problems (jaundice, dark urine, abdominal pain)
• Immediately report any signs of blood clots (swelling, pain, shortness of breath)
• Use barrier contraception for at least 6 months after infusion
• Inform healthcare providers about Hemgenix treatment before any medical procedures
• Continue follow-up appointments as recommended by your healthcare team

References

1. FDA Approval Letter: Hemgenix (etranacogene dezaparvovec-drlb). November 2022 2. Pipe SW, et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. N Engl J Med. 2023;388(8):706-718 3. ClinicalTrials.gov: HOPE-B Study (NCT03569891) 4. Miesbach W, et al. Gene therapy for haemophilia B with etranacogene dezaparvovec. Lancet Haematol. 2022;9(7):e504-e513 5. CSL Behring LLC. Hemgenix prescribing information. 2022 6. European Medicines Agency. Assessment report: Hemgenix. 2023 7. George LA, et al. Long-term follow-up of the first hemophilia B gene therapy trial. Blood. 2022;140(Supplement 1):491-493