First Patient Outcomes Reported for Gene Therapy in Severe Hemophilia A

Platelet-targeted gene therapy with human factor VIII (FVIII) exhibited promising extended neutrophil recovery and platelet transfusion independence in the first patient with severe hemophilia A and inhibitory antibodies against FVIII enrolled in a phase I trial. The results were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

Presenting author, David Wilcox, PhD, from the Medical College of Wisconsin in Milwaukee, described the intervention as a “lentiviral vector gene therapy directed to induce megakaryocytes to synthesize and store FVIII within platelets” for delivery at the site of vascular injuries.

The male patient was 29 years old with severe hemophilia A with inhibitory antibodies to FVIII quantified at 2.6 Bethesda unit (BU)/mL. Researchers noted immune tolerance to FVIII was established at baseline, and hemostatic prophylaxis was achieved with weekly emicizumab and recombinant FVIII for breakthrough bleeding events.

The primary end points informing feasibility of the intervention included the manufacturing procedure requirement of ≥4×10⁶/kg transduced clinical grade CD34+ cells, cell viability of 70% or more, and no detectable microbial contamination. The primary safety end points were hematopoietic recovery within 28 days of infusion and no grade ≥3 toxicities.

Dr. Wilcox reported the patient achieved neutrophil recovery and platelet transfusion independence 15 days after infusion and maintained the response for over 12 months. The duration of hospitalization was 21 days with no breakthrough bleeding events, and there were no readmissions. There were no reported grade ≥1 unexpected toxicities, and the patient did not require immune suppression.

Additionally, authors noted the patient discontinued emicizumab 3.6 months after infusion with no subsequent spontaneous bleeding events or need of “on-demand” FVIII. No replication competent lentivirus was observed over 12 months of follow-up, and no infusion site samples contained cell clones above 20% relative abundance.

“These findings extend the potential to treat severe hemophilia A patients who are not eligible for valoctocogene roxaparvovec (AAV5-hFVIII-SQ),” Dr. Wilcox and colleagues concluded.

Reference

Wilcox DA, Armant M, Malec L, et al. Gene therapy expressing platelet-derived factor VIII for correction of hemophilia A with a history of inhibitors. Abstract #2249. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.