14.1 Hemophilia A and B without Inhibitors in Adults and Pediatric Patients 12 Years of Age and Older

The efficacy of HYMPAVZI was established in 116 adults and pediatric patients (12 years of age and older and ≥35 kg) with severe hemophilia A (FVIII <1%) without FVIII inhibitors or moderately severe to severe hemophilia B (FIX ≤2%) without FIX inhibitors enrolled in the BASIS study (NCT03938792), open‑label, multi‑center, two‑phase study (observational and treatment phases). Patients with a history of coronary artery disease, venous or arterial thrombosis or ischemic disease were excluded from the study.

Following screening, patients entered a 6-month observation phase and were enrolled to two cohorts based on the factor replacement treatment they were receiving prior to study entry: on‑demand or routine prophylaxis. Patients who completed the observation phase were to receive 12 months of HYMPAVZI. Of the 116 patients who received HYMPAVZI, 33 patients were in the on‑demand treatment cohort and 83 were in the prophylactic treatment with FVIII or FIX cohort during the observation phase.

Patients received an initial 300 mg loading dose of HYMPAVZI followed by maintenance doses of 150 mg of HYMPAVZI once weekly for 12 months. Dose escalation to 300 mg of HYMPAVZI once weekly was permitted after 6 months of treatment in patients weighing ≥50 kg and experiencing 2 or more breakthrough bleeds. Fourteen (12%) underwent dose escalation.

The mean annualized bleeding rates (ABRs) for treated bleeds were 39.9 and 7.9 in the observational phase for the on-demand and prophylaxis cohorts, respectively. All patients in the on-demand cohort had one or more target joints at study entry and 36.4% had 3 or more target joints at study entry. In the routine prophylaxis cohort, 55.4% of the patients had one or more target joints at study entry and 16% had 3 or more target joints at study entry.

The efficacy of HYMPAVZI for each cohort was based upon the ABR of treated bleeds during treatment with HYMPAVZI compared to ABR during the observational phase. Other objectives of the study included evaluation of HYMPAVZI prophylaxis on the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

Among the 116 patients treated with HYMPAVZI in the BASIS study, the mean age was 32 years (range 13 to 66); 19 patients were 12 to less than 18 years of age and all were male. Fifty-six (56) patients were White, 58 patients were Asian, 1 patient was Black or African American and 1 patient had race information unreported; 12 patients identified as Hispanic or Latino and 104 patients identified as not Hispanic or Latino. The patient population included 91 with hemophilia A and 25 with hemophilia B.

Patients with On-Demand Factor-Based Therapy in Observational Phase
Table 3 shows the efficacy results of HYMPAVZI prophylaxis compared with on-demand factor-based therapy. HYMPAVZI prophylaxis demonstrated superiority over on-demand factor-based therapy in incidences of treated bleeds, spontaneous bleeds, joint bleeds, total bleeds and target joint bleeds.

Patients with Routine Prophylactic Factor-Based Therapy
Table 4 shows the efficacy results of HYMPAVZI prophylaxis compared with routine prophylactic factor‑based therapy. HYMPAVZI prophylaxis demonstrated non-inferiority to routine prophylactic factor‑based therapy as measured by ABR of treated bleeds as well as incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

14.2 Hemophilia A and B with Inhibitors in Adults and Pediatric Patients 12 Years of Age and Older

The efficacy of HYMPAVZI was established in 48 adults and pediatric patients (12 years of age and older and ≥35 kg) with severe hemophilia A (FVIII <1%) with FVIII inhibitors or moderately severe to severe hemophilia B (FIX ≤2%) with FIX inhibitors enrolled in the BASIS study (NCT03938792), open-label, multi-center, two-phase study (observational and treatment phases). Patients had current or history of high titer inhibitors (≥5 BU/mL) and were in need of treatment with bypassing agents in the last 6 months prior to enrollment. Patients with previous or current treatment for or history of coronary artery disease, venous or arterial thrombosis or ischemic disease were excluded from the study.

Following screening, 51 patients entered a 6‑month observation phase and received either on‑demand (N = 48) or routine prophylactic treatment (N = 3) with bypassing agents (rFVIIa or aPCC). Patients who completed the observation phase were to receive 12 months of HYMPAVZI.

Patients received an initial 300 mg loading dose of HYMPAVZI followed by maintenance doses of 150 mg of HYMPAVZI once weekly for 12 months. Dose escalation to 300 mg of HYMPAVZI once weekly was permitted after 6 months of treatment in patients weighing ≥50 kg and experiencing 2 or more breakthrough bleeds. Four (7.8%) of 51 patients underwent dose escalation.

