Valoctocogene Roxaparvovec Gene Therapy Success Detailed For Hemophilia A Patients
Overview
Valoctocogene roxaparvovec is a gene therapy utilizing an adeno-associated virus serotype 5 (AAV5) vector, approved for treating severe hemophilia A (HA). The purpose of this summary is to present the safety and efficacy outcomes observed seven years post-dosing in a phase 1/2 clinical trial (NCT02576795).
Methods involved the treatment of male patients, aged 18 years and older, with severe HA (defined as factor VIII [FVIII] levels ≤1 international unit [IU]/dL) who were previously reliant on exogenous FVIII and had no history of FVIII inhibitors or antibodies against AAV5. Participants received valoctocogene roxaparvovec and were monitored for 7 years (at a dose of 6 × 10^13 vg/kg; n = 7) and 6 years (at a dose of 4 × 10^13 vg/kg; n = 6).
Results from the final year indicated that treatment-related adverse events (AEs) were reported by one participant in each cohort: grade 1 hepatomegaly in the 6 × 10^13 group, and grade 1 splenomegaly and grade 1 hepatic steatosis in the 4 × 10^13 group. Throughout the follow-up period, the mean rates of annualized treated bleeds and the need for exogenous FVIII infusions were reduced by over 88% compared to baseline. At years 7 and 6, the mean (median) FVIII activity levels, as measured by a chromogenic assay, were 16.2 (10.3) IU/dL in the 6 × 10^13 group (n = 5) and 6.7 (7.2) IU/dL in the 4 × 10^13 group (n = 4), corresponding to mild hemophilia. Regression analysis for the last year revealed a rate of FVIII activity change of -0.001 IU/dL/week for the 6 × 10^13 group and -0.07 IU/dL/week for the 4 × 10^13 group. Two participants in the 6 × 10^13 cohort resumed prophylactic treatment in year 7: one due to a non-treatment-related grade 4 serious adverse event involving a spontaneous internal carotid artery bleed, and the other to manage recurrent bleeds and declining FVIII activity.
In conclusion, the long-term safety and efficacy of valoctocogene roxaparvovec continue to align with earlier findings, demonstrating sustained hemostatic control in most participants. However, two individuals returned to prophylaxis during the seventh year of follow-up.
Introduction
Haemophilia A (HA) is an X-linked disorder characterized by a deficiency in coagulation factor VIII (FVIII). Individuals with severe HA, defined by FVIII activity of ≤1 IU/dL, often suffer from recurrent spontaneous bleeding in muscles and joints. This can lead to chronic pain, haemophilic arthropathy, reduced mobility, and an overall diminished quality of life. The standard treatment for severe HA involves regular prophylaxis with exogenous FVIII or emicizumab. While effective, these treatments can be burdensome and do not eliminate the constant mental burden of living with haemophilia.
Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an innovative gene therapy designed to address these challenges. Valoctocogene roxaparvovec therapy utilizes a replication-incompetent adeno-associated virus (AAV) serotype 5 (AAV5) capsid to deliver the SQ variant of a B-domain–deleted FVIII coding sequence. This sequence is controlled by a hepatocyte-selective promoter, enabling increased FVIII expression in individuals with severe HA following a single infusion. Phase 1/2 and Phase 3 clinical trials have shown that valoctocogene roxaparvovec leads to sustained FVIII activity and a significant reduction in bleeding episodes compared to traditional FVIII prophylaxis. Importantly, no participants in these trials developed FVIII inhibitors.
The most common adverse event reported during these trials was asymptomatic elevation of alanine aminotransferase (ALT), which was effectively managed with glucocorticoids. Valoctocogene roxaparvovec received conditional marketing authorization from the European Medicines Agency in 2022, followed by approval from the US Food and Drug Administration in 2023. The updated findings from the phase 1/2 study, now with 7 and 6 years of follow-up for the 6 × 10^13 and 4 × 10^13 vg/kg cohorts, respectively, represent the longest follow-up data available for any HA gene therapy trial, providing valuable insights into the long-term safety and efficacy of this treatment.
Method
This open-label, phase 1/2 dose-escalation trial, previously detailed in earlier reports, investigated the safety and efficacy of valoctocogene roxaparvovec in males aged 18 years and older with severe hemophilia A (HA), defined by FVIII levels ≤1 IU/dL. Participants, who were previously receiving exogenous FVIII, were administered varying doses of the gene therapy: 6 × 10¹² vg/kg (n = 1), 2 × 10¹³ vg/kg (n = 1), 4 × 10¹³ vg/kg (n = 6), or 6 × 10¹³ vg/kg (n = 7). This summary focuses on follow-up data from the two highest dose cohorts, 4 × 10¹³ vg/kg and 6 × 10¹³ vg/kg. Eligible participants were free from a history of FVIII inhibitors or anti-AAV5 antibodies, and exclusion criteria included significant liver dysfunction, advanced liver fibrosis, or cirrhosis.
Safety evaluations included laboratory assessments and the monitoring of adverse events (AEs), graded according to the Common Terminology Criteria for Adverse Events version 4.3. The study also tracked annualized treated bleeding rates (ABRs) and FVIII infusion rates, calculated as previously described. For participants who had been on regular FVIII prophylaxis, baseline rates were based on data from the 12 months preceding enrollment. FVIII activity was measured using both chromogenic substrate assay (CSA) and one-stage assay (OSA), with assessments conducted every 26 weeks starting at week 260 for the 4 × 10¹³ vg/kg cohort and week 312 for the 6 × 10¹³ vg/kg cohort during years 6 and 7. Liver ultrasounds were performed at screening, during year-end visits beginning in year 5, and as needed based on physician discretion.
