Presentation Details
| Sustained Efficacy and Safety 3 Years Following Infusion with Etranacogene Dezaparvovec in Adults with Severe or Moderately Severe Hemophilia B in the Phase 3 HOPE-B Clinical Trial Steven W.Pipe1, Paul van der Valk2, Peter Verhamme3, Peter Kampmann4, Frank Leebeek5, Michiel Coppens6, Nigel Key7, Nathan Visweshwar8, Guy Young9, Richard Lemons10, Robert Klamroth11, Niamh O'Connell12, Sandra le Quellec13, Paul Monahan13, Cedric Hermans14. 1Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA.2Van Creveldkliniek, University Medical Center Utrecht, Utrecht, Netherlands.3Center for Molecular and Vascular Biology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.4Rigshospitalet, Copenhagen, Denmark.5Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands.6Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.7University of North Carolina, Chapel Hill, NC, USA.8University of South Florida, Tampa, FL, USA.9University of Southern California Keck School of Medicine, Children’s Hospital Los Angeles, Los Angeles, CA, USA.10University of Utah, Salt Lake City, UT, USA.11Vivantes Klinikum im Friedrichshain, Berlin, Germany.12National Coagulation Centre, St.James’s Hospital, Dublin, Ireland.13CSL Behring, King of Prussia, PA, USA.14Division of Haematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium |
Abstract
Background: Etranacogene dezaparvovec (formerly AMT-061), a gene therapy for the treatment of hemophilia B, comprises a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a factor IX (FIX) Padua R338L transgene under the control of a liver-specific promoter (LP-1). Etranacogene dezaparvovec is the first approved gene therapy for adults with hemophilia B in the EU, US and Canada. In the HOPE-B pivotal Phase 3 clinical trial (NCT03569891), etranacogene dezaparvovec demonstrated superior bleed protection compared to FIX prophylaxis up to Month 24 post-infusion. Ongoing follow-up continued from Year 2. Objectives: To report the efficacy and safety of etranacogene dezaparvovec up to Month 36 post-treatment in the HOPE-B Phase 3 clinical trial. Methods: In this open-label, single-arm, Phase 3 trial, adult male patients with severe or moderately severe hemophilia B, with or without pre-existing AAV5 neutralizing antibodies (NAbs), received a single infusion of etranacogene dezaparvovec (2×1013 gc/kg) following a ≥6-month lead-in period of FIX prophylaxis. Results: Among 54 patients who received etranacogene dezaparvovec, 52 completed 36 months’ follow-up. The two patients (3.7%) who did not complete this follow-up, one with the highest AAV5 NAb titer (1:3212) and one who received a partial dose (~10% of the planned dose), did not express FIX Padua and remained on FIX prophylaxis. Mean annualized bleeding rate (ABR) for all bleeds during Months 7–36 was reduced by 64% versus lead-in (1.52 and 4.17, respectively; P=0.0004). Mean ± SD endogenous FIX activity was sustained at 41.5±21.7 IU/dL (n=50), 36.7±19.0 IU/dL (n=50), and 38.6±17.8 IU/dL (n=48) at Years 1, 2, and 3 post‑treatment, respectively. By Year 3, 1 patient (1.9%) expressed endogenous FIX activity levels <5 IU/dL, 3 patients (5.6%) between 5–<12 IU/dL, 26 patients (48.1%) between 12–<40 IU/dL, and 18 patients (33.3%) expressed levels ≥40 IU/dL. FIX activity levels were missing/uninterpretable for 4 patients (7.4%) at Year 3; 1 patient died (unrelated to treatment), 1 patient returned to continuous FIX prophylaxis at Month 30 post-treatment following a decline of FIX levels to 2–5% and bleeding phenotype recurrence, 1 patient had a liver transplant, and 1 patient had a non-analyzable sample due to hemolysis. At Year 3 post‑treatment, 51 patients (94%) remained free of continuous FIX prophylaxis; mean annualized FIX consumption decreased by 96% versus lead-in (P<0.0001). All patients experienced at least 1 treatment-emergent adverse event (AE), with no serious AEs related to treatment (1 case of hepatocellular carcinoma [HCC] and 1 death were reported before Year 2). A total of 38/54 (70.4%) patients experienced 93 treatment-related AEs. The most common AE was increased alanine transaminase (ALT). Nine patients (16.7%) received reactive corticosteroids for a mean ± SD of 81.4±28.6 days. No new deaths, HCC, or late treatment-related ALT elevations were reported during Year 3. Conclusions: Etranacogene dezaparvovec provides long-term FIX Padua expression, with the majority of patients expressing FIX activity levels in the mild or normal range at Year 3 post‑treatment, as well as superior bleed protection compared to FIX prophylaxis and a favorable safety profile.
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