OR16 - Characterization of ALT elevations during the 5-year GENEr8-1 trial of valoctocogene roxaparvovec gene transfer for severe hemophilia A
OR16
Characterization of ALT elevations during the 5-year GENEr8-1 trial of valoctocogene roxaparvovec gene transfer for severe hemophilia A
R. Klamroth1,2,*, A. D. Leavitt3, F. Peyvandi4,5, S. W. Pipe6, J. Oldenburg7, K.-M. Chavele8, G. E. Clague9, K. Gu9, H. Sutton9, V. La Mura4,5
1Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, Bonn, 2Vascular Medicine and Haemostaseology, Vivantes Klinikum im Friedrichshain, Berlin, Germany, 3Department of Medicine, University of California San Francisco, Adult Hemophilia Treatment Center, San Francisco, United States, 4Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 5 Department of Vascular Medicine and Haemostaseology Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy, 6Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, United States, 7Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany, 8BioMarin UK Ltd, London, United Kingdom, 9BioMarin Pharmaceutical Inc., Novato, United States
Introduction: Valoctocogene roxaparvovec, the first approved gene therapy for severe HA (FVIII <1 IU/dL), uses an AAV5 vector to deliver a FVIII cDNA to enable FVIII production in hepatocytes to provide bleed protection. The open-label, phase 3 GENEr8-1 trial (NCT03370913) investigated safety and efficacy of valoctocogene roxaparvovec in 134 participants with severe HA. The most common adverse event was asymptomatic transient alanine aminotransferase (ALT) elevation, hypothesized to result from immune-mediated damage to transduced hepatocytes. Here, we characterize ALT elevations from central laboratory data during the 5-year trial.
Methods: Adult male participants with severe HA without history of significant liver dysfunction received an infusion of 6x1013 vg/kg valoctocogene roxaparvovec. ALT was monitored throughout the trial. Reactive glucocorticoids (GCs) were used for ALT elevation at the investigator’s discretion. Central lab-reported ALT elevation was defined for all participants as ALT >43 U/L (upper limit of normal [ULN]). Number of participants with elevations, number of distinct elevation events per year (onset), severity, and GC use for ALT elevations are reported. Duration of an elevation was considered from onset >ULN to next measurement <ULN.
Results: At baseline, 14.9% and 30.6% of participants had history of hepatitis B and C. The number and severity of ALT elevations were highest in year (Y)1 after gene transfer with 297 elevations in 105/134 (78.4%) participants; all 105 participants received GCs. Subsequently, the number of ALT elevations and participants with elevations decreased and stabilized (Y2, 48 events in 39/134 [29.1%] participants; Y3, 24 events in 20/130 [15.4%] participants; Y4, 27 events in 21/131 [16.0%] participants; Y5, 27 events in 23/129 [17.8%] participants). In Y2, 45/134 (33.6%) participants initiated GCs; 0 did in Y3–5. Over 5 years, 65.0% of ALT elevations were >1–1.5x ULN, 18.6% were >1.5–2x, 10.0% were >2–3x, 3.9% were >3–5x, and 2.6% >5x ULN. After Y2, 0 elevations >5x ULN occurred. Most elevations were transient. Potential confounding factors contributing to ALT elevation will be presented.
Discussion/Conclusion: In 5 years post-gene transfer, ALT elevations were generally transient and mild, peaking in Y1 before lessening and stabilizing. These data help inform the understanding of the valoctocogene roxaparvovec safety profile.
Disclosure of Interest: R. Klamroth Grant/Research support from: Bayer, CSL Behring, and LEO Pharma, Consultant for: Bayer, BioMarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda, Speaker Bureau of: Bayer, BioMarin, Biotest, CSL Behring, Daiichi Sankyo, Grifols, LEO Pharma, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, Shire/Takeda, and uniQure, A. Leavitt Grant/Research support from: BioMarin and Pfizer , Consultant for: BioMarin, CSL, Pfizer, Sanofi, and Sobi, F. Peyvandi Consultant for: BioMarin, Grifols, Roche, Sanofi, Sobi, and Takeda, S. Pipe Consultant for: Bayer, BioMarin, CSL Behring, HEMA Biologics, Inovio, LFB, Metagenomi, Novo Nordisk, Pfizer, Poseida Therapeutics, Roche/Genentech, Sanofi, Spark Therapeutics, and Takeda Equilibra Bioscience and GeneVentiv. , J. Oldenburg Grant/Research support from: Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda, Consultant for: Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda, K.-M. Chavele Employee of: BioMarin, G. Clague Employee of: BioMarin, K. Gu Employee of: BioMarin, H. Sutton Employee of: BioMarin, V. La Mura Grant/Research support from: Gilead and travel grants from Sanofi, Sobi, and Takeda, Consultant for: BioMarin, CSL Behring, and Pfizer; is a speaker for Gore and Alfasigma