Statistical analysis involved summarizing data with descriptive statistics, without imputation for missing data. The yearly rate of change in FVIII activity was analyzed using a linear regression model, and end-of-year mean FVIII activity values were employed to determine the annual absolute percentage change in FVIII activity. According to the statistical analysis plan, data from participants who resumed prophylaxis were excluded from subsequent analyses following their return to prophylaxis.
Result
Prior to enrollment, one participant from the 6 × 10^13 vg/kg cohort was utilizing on-demand FVIII treatment, while the remaining participants in both the 6 × 10^13 and 4 × 10^13 vg/kg cohorts were on prophylaxis with exogenous FVIII. Baseline characteristics of these participants had been previously published. Up until now, all seven participants from the 6 × 10^13 vg/kg cohort and five from the 4 × 10^13 vg/kg cohort have remained in the study, with follow-ups lasting 7 and 6 years, respectively. One participant from the 4 × 10^13 vg/kg cohort was lost to follow-up after 288 weeks, with their last FVIII activity measured during week 288, indicating moderate hemophilia levels.
Throughout the study, the most frequent adverse event (AE) associated with valoctocogene roxaparvovec treatment was mild to moderate transient ALT elevations. No ALT elevations were observed in the last year, and no long-term effects from corticosteroid treatment were noted. There were no thrombotic events or the development of FVIII inhibitors among participants.
During the last year of follow-up, no new treatment-related serious adverse events (SAEs) were recorded in either cohort, although one participant from each cohort did experience treatment-related AEs. In the 6 × 10^13 vg/kg cohort, one participant was diagnosed with grade 1 hepatomegaly during a routine liver ultrasound, which lasted approximately 35 weeks before resolving. In the 4 × 10^13 vg/kg cohort, a participant with a history of fatty liver disease was found to have grade 1 splenomegaly and worsening hepatic steatosis, both of which were resolving at the last follow-up.
One participant from the 6 × 10^13 vg/kg cohort experienced a non-treatment-related SAE involving internal carotid artery bleeding due to a carotid artery dissection. This led to a return to prophylaxis and was managed with on-demand FVIII infusions before surgery. The participant recovered from the bleeding event but developed grade 3 hypertension during hospitalization.
Over the study period, the 6 × 10^13 vg/kg cohort showed a mean annual bleed rate (ABR) of 0.75 bleeds per year, representing a 96% reduction from baseline. The mean annual FVIII infusion rate for this cohort was 6.38 infusions per year, a 95% decrease from baseline. During year 7, the mean ABR increased slightly to 0.9 bleeds per year, and the FVIII infusion rate rose to 17.4 infusions per year. Two participants resumed prophylaxis due to bleeding events.
In the 4 × 10^13 vg/kg cohort, the overall mean ABR was 1.45 bleeds per year, marking an 88% reduction from baseline. The mean FVIII infusion rate was 9.32 infusions per year, a 93% decline from baseline. During year 6, the mean ABR and FVIII infusion rates were 2.5 and 3.5 infusions per year, respectively. One participant reported 15 treated bleeds, primarily in the ankle joints, but chose to remain off regular prophylaxis.
Beyond one year post-dose, the decline in FVIII activity was consistent with previous years for both cohorts. The estimated change in FVIII activity during year 7 for the 6 × 10^13 vg/kg cohort was negligible, while the 4 × 10^13 vg/kg cohort saw a slight decrease. At the end of the follow-up period, most participants had FVIII activity within the mild to moderate hemophilia range.
Overall, five out of seven participants from the 6 × 10^13 vg/kg cohort and three out of five from the 4 × 10^13 vg/kg cohort maintained FVIII activity in the mild to moderate hemophilia range, with one participant from each cohort showing activity in the non-hemophilic range.
Conclusion
This open-label, phase 1/2 dose-escalation trial investigated the long-term safety and efficacy of valoctocogene roxaparvovec in adult males with severe Hemophilia A (HA) over a period of 7 and 6 years for the 6 × 10^13 vg/kg and 4 × 10^13 vg/kg cohorts, respectively. It represents the longest follow-up for any HA gene therapy trial to date. The incidence of treatment-related adverse events (AEs) remained consistent with previous reports, with common AEs including elevations in ALT and liver dysfunction, particularly during the first year after treatment. However, no participants developed FVIII inhibitors throughout the study duration.
The trial demonstrated sustained clinical benefits, with reduced annualized bleeding rates (ABRs) and low rates of exogenous FVIII infusions compared to baseline. While two participants from the 6 × 10^13 vg/kg cohort resumed prophylactic treatment due to severe bleeding events, most participants maintained effective haemostatic control without the need for regular prophylaxis. Liver biopsy investigations indicated that the long-term expression of FVIII is likely driven by the formation of circular episomes in hepatocytes.
Over the 7- and 6-year periods, the safety outcomes were consistent with earlier findings, and the slow decline in FVIII levels did not significantly impair haemostasis for most participants. The study highlights the prolonged efficacy and safety of valoctocogene roxaparvovec in managing severe HA, although further exploration is warranted to understand interindividual variability and long-term outcomes.
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