It’s in Our Blood: An Exploration of Gene Therapies for Hemophilia A and B

By: Holly Nguyen, PharmD Candidate ℅ 2024

Hemophilia is a severe hereditary hemorrhagic disorder derived from gene mutations that make clotting factors VIII and IX for hemophilia types A and B, respectively.¹ The sex-linked hemophilia recessive allele on the X chromosome gives sons a 50% chance of inheriting the hemophilia allele from a heterozygous or homozygous recessive mother, and the son who inherits the hemophilia allele from his mother will have hemophilia.^2,3 Daughters have a 50% chance of inheriting the hemophilia allele as carriers from a heterozygous mother, homozygous recessive mother, or homozygous recessive father and may experience the symptoms of mild hemophilia.^3,4 In the search to find cures for rare diseases, pharmaceutical and biotechnology companies are capitalizing on the novel gene therapy market. Gene transfer therapy involves mutated gene replacement or recovery of gene function with a different gene.⁵ All genetic changes are compressed and then transferred to the patient in an intravenous vector injection or through a sample of vector-exposed cells performed in the laboratory.⁵ Genome editing snips parts of the deoxyribonucleic acid (DNA) sequence for insertion, replacement, or deletion; the most advanced genome editing tool, clustered regularly interspaced short palindromic repeats (CRISPR), was released in 2009.⁶ In the past 12 months, gene therapies for hemophilia A and B have either received Food and Drug Administration (FDA) approval or are undergoing the final phases of clinical development, and the prospect of these new therapies is exciting for the future of hemophilia treatments.

Hemophilia gene therapies are specialized in-vivo recombinant adeno-associated viruses (AAV) produced by transiently transfected human HEK293 cells or baculovirus infected Sf9 insect cells in the liver, and are thus prone to hepatotoxicity and capsid-immune responses; the latter results in the decline of factor activity and necessitates treatment with immunomodulating agents.⁷ Valoctocogene roxaparvovec-rvox (Roctavian) by BioMarin Pharmaceutical Inc. received FDA approval for hemophilia A in June 2023, and is the sole contender of the post-marketing surveillance space.⁸  The decision was supported by a safety and efficacy study of 112 adult male patients between 18 to 70 years old previously treated with factor VIII replacement therapy; a yearly mean bleeding rate decrease from 5.4 to 2.6 bleeds per year reduced the use of factor replacement by 96.8% compared to baseline.^9,10 BioMarin will price Roctavian at $2.9 million with an outcomes-based warranty program, set to “fully reimburse government and commercial payers if expectations are not met, and partially reimburse patients who lose response to the therapy in the first four years after dosing”.¹⁰ Starting plans to launch in Germany, BioMarin is currently guiding physicians through the concerns of opioid use post-AAV therapy and identifying eligible patients to receive the first treatments of Roctavian worldwide.¹¹

Expanding on in-vivo recombinant AAV viruses, gene therapies for hemophilia B benefit from the discovery of the Padua variant for the factor IX gene, resulting in 5-10 times higher factor IX activity and higher levels of factor IX.¹² Etranacogene dezparvovec (Hemgenix) by CSL Behring received FDA approval in November 2022 and is also the only gene therapy in the post-marketing surveillance space for hemophilia B.¹³ The safety and efficacy trial evaluated 57 adult male patients between 18-75 years, diagnosed with severe or moderately severe hemophilia B, and 54 participants displayed a 54% reduction in annual bleeding rates compared to baseline, in addition to a rise of factor IX activity levels and a decreased need for factor IX replacement therapy.¹³ Hemgenix is a single-dose IV infusion priced at $3.5 million per dose, currently holding the spot as the most expensive drug in the world.^13,14 Exceeding the Institute for Clinical and Economic Review’s (ICER) recommended price of $2.9 million, it is unknown whether CSL Behring will cede to a price reduction, since it argues that healthcare systems already spend over $20 million on prophylactic and therapeutic treatments of moderate to severe hemophilia B.¹⁴ While CSL Behring continues to navigate the post-marketing stages for Hemgenix, Pfizer announced the FDA acceptance of its Biologics License Application for its hemophilia B gene therapy, fidanacogene elaparvovec, in June 2023.¹⁵ In its Phase 3 BENGENE-2 study, 45 participants were enrolled with a prior six-month prophylactic therapy of factor IX therapy, followed by an IV dose of fidanacogene elaparvovec at 5e11 vg/kg; the primary endpoint of decreased annual bleeding rates of 1.3 for 12 months was superior to an annual bleeding rate of 4.43 during prophylactic therapy.¹⁶ With grants for breakthrough Regenerative Medicines Advanced Therapy (RMAT) and orphan drug designations, Pfizer is working to meet the Prescription Drug User Fee Act (PDUFA) goal set by the FDA for the second quarter of 2024.¹⁵

Roctavian, Hemgenix, fidanacogene elaparvovec, and the overall impact of hemophilia gene therapy reaches beyond the hemophilia and hematology communities. Spearheaded by the latest AAV technologies and meticulous implementation of the final Phase III trials, hemophilia gene therapies are the first of many opportunities to lock in cells and genes as sustainable solutions for the future of rare inherited and degenerative diseases.

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