Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A

Abstract

Introduction: Valoctocogene roxaparvovec is an investigational AAV5-based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A.

Aim: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795).

Methods: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti-AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6).

Results: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was -0.14 (95% confidence interval [CI]: -.32 to .03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and -.06 (95% CI: -.14 to .01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo-QOL-A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo-QOL-A scores persisted.

Conclusion: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A.

Keywords: factor VIII; genetic therapy; haemophilia A; haemostasis; quality of life.

Conflict of interest statement

K John Pasi is an employee for Roche and reports receiving consulting payments from Alnylam, APCintex, BioMarin, Bioverativ, Catalyst Bio, Catapult, Chugai, Roche, Novo Nordisk, Sanofi, and Sobi; participating as a clinical trial investigator for BioMarin, Sanofi, and UniQure; receiving speaker fees from Bayer, BioMarin, Biotest, Novo Nordisk, Sanofi, Shire, Sobi, Octapharma, Pfizer, and UniQure; and receiving travel support from Alnylam, Bayer, BioMarin, Bioverativ, Novo Nordisk, Octapharma, Pfizer, Sobi, Sanofi, and Shire. Michael Laffan reports receiving grants from BioMarin; personal fees from Bayer, LEO Pharma, LFB Biopharmaceuticals, Pfizer, Roche, Shire, and Sobi; and travel support from Bayer, LFB Biopharmaceuticals, and Sobi. Savita Rangarajan reports receiving grants from Roche and Sangamo; travel support from Reliance Life Sciences and Shire/Takeda; and consulting payments from Pfizer, Reliance Life Sciences, Sanofi, and Shire/Takeda. Will Lester reports receiving grants from BioMarin; personal fees from Bayer, LFB, Novo Nordisk, Sobi, and Takeda; and travel support from Takeda and CSL. Emily Symington reports receiving grants from BioMarin and travel support from CSL Behring and Novo Nordisk. Bella Madan reports nothing to disclose. Nina Mitchell is a former employee of BioMarin Pharmaceutical and may own stock. Tara M. Robinson, Xinqun Yang, Benjamin Kim, and Wing Yen Wong are employees and stockholders of BioMarin Pharmaceutical. Glenn F. Pierce is an employee of Voyager Therapeutics; reports receiving consulting payments from Ambys Medicines, BioMarin Pharmaceutical, BridgeBio, CRISPR Therapeutics, Decibel Therapeutics, Frontera, Generation Bio, Geneception, Novo Nordisk, Pfizer, Regeneron, Spark, and Third Rock Ventures; and is a board member of the World Federation of Haemophilia, Voyager Therapeutics, Global Blood Therapeutics, VarmX, and the Medical and Scientific Advisory Council of the US National Haemophilia Foundation.

© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Figures

FIGURE 1

FVIII activity measured by the chromogenic substrate assay for participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts over 5 and 4 years, respectively. FVIII activity levels taken within 72 h of exogenous FVIII administration were excluded. FVIII activity that fell below the lower limit of quantitation (<3.0 IU/dl) was imputed as 0 IU/dl. Whiskers represent the minimum and maximum values; boxes represent the 25th and 75th percentiles. Diamonds represent the mean, and horizontal bars represent the median. CSA, chromogenic substrate assay; FVIII, factor VIII; OSA, one‐stage assay

FIGURE 2

FVIII activity measured by the chromogenic substrate assay and regression for all samples. (A) Participants in the 6 × 1013 vg/kg cohort over 5 years, and (B) participants in the 4 × 1013 vg/kg cohort over 4 years. FVIII activity levels taken within 72 h of exogenous FVIII administration were excluded. FVIII activity that fell below the lower limit of quantitation (<3 IU/dl) was imputed as 0 IU/dl. FVIII, factor VIII

