Presentation Details
| Improved Joint Health After Gene Therapy with Dirloctocogene Samoparvovec (SPK-8011) in People with Hemophilia A Benjamin Samelson-Jones1, Peter Cygan2, Stacy Croteau3, Huyen Tran4, Margaret Ragni5, Jerome Teitel6, John Rasko 7, Spencer Sullivan 8, Jill Moormeier9, Kristina Haley10, Kristen Jaworski11, Amy MacDougall11, Alexander Long 11, Savina Jaeger 11, Tiffany Chang11, Gallia Levy11. 1Division of Hematology and the Raymond G.Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.2Department of Medicine, Division of Blood and Vascular Disorders, Penn State Health Milton S.Hershey Medical Center, Hershey, PA, USA.3Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children’s Hospital, Boston, MA, USA.4Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.5Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.6St Michael's Hospital Haemophilia Treatment Centre, University of Toronto, Toronto, ON, Canada.7Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney, Camperdown, Australia.8Mississippi Center for Advanced Medicine, Madison, MS, USA.9Department of Medicine, UMKC School of Medicine, Kansas City, MO, USA.10Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.11Spark Therapeutics, Inc., Philadelphia, PA, USA |
Abstract
Background: Despite advances in new prophylactic regimens, joint health preservation in hemophilia A (HA) remains a concern. Dirloctocogene samoparvovec (SPK-8011), an investigational liver-directed adeno-associated viral-based vector gene therapy for HA, demonstrated reductions in annualized bleed rate of 82% (95% confidence interval [CI]: 55–93) and 99% (95% CI: 98–100) for participants who had previously received factor (F)VIII prophylaxis or on-demand treatment, respectively, in a Phase I/II trial. Objectives: To report outcomes of joint health measures in the same interim analysis of the Phase I/II trial. Methods: In this open-label, multicenter, single-arm trial with a long-term extension (NCT03003533/NCT03432520; funded by Spark Therapeutics), males with HA (FVIII activity ≤2%) received dirloctocogene samoparvovec (George, et al. NEJM 2021). Joint health was assessed longitudinally after treatment using the Hemophilia Joint Health Score (HJHS) v2.1. Presence and resolution of target joints (TJs) were recorded using ISTH definitions. Impact on self-perceived function was assessed via the Hemophilia Activities List (HAL) questionnaire. Results: Participants with baseline and Year (Y)1 data were included; two who lost transgene expression were excluded. Seven participants had 13 TJs at baseline prior to receiving dirloctocogene samoparvovec; in participants with sufficient follow-up time to assess for TJ resolution (n=5), all TJs (n=10) were resolved by Y1. By data cut-off (October 4, 2022), mean total HJHS improved from 20.0 (standard deviation [SD]: 11.7) at baseline (n=11) to 14.4 (SD: 6.5) at Y3 (n=7). Clinically meaningful improvements (a decrease of ≥4) from baseline were persistent at Y2 (−4.1) and Y3 (−6.4); improvements were observed regardless of prior treatment (on-demand or prophylactic FVIII) or the presence of TJs at baseline. Participants’ self-perceived function (mean HAL score) improved from baseline to Y3, irrespective of TJ status or prior treatment. Conclusions: In a Phase I/II trial of HA gene therapy, clinically meaningful improvements in joint health, ongoing at Y3, were persistent in participants who received dirloctocogene samoparvovec, suggesting that this treatment has the potential to improve the pain and musculoskeletal impact of HA. Improvement in participants’ self-reported function and resolution of TJs supported these results. The small sample size limits interpretation. These observations will be further explored in a planned pivotal trial.
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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.