Emicizumab Prophylaxis in People with Moderate or Mild Hemophilia A Aged ≥40 Years, with and without Comorbidities - Findings from the Phase III HAVEN 6 Study

Abstract

Background: Emicizumab is a bispecific antibody licensed by the FDA and other regulatory authorities for prophylaxis in people of all ages with hemophilia A (HA) of any severity, with or without factor (F)VIII inhibitors (label varies by country). Few data exist specifically on older people with HA (PwHA), particularly those with comorbidities, such as cardiovascular (CV) conditions, hepatitis, and human immunodeficiency virus (HIV), and in people with moderate or mild HA. Therefore, we present a post hoc analysis of PwHA aged ≥40 years from the HAVEN 6 study (NCT04158648), which was conducted to evaluate the safety and efficacy of emicizumab in people with non-severe HA without FVIII inhibitors. Methods: HAVEN 6 is a global, multicenter, open-label, single-arm, Phase III trial conducted in individuals of all ages with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) HA without FVIII inhibitors, warranting prophylaxis as assessed by the investigator (Negrier et al. Lancet Haematol 2023). As a loading dose, emicizumab was administered subcutaneously once weekly at 3mg/kg for 4 weeks. This was then followed by the participant's choice of maintenance dose, which included the options of 1.5mg/kg weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. The primary study objective was safety, including thromboembolic events (TEs) and thrombotic microangiopathy (TMA). The primary efficacy endpoint was the annualized bleed rate (ABR) for treated bleeds. An age cut-off of ≥40 years was selected for this exploratory analysis in order to obtain a population with a high proportion of PwHA with comorbidities. In this analysis, comorbidities included CV risk factors (past medical history of CV disease; hypertension; hyperlipidemia; diabetes; body mass index ≥30kg/m 2), HIV, and current or previous history of hepatitis C virus (HCV) infection. Results: At data cut-off (Oct 30, 2021), 72 participants were enrolled in HAVEN 6. Of these, 16 individuals were aged ≥40 years and were included in this analysis; among the 16 participants aged ≥40 years, 8 (50%) were aged ≥50 years. The median (range) age was 50.5 (41-71) years and all were male. Ten (62.5%) participants had moderate HA and 6 (37.5%) had mild HA. Prior to study entry, 6 (37.5%) participants had been receiving prophylactic FVIII, while the other 10 (62.5%) had been receiving episodic FVIII infusions. In the 24 weeks prior to study entry, the median (range) number of bleeds reported by these 16 participants was 3.5 (0-60) and the mean (SD) was 7.4 (14.5), with two individuals experiencing ≥9 bleeds. Nine (56.3%) of the 16 participants had at least one CV risk factor, with 5 (31.3%) having two or more. Three (18.8%) individuals had HCV only, 1 (6.3%) had HIV only, and 2 (12.5%) had HCV and HIV co-infection. Five (31.3%) of the 16 participants did not have any of the comorbidities defined in this analysis. At the data cut-off, the median (range) duration of emicizumab exposure for the 16 participants aged ≥40 years was 1.09 (0.61-1.72) years. Fifteen (93.8%) of the 16 participants experienced ≥1 adverse event (AE) during the study. Three (18.8%) individuals experienced a serious AE and 1 (6.3%) a Grade 3/4 AE; all were deemed unrelated to emicizumab ( Table 1). There were no fatal AEs, AEs leading to withdrawal from treatment or dose modification/interruption, or TMAs. One individual, who had no CV risk factors or HIV/HCV infection, experienced a TE (Grade 1 thrombosed hemorrhoids); this was deemed unrelated to emicizumab. Three participants experienced a total of six treatment-related AEs; three of these were local injection-site reactions, with the other three being fatigue, head discomfort, and accidental overdose. During the study, the mean (95% confidence interval) ABR for treated bleeds for the 16 participants aged ≥40 years was 1.03 (0.03, 5.62), which is similar to that recorded for the overall population of HAVEN 6 (0.94 [0.02, 5.48]; Table 2). A total of 11 (68.8%) participants had zero bleeds during the study, which is comparable with the 66.7% reported for the total population. Conclusions: The small number of individuals aged ≥40 years included in the current analysis is a limitation that precludes drawing firm conclusions from the data. However, the safety and efficacy of emicizumab in these participants did not differ notably from those observed in the overall population of people with moderate or mild HA in HAVEN 6.