The efficacy of HYMPAVZI was based upon the ABR of treated bleeds during treatment with HYMPAVZI compared to ABR during on-demand bypassing agent therapy during the observational phase. Other objectives of the study included evaluation of HYMPAVZI prophylaxis in comparison with on-demand bypassing agent therapy as measured by the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

Among the 51 male patients treated with HYMPAVZI, the mean age was 27.7 years (range 12 to 75); 25.5% of patients were 12 to less than 18 years, 74.5% were 18 years and older. In this study, 29.4% of patients were White, 54.9% were Asian, 15.7% were Black or African American, 2.0% of patients identified as Hispanic or Latino. All patients had a documented history of inhibitors (78.4% hemophilia A, 21.6% hemophilia B).

Efficacy was established in 48 patients that previously received on-demand bypassing agents before crossing over to HYMPAVZI. This population was characterized by a severe bleeding phenotype. The mean ABR for treated bleeds was 19.8 in the observational phase, prior to crossing over to weekly HYMPAVZI prophylaxis. Of the 48 patients, 70.8% had one or more target joints at study entry and 25.0% had 3 or more target joints at study entry.

Patients with On-Demand Bypassing Agent Therapy in Observational Phase
Table 5 shows the efficacy results of HYMPAVZI prophylaxis compared with on‑demand bypassing agent therapy. HYMPAVZI prophylaxis demonstrated superiority over on-demand therapy in incidences of treated bleeds, spontaneous bleeds, joint bleeds, total bleeds and target joint bleeds.

14.3 Hemophilia A and B with or without Inhibitors in Pediatric Patients 6 to less than 18 Years of Age

The efficacy of HYMPAVZI was established in 57 pediatric patients 6 to less than 18 years of age with severe hemophilia A (FVIII <1%) with or without FVIII inhibitors or moderately severe to severe hemophilia B (FIX ≤2%) with or without FIX inhibitors, enrolled in the BASIS KIDS study (NCT05611801), an ongoing open‑label, multi‑center clinical study. Patients were enrolled sequentially in 2 age groups: 12 to less than 18 years of age (≥25 kg) and 6 to less than 12 years of age (≥19 kg). Patients enrolled in the study required at least 12 months of documented historical bleeding events while on on-demand or on prophylactic treatment with bypassing agents or factor replacement therapy. Patients with a history of coronary artery disease, venous or arterial thrombosis or ischemic disease were excluded from the study. The efficacy of HYMPAVZI was established in these pediatric patients who were dosed at least 12 months before the data cutoff.

Patients 6 to less than 12 years of age (N = 34) received an initial 150 mg loading dose of HYMPAVZI followed by maintenance doses of 75 mg of HYMPAVZI once weekly for 12 months. Patients 12 to less than 18 years of age (N = 23) received an initial 300 mg loading dose of HYMPAVZI followed by maintenance doses of 150 mg of HYMPAVZI once weekly for 12 months. Dose escalation to 150 mg of HYMPAVZI once weekly for patients 6 to less than 12 years of age weighing ≥25 kg or 300 mg for patients 12 to less than 18 years of age weighing ≥50 kg was allowed after 3 months for patients experiencing 2 or more breakthrough bleeds. Two (5.9%) of the 34 patients 6 to less than 12 years of age, and 3 (13%) of the 23 patients 12 to less than 18 years of age underwent dose escalation.

The efficacy of HYMPAVZI was based upon the ABR of treated bleeds during treatment with HYMPAVZI prophylaxis versus ABR of treated bleeds retrospectively collected during the 12-month historical phase. During this historical phase, in the non-inhibitor cohort (N = 36), all patients received routine prophylactic treatment with factor replacement therapy and in the inhibitor cohort (N = 21), patients received either on‑demand bypassing agents (N = 14) or routine prophylactic bypassing agents (N = 7). Other endpoints of the study included evaluation of HYMPAVZI prophylaxis as measured by the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

Among the 57 male patients treated with HYMPAVZI who were evaluated for efficacy, the mean age was 11 years (range 6 to 18); 59.6% of patients were 6 to less than 12 years of age and 40.4% were 12 to less than 18 years of age. In this study 35.1% of patients were White, 49.1% were Asian, 10.5% were Black or African American, 1.8% were American Indian or Alaska Native, and 3.5% race was not reported; 8.8% of patients identified as Hispanic or Latino. The patient population included 35 with hemophilia A (10 with inhibitors; 25 without inhibitors) and 22 with hemophilia B (11 with inhibitors; 11 without inhibitors).

Pediatric Patients 6 to less than 18 Years of Age with Hemophilia A or B without Inhibitors with Historic Routine Prophylactic Factor-Based Therapy
The results for the ABRs of patients without inhibitors with historic routine prophylactic factor-based therapy are shown in Table 6.

Pediatric Patients 6 to less than 18 Years of Age with Hemophilia A or B with Inhibitors
The results for the ABRs of patients with inhibitors and prior on-demand bypassing therapy are shown in Table 7.