FIGURE 3

Pre‐ and postinfusion of valoctocogene roxaparvovec annualised rates of bleeding and FVIII infusion. (A) Annualised rates of bleeding and FVIII infusion for the 6 × 1013 vg/kg cohort at baseline and in years 1, 2, 3, 4, and 5. (B) Annualised rates of bleeding and FVIII infusion for the 4 × 1013 vg/kg cohort at baseline and in years 1, 2, 3, and 4. The participant in the 6 × 1013 cohort receiving on‐demand FVIII treatment at baseline was excluded. Year 1 included weeks 5–52 only; Year 2 included weeks 53–104; Year 3 included weeks 105–156; Year 4 included weeks 157–208; Year 5 included weeks 209–260. †In year 5, in addition to treatment for bleeding, two participants in the 6 × 1013 vg/kg cohort had 12 instances of exogenous FVIII use due to surgery. ‡In year 4, in addition to treatment for bleeding, two participants in the 6 × 1013 vg/kg cohort had two instances of exogenous FVIII use due to surgery. §In year 3, in addition to treatment for bleeding, one participant in the 6 × 1013 vg/kg cohort had 23 instances of exogenous FVIII use due to surgery, including knee replacement. ¶In year 2, in addition to treatment for bleeding, two participants in the 6 × 1013 vg/kg cohort had 48 instances of exogenous FVIII use due to surgery. ††In year 1, in addition to treatment for bleeding, no participants in the 6 × 1013 vg/kg cohort used exogenous FVIII as prophylaxis for surgery. ‡‡In year 4, in addition to treatment for bleeding, one participant in the 4 × 1013 vg/kg cohort had three instances of FVIII use due to surgery, including colonoscopy with biopsy. §§In year 3, in addition to treatment for bleeding, three participants in the 4 × 1013 vg/kg cohort had 46 instances of exogenous FVIII use due to surgery, including knee replacement and liver biopsy. ¶¶In year 2, in addition to treatment for bleeding, one participant in the 4 × 1013 vg/kg cohort had one instance of exogenous FVIII use due to sigmoidoscopy. †††In year 1, in addition to treatment for bleeding, one participant in the 4 × 1013 vg/kg cohort had one instance of exogenous FVIII use due to surgery. FVIII, factor VIII

FIGURE 4

Individual participants’ annualised FVIII infusion rate and ABR at baseline and from week 5 and onward and FVIII activity at the end of year 5 or 4. (A) The 6 × 1013 vg/kg cohort. (B) The 4 × 1013 vg/kg cohort. Participants are ordered by descending current FVIII activity (week 260 for 6 × 1013 cohort; week 208 for 4 × 1013 cohort). Current FVIII activity ranges are based on median value in a ±4‐week window. †From week 5 onward, participant nine had one instance of exogenous FVIII use for surgery prophylaxis. ‡From week 5 onward, in addition to treatment for bleeding, participant four had four instances of exogenous FVIII use due to prophylaxis for surgery and liver biopsy. §From week 5 onward, in addition to treatment for bleeding, participant six had 47 instances of exogenous FVIII use due to surgery prophylaxis, including total knee replacement. ¶From week 5 onward, participant three had 34 instances of exogenous FVIII use due to prophylaxis for total knee replacement surgery and liver biopsy. ††From week 5 onward, in addition to treatment for bleeding, participant 11 had two instances of exogenous FVIII use due to liver biopsy. ‡‡From week 5 onward, participant 14 only used exogenous FVIII as treatment for bleeding. §§From week 5 onward, in addition to treatment for bleeding, participant 10 had one instance of exogenous FVIII use due to prophylaxis for a sigmoidoscopy. ¶¶From week 5 onward, in addition to treatment for bleeding, participant 12 had three instances of exogenous FVIII use due to prophylaxis for procedures, including colonoscopy with biopsies taken. †††From week 5 onward, in addition to treatment for bleeding, participant 13 had three instances of exogenous FVIII use due to prophylaxis for surgery, a tooth extraction, and steroid injection. ‡‡‡From week 5 onward, in addition to treatment for bleeding, participant 15 had 43 instances of exogenous FVIII use due to general surgery, total knee replacement, and liver biopsy. ABR, annualised bleeding rate; CS, chromogenic substrate assay; FVIII, factor VIII; LLOQ, lower limit of quantitation; OS, one‐stage assay; SAE, serious adverse event. [Correction added on 28 August 2021, after first online publication: In Figure 4, the values for Participants 3 and 13 were wrongly aligned and have been corrected in this version.]

FIGURE 5

Haemo‐QOL‐A Total Score over 5 years. Dotted lines indicate baseline values for each cohort. Total score is based on six domains: Consequences of Bleeding (7 items), Emotional Impact (6 items), Physical Functioning (9 items), Role Functioning (11 items), Treatment Concern (3 items), and Worry (5 items). Haemo‐QOL‐A, haemophilia‐specific health‐related QOL questionnaire for adults; SD, standard deviation