In adults with severe hemophilia A without inhibitors, use of valoctocogene roxaparvovec appeared to show robust hemostatic efficacy in comparison with factor VIII (FVIII) prophylaxis, in an analysis of a phase 3 study conducted at 3 years.

Study results were presented at the International Society of Thrombosis and Haemostasis (ISTH) 2023 Congress by Johnny Mahlangu, BSc, MBBCh, MMed, FCPath, of the University of the Witwatersrand and National Health Laboratory Service in Johannesburg, South Africa, and colleagues.

Valoctocogene roxaparvovec is being investigated as a possible gene therapy aimed at supporting endogenous FVIII production. The open-label, global, multicenter phase 3 GENEr8-1 trial ( Identifier: NCT03370913) enrolled adult men with severe hemophilia A (FVIII levels ≤1 IU/dL) without inhibitors who were receiving routine FVIII prophylaxis. Participants were treated with valoctocogene roxaparvovec at a dose of 6×1013 vector genomes per kilogram.

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Endpoints of interest in this study were safety, FVIII activity, quality of life (QoL), and the change from baseline during postprophylaxis in both the annualized bleeding rate (for treated and all bleeds) and the annualized FVIII utilization rate. Valoctocogene roxaparvovec was infused at week 0, and the postprophylaxis period began at the start of week 5 or prophylaxis discontinuation. Dr Mahlangu and colleagues presented an update of outcomes after 3 years following gene transfer.

The intention-to-treat (ITT) population included 134 patients, and a modified ITT population included 132 patients. In the modified ITT population, FVIII activity appeared to persist at hemostatic levels for up to 4 years. Also, at year 3, 10.6% of the modified ITT population had ≥40 IU/dL FVIII activity per chromogenic substrate assay, with 56.1% having activity at >5 to <40 IU/dL, 9.1% having activity at 3 to 5 IU/dL, and 24.2% having activity <3 IU/dL. At the time of Dr Mahlangu’s presentation, 17 participants in the ITT population had returned to prophylaxis.

In an analysis of bleeding episodes in 112 patients, there was an 82.9% reduction in treated bleeds over the postprophylaxis period, compared with baseline (P <.0001). The mean annualized bleeding rate for treated bleeds during year 3 was 1.0 bleeds per year, and the percentage of participants with 0 treated bleeds during year 3 was 75%. There was also a 96.8% reduction in FVIII usage postprophylaxis, compared with baseline (P <.0001).

In a safety analysis of 134 patients, Dr Mahlangu indicated there were no new safety signals seen in year 3. Alanine aminotransferase elevation remained the most common adverse event and was seen in 25.4% of patients during year 3, mostly of grade 1.

There was no development of anti-FVIII neutralizing antibodies or thromboembolic events observed in the study. B-cell acute lymphoblastic leukemia was diagnosed in 1 patient in year 3, but after analyses this was considered very unlikely to be related to valoctocogene roxaparvovec therapy.

“A single infusion of valoctocogene roxaparvovec provided durable, robust hemostatic efficacy relative to the factor VIII prophylaxis over 3 years,” Dr Mahlangu said in his presentation. Additionally, QoL analyses reportedly showed that significant, meaningful improvements had been maintained at the end of year 3.

Disclosures: This research was supported by BioMarin Pharmaceutical Inc. Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Mahlangu J, Maxeke C, von Drygalski A, et al. Bleeding, FVIII activity, and safety 3 years after gene transfer with valoctocogene roxaparvovec: results from GENEr8-1. ISTH 2023 Congress; June 24-28, 2023. Abstract OC 20.1.