First-in-human Four-year Follow-up Study of Durable Therapeutic Efficacy and Safety: AAV Gene Therapy With Valoctocogene Roxaparvovec for Severe Haemophilia A

First-in-human Four-year Follow-up Study of Durable Therapeutic Efficacy and Safety: AAV Gene Therapy With Valoctocogene Roxaparvovec for Severe Haemophilia A
Highlights from the WFH Virtual Summit 2020

First-in-human Four-year Follow-up Study of Durable Therapeutic Efficacy and Safety: AAV Gene Therapy With Valoctocogene Roxaparvovec for Severe Haemophilia A

K. John Pasi, MB, ChB, PhD, FRCP, FRCPath, FRCPCH1; Savita Rangarajan, MBBS, FRCP, FRCPath2; Nina Mitchell, MB, BChir3; Will Lester, MB, ChB, PhD, FRCP, FRCPath4; Emily Symington, BSc, MBBS, MRCP, FRCPath5; Bella Madan, MD, FRCP, FRCPath6; Michael Laffan, DM, FRCP, FRCPath7; Chris B. Russell, PhD3; Mingjin Li, MSc3; Benjamin Kim, MD, MPhil3; Glenn F. Pierce, MD, PhD8; Wing Yen Wong, MD3

1Barts and the London School of Medicine and Dentistry, London, UK

2University Hospital Southampton, Southampton, UK

3BioMarin Pharmaceutical Inc., Novato, CA, USA

4University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

5Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

6Guy’s & St. Thomas’ NHS Foundation Trust, London, UK

7Centre for Haematology, Imperial College London, London, UK.

8Consultant, La Jolla, CA, USA

Key Data Points

This diagram on the left summarizes the cohort dosing for BMN 270 (valoctocogene roxaparvovec). The 2 patients at the lowest doses (6 x 1012 and 2 x 1013 vg/kg) did not demonstrate sufficient FVIII expression. Study results are reviewed for the 13 patients in the 2 higher dosing cohorts: 7 at 6 x 1013 vg/kg (6E13)and 6 at 4 x 1013 vg/kg (4E13). Baseline characteristics for all 15 patients are shown on the right side. Notably, 14 of 15 patients were on prophylactic therapy at baseline, with a mean annualized bleed rate (ABR) of 6.5.

Patients in both dosing cohorts showed substantial reductions in ABR that have been sustained for up to 4 years post-infusion in the 6E13 cohort and 3 years in the 4E13 cohort. The mean cumulative ABR was reduced by 95% to 0.8 in the 6E13 cohort and by 93% to 0.9 in the 4E13 cohort. There have been no spontaneous bleeds in year 4 for 6 of 7 participants in the 6E13 cohort and in year 3 for 5 of 6 participants in the 4E13 cohort. All participants remain off FVIII prophylaxis.

Patients in the 2 dosing cohorts (6E13 in green, 4E13 in yellow) demonstrated dose-dependent, sustained increases in FVIII activity levels for up 208 weeks in the 6E13 cohort and 156 weeks in the 4E13 cohort (based on the chromogenic assay). Mean FVIII levels were generally higher for the higher dose cohort (n = 7), peaking at 70%-80% over weeks 16 to 52, followed by a slow decline. Mean FVIII levels in the lower dose cohort (n = 6) peaked at 20%-30% over the same period, also followed by a slow decline.

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