In patients with severe hemophilia A, prophylactic treatment with valoctocogene roxaparvovec gene therapy provided a lower annualized bleeding rate (ABR) and a higher probability of zero bleeds than emicizumab, according to a study published in Haemophilia. The findings also indicate that emicizumab was more effective than standard half-life factor VIII (FVIII) prophylaxis.
“This study shows that gene therapy can improve outcomes compared to the existing treatment options with a lower ABR and more patients with zero bleeds,” said study author Robert Klamroth, MD, PhD, of Vivantes Klinikum im Friedrichshain in Berlin.
The efficacy of emicizumab prophylaxis was previously shown in the phase III HAVEN 3 trial that included one arm in which participants with severe hemophilia A received FVIII prophylaxis before being treated with emicizumab. Meanwhile, the efficacy of valoctocogene roxaparvovec was demonstrated in the phase III GENEr8-1 trial. This included patients with severe hemophilia A who had previously received regular prophylaxis with exogenous FVIII in the 270−902 study. However, a head-to-head comparison of valoctocogene roxaparvovec with emicizumab is not available.
In this study, the researchers completed cross-trial comparisons of valoctocogene roxaparvovec treatment (single 6 × 1013 vg/kg dose) outcomes from GENEr8-1 with emicizumab treatment (1.5 mg/kg QW) outcomes from HAVEN 3 and treatment outcomes with FVIII prophylaxis taken from the 270−902 study. They used matching-adjusted indirect comparison (MAIC) methods to account for differences at baseline between study populations.
“Existing prophylactic treatment of patients with severe hemophilia A is effective to prevent bleeding. Due to the lack of randomized controlled trials, it is difficult to compare the efficacy of different treatment options,” Dr. Klamroth said. “MAIC allowed us to compare outcomes of patients with severe hemophilia A who participated in phase III studies with different treatment options.”
After MAIC weighting to equalize the aggregate baseline characteristics of 63 participants in HAVEN 3, the effective sample size from GENEr8-1 was 76.2, and the effective sample size of participants in the 270−902 study was 150.6. Participants had a mean age of 36.4 years, 74.6% were white, their mean body mass index was 25.56, the mean ABR was 6.4, and the rate of less than nine bleeds in 24 weeks prior to enrollment was 84.1%, as was the rate of standard half-life FVIII product use before trial entry. The ABRs and proportions of participants without bleeds for all bleeds, treated bleeds, treated joint bleeds, and treated spontaneous bleeds were compared for each treatment.
The ABR for all bleeds was lower with valoctocogene roxaparvovec when compared with emicizumab (95% CI 0.33-0.93). Additionally, a higher proportion of participants had no treated joint bleeds (odds ratio [OR] = 2.75; 95% CI 1.20-6.31) and no treated bleeds (OR=3.25; 95% CI 1.53-6.90) with valoctocogene roxaparvovec compared with emicizumab. When compared with FVIII prophylaxis, the mean ABRs, except for all bleeds, were lower with emicizumab. Meanwhile, a higher proportion of patients taking emicizumab reported no bleeds for all outcomes compared with FVIII prophylaxis.
“Overall, the most important indicator of efficacy for any hemostatic therapy is the frequency of bleeding, particularly bleeding in joints. Thus, our finding that higher proportions of participants had zero treated bleeds and zero treated joint bleeds with valoctocogene roxaparvovec therapy compared with emicizumab is particularly noteworthy,” the authors stated. “However, additional data on the impact of these treatments on joint health using joint-specific measurements are needed.”
One limitation to the study was that the MAIC method was unable to account for factors not included in reporting that could have affected bleeding outcomes. While data beyond 52 weeks were available for participants in GENEr8-1, this analysis used only data from a 24-week follow-up period to match those from HAVEN 3 participants.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Astermark J, Buckner TW, Frenzel L, et al. Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis. Haemophilia. 2023;29(4):1087-1094.
Perspectives
Therapeutic options for hemophilia A prophylaxis continue to expand for those who have severe disease based on laboratory criteria (<1%) or a clinically severe bleeding phenotype. Innovations include engineered FVIII concentrates to improve the half-life (notably efanesoctocog alfa1); non-factor substitution therapy as such the bispecific antibody FVIIIa mimetic, emicizumab;2 and liver-directed, AAV-mediated FVIII gene transfer.3
No head-to-head clinical trials have investigated the comparative efficacy of the newest hemophilia A prophylaxis options. This study by Jan Astermark, MD, PhD, and colleagues4 leveraged a matching-adjusted indirect comparison to analyze bleeding rates among a subset of participants from the 6 x 1013 vg/kg valoctocogene roxaparvovec (GENEr8-1) and 1.5 mg/kg emicizumab weekly (HAVEN 3) clinical trials and those who participated in a prospective, non-interventional FVIII prophylaxis lead-in study to the GENEr8-1 trial (270–902). The ABR and proportion of participants without bleeds for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds were all better in the groups treated with valoctocogene roxaparvovec or emicizumab compared to conventional FVIII prophylaxis. Researchers also found that the proportion of patients with no treated bleeds and no treated joint bleeds was greater for participants who received valoctocogene roxaparvovec compared with emicizumab.
The limitations of this study include that individual data were available for those on the GENEr8-1 trial, while group-level data were available for the emicizumab HAVEN 3 trial, and the median follow-up period was 48 weeks for those who received valoctocogene roxaparvovec gene therapy compared to 33 weeks for those on emicizumab. Longer-term emicizumab follow-up data have demonstrated further improvement in bleed rates longitudinally, which may negate the differences calculated, while the median FVIII activity levels for those more than 52 weeks post-valoctocogene roxaparvovec fall significantly, which may also impact bleed rates over time.
New approaches to hemophilia therapies have reduced bleed rates by improving overall hemostatic protection with less arduous treatment burden. It has been demonstrated that boosting trough FVIII levels (hemostatic protection) with more aggressive FVIII concentrate prophylaxis increases the proportion of patients with no bleed events.5 Only a fraction of patients with clinically severe hemophilia A are eligible for gene therapy because of limitations of pre-existing neutralizing antibodies, liver health, and other comorbidities, while emicizumab has far fewer limitations to use. How bleed rates for patients using the newest “ultra” extended half-life FVIII concentrate, which permits weekly infusion and provides marked improvement in trough FVIII levels into the 10-20% range, compares to either non-factor or gene therapy prophylaxis requires investigation. Having multiple therapeutic approaches allows providers and patients to optimize the prophylactic strategy that best suits their hemophilia needs, comorbidities, and comfort with risk/benefit profiles. At present, there is not one therapy to rule them all.
Stacy E. Croteau, MD, MMS
Boston Children’s Hospital
Boston, Massachusetts
References
- von Drygalski A, Chowdary P, Kulkarni R, et al. Efanesoctocog alfa prophylaxis for patients with severe hemophilia A. N Engl J Med. 2023;388(4):310-318.
- Callaghan MU, Negrier C, Paz-Priel I, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021;137(16):2231-2242.
- Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386(11):1013-1025.
- Astermark J, Buckner TW, Frenzel L, et al. Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis. Haemophilia. 2023;29(4):1087-1094.
- Klamroth R, Windyga J, Radulescu V, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood. 2021;137(13):1818-1827.
