Abstract Number: PB1094
Meeting: ISTH 2020 Congress
Background: GENEr8-1 is an ongoing phase 3 clinical study evaluating the safety and efficacy of valoctocogene roxaparvovec, an AAV5-mediated gene therapy encoding human B-domain-deleted FVIII (hFVIII-SQ) for the treatment of hemophilia A. Following administration, substantial increases in FVIII activity levels were observed with an acceptable safety profile. The most common adverse event was a mild, transient increase in ALT, which was managed using glucocorticoids.
Aims: Evaluate humoral and cellular immune responses following administration of valoctocogene roxaparvovec and assess impact on patient safety and therapeutic efficacy.
Methods: Plasma and PBMCs were collected at specified timepoints prior to and following administration of valoctocogene roxaparvovec from the first 16 patients with ≥26 weeks follow-up. FVIII inhibitors were assessed using the Nijmegen-modified Bethesda assay. FVIII and AAV5 total binding antibody (TAb) titers were determined by ECLA. Patients testing positive at screening for AAV5 TAb, or with a history of FVIII inhibitors, were excluded from the study. PBMCs were analyzed by IFN-γ ELISpot assay for capsid-specific and hFVIII-SQ-specific cellular immune responses.
Results: No patients developed FVIII inhibitors after dosing. All patients were AAV5 TAb positive by week 8 and remained positive at all subsequent timepoints. TAb titers were not associated with ALT elevations or FVIII activity measures. Most patients tested positive for cellular immune responses to AAV5; positivity was largely transient, self-limiting, and not consistently associated with changes in ALT or FVIII activity measures. Detection of FVIII-specific cellular immune responses was rare. Responses to both AAV5 and FVIII could be detected during and outside periods of glucocorticoid use.
Conclusions: The immune response to valoctocogene roxaparvovec is primarily directed toward the AAV5 capsid with only sporadic, transient responses toward hFVIII-SQ. These responses have not been associated with safety or efficacy outcomes. FVIII inhibitor responses have not been detected in any valoctocogene roxaparvovec recipient to date.
To cite this abstract in AMA style:Long B, Vettermann C, Lawal A, Kim B, Wong WY, Hayes G, Seitel T, Lau K, Sandza K, Patton K, Yang X, Schweighardt B. Clinical Immunogenicity of Valoctocogene Roxaparvovec in GENEr8-1, a Phase 3 Study of AAV5-Mediated Gene Therapy Encoding Human FVIII for the Treatment of Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/clinical-immunogenicity-of-valoctocogene-roxaparvovec-in-gener8-1-a-phase-3-study-of-aav5-mediated-gene-therapy-encoding-human-fviii-for-the-treatment-of-hemophilia-a/. Accessed October 1, 2023.
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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/clinical-immunogenicity-of-valoctocogene-roxaparvovec-in-gener8-1-a-phase-3-study-of-aav5-mediated-gene-therapy-encoding-human-fviii-for-the-treatment-of-hemophilia-a/