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Thank you for attending THSNA 2026. The virtual meeting is now closed.
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| Update on a Novel Investigational Adeno-associated Virus Gene Therapy, SPK-8011QQ: Rationale and Design of a Phase IIb Trial Andrew D.Leavitt1, Alice Cohen2, M.Elaine Eyster3, Kristina Haley4, Akshat Jain5, Daniel J.Lee6, Maddalena Marchesi7, Catherine McGuinn8, Nicolas Receveur7, Michael Recht 9, Amit Soni 10, Sasha Sreckovic11, Miles Viljanen11. 1Departments of Medicine and of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.2Newark Beth Israel Medical Center, Newark, NJ, USA.3Penn State Hershey Medical Center, Hershey, PA, USA.4Hemostasis and Thrombosis Center, Oregon Health and Science University, Portland, OR, USA.5Department of Pediatrics, Division of Hematology/Oncology, Loma Linda University School of Medicine, Loma Linda, CA, USA.6Department of Hematology/Oncology, Kaiser Permanente, Vallejo/Vacaville, CA, USA.7F.Hoffmann-La Roche Ltd, Basel, Switzerland.8Department of Pediatrics, Weill Cornell Medicine College, New York, NY, USA.9Hemophilia Treatment Center and Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, CT, USA.10Center for Inherited Blood Disorders, Orange, CA, USA.11Genentech, Inc., South San Francisco, CA, USA |
Abstract
Background: SPK-8011 (dirloctocogene samoparvovec), an investigational adeno-associated virus (AAV) gene therapy, has been investigated for the prevention of bleeding in 25 people with severe hemophilia A (HA). Data from up to 6.5 years of follow-up from a Phase I/II trial of SPK-8011 (data cut-off date: March 8, 2024) demonstrated the potential for a low-dose approach to minimize dose-dependent toxicities and immunogenicity, and provide durable expression, which is a crucial requirement in a setting where future re-dosing may not be feasible (George et al. ISTH 2024). Five participants returned to prophylaxis. Consequently, a modified vector construct was developed, utilizing the existing clinically evaluated SPK-8011 capsid and low-dose approach, while replacing the factor (F)VIII transgene with an enhanced-function variant (“FVIII-QQ”; Wilhelm et al. Blood 2021). Incorporating a 5-nucleotide change, FVIII-QQ is resistant to cleavage by activated protein C (aPC), potentially providing increased hemostatic potency by increasing the durability of expressed FVIII. Objectives: To build on the clinically established safety and durability of the SPK-8011 platform by introducing the enhanced-function FVIII-QQ variant, to assess the safety and preliminary efficacy of SPK-8011QQ in a Phase IIb trial. Methods: Initial preclinical studies were conducted, including human in vitro and murine models. Plasma samples from individuals with severe HA were spiked with recombinant FVIII-QQ or FVIII-wildtype (WT) and assessed using aPC-sensitive chromogenic substrate assays (CSA) and thrombin generation assays (TGA). Surrogate AAV vectors for SPK-8011QQ or SPK-8011 were also administered intravenously to FVIII knock-out mice. Seven days post vector administration, plasma samples were collected and analyzed using aPC-sensitive CSAs and TGAs. These preclinical studies provide rationale for the Phase IIb trial, planned to start in 2026. A minimum of five men will be recruited aged ≥18 years with moderate or severe HA (FVIII levels ≤3%), previously receiving on-demand or prophylactic FVIII, with no current FVIII inhibitors. Participants will receive a single intravenous infusion of 1.5×1012 vg/kg SPK-8011QQ, plus scheduled immunomodulation to mitigate potential immunogenic reactions. The primary endpoint is safety. Exploratory endpoints include efficacy, health-related quality of life, joint health, pharmacokinetics, pharmacodynamics, immunogenicity, and biomarkers. Study design, endpoints and duration are summarised in Figure 1. Results: The preclinical studies showed that FVIII-QQ demonstrates enhanced hemostatic function in human in vitro assays in the presence of aPC: a CSA showed enhanced FVIII activity for FVIII-QQ compared with FVIII-WT, while FVIII-QQ also displayed greater thrombin generation compared with FVIII-WT in the presence of aPC. These results were corroborated in the murine ex vivo assays (Figure 2). Furthermore, FVIII-QQ also achieved complete bleed correction at markedly lower FVIII activity levels than FVIII-WT in the murine tail-clip model, demonstrating enhanced potency and efficient hemostatic control. An update on Phase IIb trial status will be provided. Conclusions: Preclinical data support leveraging the low-dose SPK-8011 platform, while introducing the aPC-resistant enhanced-function FVIII-QQ variant. The Phase IIb trial will provide insights into the safety of the investigational AAV gene therapy, SPK-8011QQ.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.