Slide 1: Efficacy and safety of valoctocogene roxaparvovec gene transfer: phase 3 GENEr8-1 results
Efficacy and safety of valoctocogene roxaparvovec adeno- associated virus gene transfer for severe hemophilia A: Results from the phase 3 GENEr8-1 trial Margareth C Ozelo,1 Johnny Mahlangu,2 K John Pasi,3 Adam Giermasz,4 Andrew D Leavitt,5 Michael Laffan,6 Emily Symington,7 Doris V Quon,8 Jiaan-Der
Slide 2: Disclosures for Margareth Ozelo
Disclosures for Margareth Ozelo In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/PI Research grants from Pfizer, Roche, Takeda; clinical trial investigator for BioMarin, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda Employee No releva
Slide 3: Valoctocogene roxaparvovec gene therapy for severe hemophilia A
Valoctocogene roxaparvovec gene therapy for severe hemophilia A • Hemophilia A is an X-linked bleeding disorder caused by deficiency in coagulation FVIII • Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) transfers a FVIII coding sequence to hepatocytes, enabling FVIII production in people with hemophili
Slide 4: Phase 3 GENEr8-1 study design
Phase 3 GENEr8-1 study design Eligible participants (directly enrolled or rolling over from 270-902) • Adult men with severe hemophilia A (FVIII ≤1 IU/dL) • Previously receiving FVIII prophylaxis Primary efficacy endpoint • No history of FVIII inhibitors or anti-AAV5 antibodies Change from baseline
Slide 5: Participant disposition
Participant disposition 5 AAV5, adeno-associated virus serotype 5; FVIII, factor VIII; HIV, human immunodeficiency virus; ITT, intent-to-treat; mITT, modified ITT.
Slide 6: Baseline demographics and characteristics
Baseline demographics and characteristics mITT ≥2-year Rollover population mITT ITT Baseline Characteristics n = 17 n = 112 n = 132 n = 134 Age, years, mean ± SD 29.5 ± 6.0 31.8 ± 10.6 31.4 ± 10.1 31.7 ± 10.3 Race, n (%) White 14 (82.4) 78 (69.9) 94 (71.2) 96 (71.6) Asian 1 (5.9) 17 (15.2) 19 (14.4)
Slide 7: FVIII activity over weeks in the mITT
FVIII activity over 52 weeks in the mITT • At weeks 49–52, mean (95% CI) change from baseline in FVIII activity was 41.9 (34.1–49.7) IU/dL (P <0.001) o Median (Q1, Q3) change from baseline was 22.9 (10.9, 61.3) IU/dL 500 500 Median 400 400 Mean 300 300 Factor VIII activity (IU/dL) Factor VIII activi
Slide 8: FVIII activity over weeks in the mITT dosed ≥2 years prior
FVIII activity over 104 weeks in the mITT dosed ≥2 years prior Weeks 49–52 Week 104 Mean 42.2 Mean 24.4 250 Median 23.9 Median 14.7 250 Median 200 200 Mean 150 150 Factor VIII activity (IU/dL) Factor VIII activity (IU/dL) 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 Week 12 56 6
Slide 9: Reduction in annualized treated bleeding rate in rollover population
Reduction in annualized treated bleeding rate in rollover population ABR (treated bleeds/year) P <0.001 • Mean change in ABR was a decrease of 4.1 treated 10 bleeding events/year Annualized treated bleed rate, o 95% CI: −5.3 to −2.8 8 • 83.8% reduction from baseline events/year 6 4.8 • Superiority t
Slide 10: Annualized treated bleeding rates in all study participants
Annualized treated bleeding rates in all study participants 71 Zero bleeds 166 Zero bleeds Fewer bleeds 12.3 7.9 Weeks 49–52 FVIII activity 207 4 121/134 (90.3%) had an ABR Weeks 49–52 FVIII activity Weeks 49–52 FVIII activity 23 129 83 • pre- and 123 post-infusion 14 19 80 post-infusion 6.9 6.6 15
Slide 11: Reduction in annualized FVIII utilization and infusion rates
Reduction in annualized FVIII utilization and infusion rates FVIII utilization rate (IU/kg/year) FVIII infusion rate (infusions/year) Mean change was a decrease of 3904 IU/kg/year Mean change was a decrease of 134 infusions/year (98.6% reduction); 95% CI: −4233 to −3576 (98.6% reduction); 95% CI: −1
Slide 12: Safety
Safety ITT (n = 134) n % • No participants withdrew due to AEs, Any AE 134 100 AEs occurring in ≥20% developed FVIII inhibitors, or experienced ALT increased 115 85.8 thrombosis Headache 51 38.1 Nausea 50 37.3 • Infusion reactions were defined as any AST increased 47 35.1 AEs occurring within 48 hou
Slide 13: ALT elevation and corticosteroids
ALT elevation and corticosteroids ITT (n = 134) n/N % • ALT elevation was the most common AE Participants with AE of post-baseline ALT 115/134 85.8 elevation • Overall, 79% of participants received Total number of ALT elevations 318 Grade 1 266/318 83.6 corticosteroids per protocol as treatment Grad
Slide 14: Conclusions
Conclusions In the global phase 3 GENEr8-1 study of 134 participants with severe hemophilia A, valoctocogene roxaparvovec yielded sustained expression of endogenous FVIII The study met its primary efficacy endpoint of change from baseline in FVIII activity at weeks 49–52 and also met its seconda
Slide 15: Acknowledgements
Acknowledgements • Thank you to all the trial participants, their families, study site personnel, and the GENEr8-1 Trial Group • Thank you to the members of the valoctocogene roxaparvovec Chemistry, Manufacturing and Controls (CMC); Early Development; Study Execution; Clinical Development; and Core
Slide 16: Summary of participant FVIII activity
Summary of participant FVIII activity 100 91 88 88 82 82 80 76 71 % participants 65 60 >150 IU/dL 47 ≥40 IU/dL 38 40 35 ≥15 IU/dL ≥5 IU/dL 18 ≥3 IU/dL 20 5 6 0 0 mITT (n = 132) mITT ≥2-year (n = 17*) Week 49–52 Week 49–52 Week 104 Mean ± SD 42.9 ± 45.5 42.2 ± 50.9 24.4 ± 29.2 Median (Q1, Q3) 23.9 (1