Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3 GENEr8-1 trial

Abstract

Background: Valoctocogene roxaparvovec, an adeno-associated virus-mediated gene therapy for severe hemophilia A, enables endogenous factor (F)VIII expression and provides bleed protection.

Objectives: Determine valoctocogene roxaparvovec durability, efficacy, and safety 4 years after treatment.

Methods: In the phase 3 GENEr8-1 trial, 134 adult male persons with severe hemophilia A without inhibitors and previously using FVIII prophylaxis received a 6 × 10¹³ vg/kg infusion of valoctocogene roxaparvovec. Efficacy endpoints included annualized bleed rate, annualized FVIII infusion rate, FVIII activity, and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Adverse events and immunosuppressant use were assessed. Change from baseline was assessed after participants discontinued prophylaxis (scheduled for week 4).

Results: Median follow-up was 214.3 weeks; 2 participants discontinued since the previous data cutoff. Declines from baseline in mean treated annualized bleed rate (-82.6%; P < .0001) and annualized FVIII infusion rate (-95.5%; P < .0001) were maintained from previous years in the primary analysis population of 112 participants who enrolled from a noninterventional study. During year 4, 81 of 110 rollover participants experienced 0 treated bleeds. Week 208 mean and median chromogenic FVIII activity were 16.1 IU/dL and 6.7 IU/dL, respectively, in 130 modified intention-to-treat participants. Seven participants resumed prophylaxis since the previous data cutoff. Mean change from baseline to week 208 in Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score (P < .0001) remained clinically meaningful for modified intention-to-treat participants. Alanine aminotransferase elevation was the most common adverse event during year 4 (56/131 participants); none required immunosuppressants.

Conclusion: Valoctocogene roxaparvovec provides persistent FVIII expression, hemostatic control, and health-related quality of life improvements with no new safety signals.

Keywords: adeno-associated virus; clinical trial; gene therapy; hemophilia A; quality of life.

Figure 1

Changes from baseline to after prophylaxis in the rollover population (N = 112) in (A) annualized bleed rate (ABR) for treated bleeds, (B) proportion of participants with 0 treated bleeds, (C) ABR for all bleeds, (D) proportion of participants with 0 bleeds, and (E) annualized factor VIII infusions. Years 3 and 4 data were based on n = 110 due to participants who discontinued from the study. AFR, annualized rate of exogenous factor VIII infusions; Q, quartile.

Figure 2

Factor (F)VIII activity per chromogenic substrate assay (CSA) over 4 years after treatment with valoctocogene roxaparvovec in the modified intention-to-treat (mITT) population (N = 132). (A) Mean FVIII activity over time in the mITT population and a subgroup of the mITT population dosed ≥5 years (n = 17). (B) Distribution of median FVIII activity at the end of each year after infusion. Median FVIII activity was calculated for 4- or 6-week windows. FVIII activity was imputed as 1 IU/dL at baseline, 0 IU/dL if the participant discontinued the study, and the smaller of the median values of the previous or next 4- or 6-week window for other missing values (or via linear extrapolation using values of the previous 2 windows if the next window was missing and capped at the value of the previous window). Q, quartile.

Figure 3

(A) Kaplan–Meier curve of prophylactic treatment-free probability. (B) Annualized bleed rate (ABR) for treated bleeds at baseline, ABR for treated bleeds up to return to prophylaxis (RTP), and factor (F)VIII activity for participants who resumed prophylaxis since the previous data cutoff. Prophylaxis was defined as a FVIII infusion categorized as “usual FVIII prophylaxis” administered at least once a week for ≥4 consecutive weeks or ≥2 emicizumab injections in 1 month. The latest valid FVIII activity measurement prior to RTP is presented. The lower limit of quantification for chromogenic substrate assay (CSA) was 1.5 IU/dL (previously 3 IU/dL). ITT, intention-to-treat.

Figure 4

Change from baseline in health-related quality of life outcomes in the modified intent-to-treat (mITT) population (N = 132) excluding data after participants resumed prophylaxis. (A) Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A) Total Score and domain scores. (B) Haemophilia Activities List (HAL) Summary Score. (C) Work Productivity and Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS). ^aA clinically important difference (CID) for the Treatment Concern domain has not yet been estimated. ∗P < .05; ∗∗P < .001 based on a 2-tailed t-test against the null hypothesis of no change from baseline. Missing data were not imputed. Mean changes from baseline are based on available data at each time point, which may differ from the given N. Data after participants resumed prophylaxis were censored.