# Development of a universal gene therapy for hemophilia A or B with or without inhibitors

> **NIH NIH R44** · GENEVENTIV THERAPEUTICS, INC. · 2024 · $1,230,198

## Abstract

Summary/Abstract
Hemophilia is an inherited bleeding disorder caused by a deficiency of the functional clotting factor FVIII
(hemophilia A) or FIX (hemophilia B) in the contact activation pathway of the coagulation cascade. Current
treatment by protein replacement therapy is constrained by the short half-life of the clotting factors, requiring
repeated infusions at relatively large doses. The development of inhibitors (alloantibodies to clotting factors)
remains the single most important obstacle to managing hemophilia with protein therapy. Approximately 20–30%
of patients with hemophilia A and 5% of patients with hemophilia B develop inhibitors after protein replacement
therapy. In patients with inhibitors, the administration of clotting factors is ineffective, and poor control of
hemorrhagic episodes increases complications associated with the disease. Bispecific Factor IXa and X-directed
antibodies can be given to hemophilia A patients with or without inhibitors and are an improvement over infusions.
However, 47% of patients still require infusions for breakthrough bleeds. Hemophilia A gene therapies in
development for non-inhibitor patients have demonstrated limited durability of effect after a single infusion. To
date there have been no approved AAV based gene therapies in development for hemophilia patients with
inhibitors.
GeneVentiv is directly addressing this critical unmet need through the development of GENV-HEM, the first
universal gene therapy for all hemophilias and the first designed to treat inhibitor patients. GENV-HEM is an
AAV8 vector encoding human FVa (hFVa) driven by a liver-specific promoter. Within the coagulation pathway,
FVa functions downstream as a co-factor of activated Factor X (FXa) to amplify thrombin generation. FVa acts
in the common coagulation pathway and can generate thrombin via the prothrombinase complex without FVIII
or Factor IX. GENV-HEM offers a potential platform therapy that can treat multiple types of hemophilia including
hemophilia A and B with or without inhibitors and FV deficiency, including multi-year durability of effect. We have
demonstrated proof-of-concept in mouse models of hemophilia. The next major steps to allow commercialization
of this innovative technology are encompassed in the following Specific Aims: (1) Optimization of lead GENV-
HEM candidate in a mouse model of hemophilia with a reduced minimum effective dose; (2) Manufacture GLP-
grade GENV-HEM for IND-enabling studies; (3) Demonstrate efficacy of GENV-HEM in a canine model of
hemophilia; and (4) Develop bioanalytical methods in nonhuman primates in preparation for IND-enabling
pharmacology/toxicology studies. This data resulting from these studies will be used to inform IND-enabling
studies in dog and NHPs and predict starting doses for Phase 1 clinical trials. The successful outcome of this
Direct to Phase II project will support the commercialization of a technology that bypasses missing factors VIII
or IX and any inhibitors,...

## Key facts

- **NIH application ID:** 10918424
- **Project number:** 1R44HL174236-01
- **Recipient organization:** GENEVENTIV THERAPEUTICS, INC.
- **Principal Investigator:** Paris Margaritis
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,230,198
- **Award type:** 1
- **Project period:** 2024-04-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918424

## Citation

> US National Institutes of Health, RePORTER application 10918424, Development of a universal gene therapy for hemophilia A or B with or without inhibitors (1R44HL174236-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10918424. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*