Lindsey A George1, Paul E Monahan1, M Elaine Eyster1, Spencer K Sullivan1, Margaret V Ragni1, Stacy E Croteau1, John E J Rasko1, Michael Recht1, Benjamin J Samelson-Jones1, Amy MacDougall1, Kristen Jaworski1, Robert Noble1, Marla Curran1, Klaudia Kuranda1, Federico Mingozzi1, Tiffany Chang1, Kathleen Z Reape1, Xavier M Anguela1, Katherine A High1. 1. From the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), and Spark Therapeutics (P.E.M., A.M., K.J., R.N., M.C., K.K., F.M., T.C., K.Z.R., X.M.A., K.A.H.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department 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 - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Abstract
BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).
BACKGROUND: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. METHODS: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. RESULTS: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). CONCLUSIONS: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).
Authors: Federico Mingozzi; Marcela V Maus; Daniel J Hui; Denise E Sabatino; Samuel L Murphy; John E J Rasko; Margaret V Ragni; Catherine S Manno; Jurg Sommer; Haiyan Jiang; Glenn F Pierce; Hildegund C J Ertl; Katherine A High Journal: Nat Med Date: 2007-03-18 Impact factor: 53.440
Authors: Amelia R Wilhelm; Nicole A Parsons; Benjamin J Samelson-Jones; Robert J Davidson; Charles T Esmon; Rodney M Camire; Lindsey A George Journal: Blood Date: 2021-05-06 Impact factor: 22.113
Authors: Amit C Nathwani; Ulreke M Reiss; Edward G D Tuddenham; Cecilia Rosales; Pratima Chowdary; Jenny McIntosh; Marco Della Peruta; Elsa Lheriteau; Nishal Patel; Deepak Raj; Anne Riddell; Jun Pie; Savita Rangarajan; David Bevan; Michael Recht; Yu-Min Shen; Kathleen G Halka; Etiena Basner-Tschakarjan; Federico Mingozzi; Katherine A High; James Allay; Mark A Kay; Catherine Y C Ng; Junfang Zhou; Maria Cancio; Christopher L Morton; John T Gray; Deokumar Srivastava; Arthur W Nienhuis; Andrew M Davidoff Journal: N Engl J Med Date: 2014-11-20 Impact factor: 176.079
Authors: Leszek Lisowski; Allison P Dane; Kirk Chu; Yue Zhang; Sharon C Cunningham; Elizabeth M Wilson; Sean Nygaard; Markus Grompe; Ian E Alexander; Mark A Kay Journal: Nature Date: 2013-12-25 Impact factor: 49.962
Authors: Giang N Nguyen; John K Everett; Samita Kafle; Aoife M Roche; Hayley E Raymond; Jacob Leiby; Christian Wood; Charles-Antoine Assenmacher; Elizabeth P Merricks; C Tyler Long; Haig H Kazazian; Timothy C Nichols; Frederic D Bushman; Denise E Sabatino Journal: Nat Biotechnol Date: 2020-11-16 Impact factor: 54.908
Authors: Denise E Sabatino; Frederic D Bushman; Randy J Chandler; Ronald G Crystal; Beverly L Davidson; Ricardo Dolmetsch; Kevin C Eggan; Guangping Gao; Irene Gil-Farina; Mark A Kay; Douglas M McCarty; Eugenio Montini; Adora Ndu; Jing Yuan Journal: Mol Ther Date: 2022-06-10 Impact factor: 12.910
Authors: Liron Elkouby; Sean M Armour; Raffaella Toso; Marti DiPietro; Robert J Davidson; Giang N Nguyen; Mallory Willet; Stephanie Kutza; Joseph Silverberg; Jennifer Frick; Marco Crosariol; Yuhuan Wang; Chuansong Wang; Katherine A High; Denise E Sabatino; Xavier M Anguela Journal: Mol Ther Methods Clin Dev Date: 2021-11-24 Impact factor: 6.698