Hemlibra (Page 5 of 8)

14.2 Hemophilia A with FVIII Inhibitors

The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was evaluated in three clinical trials [adult and adolescent studies (HAVEN 1 and HAVEN 4) and a pediatric study (HAVEN 2)].

HAVEN 1 (Adult and Adolescent Patients)

The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients received HEMLIBRA prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter, or no prophylaxis (Arm B). Patients in Arm B could switch to HEMLIBRA prophylaxis after completing at least 24 weeks without prophylaxis. Dose up-titration to 3 mg/kg once every week was allowed after 24 weeks on HEMLIBRA prophylaxis for patients who experienced two or more qualified bleeds (i.e., spontaneous and clinically significant bleeds occurring at steady state). During the study, two patients underwent up-titration of their maintenance dose; however, this study was not designed to investigate the 3 mg/kg once every week dosing regimen.

Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized in a 2:1 ratio to receive HEMLIBRA prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C to receive HEMLIBRA prophylaxis. Seven patients previously treated with episodic (on-demand) bypassing agents who had participated in the NIS prior to enrollment, but were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D to receive HEMLIBRA prophylaxis.

Efficacy was evaluated after a minimum of 24 weeks of follow-up based on the bleed rate for bleeds requiring treatment with coagulation factors among patients previously treated with episodic bypassing agents who were randomized to HEMLIBRA prophylaxis (Arm A) compared with those receiving no prophylaxis (Arm B). The study also evaluated the randomized comparison of Arms A and B for the efficacy of HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning.

The efficacy of HEMLIBRA prophylaxis compared with previous prophylactic bypassing agents was also evaluated in patients who had participated in the NIS prior to enrollment (Arm C). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity as that used in HAVEN 1.

The efficacy results of HEMLIBRA prophylaxis 1.5 mg/kg once every week compared with no prophylaxis with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in Table 8.

Table 8 Annualized Bleed Rate with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients ≥ 12 Years of Age with Factor VIII Inhibitors
Endpoint HEMLIBRA1.5 mg/kg once every week(N = 35) No Prophylaxis(N = 18)
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.
*
Based on negative binomial regression model.
Treated Bleeds
ABR (95% CI) * 2.9 (1.7, 5.0) 23.3 (12.3, 43.9)
% reduction (95% CI)p-value 87% (72.3%, 94.3%)< 0.0001
% patients with 0 bleeds (95% CI) 62.9 (44.9, 78.5) 5.6 (0.1, 27.3)
Median ABR (IQR) 0 (0, 3.7) 18.8 (13.0, 35.1)
All Bleeds
ABR (95% CI) * 5.5 (3.6, 8.6) 28.3 (16.8, 47.8)
% reduction (95% CI)p-value 80% (62.5%, 89.8%)< 0.0001
% patients with 0 bleeds (95% CI) 37.1 (21.5, 55.1) 5.6 (0.1, 27.3)
Median ABR (IQR) 2 (0, 9.9) 30.2 (18.3, 39.4)
Treated Spontaneous Bleeds
ABR (95% CI) * 1.3 (0.7, 2.2) 16.8 (9.9, 28.3)
% reduction (95% CI)p-value 92% (84.6%, 96.3%)< 0.0001
% patients with 0 bleeds (95% CI) 68.6 (50.7, 83.1) 11.1 (1.4, 34.7)
Median ABR (IQR) 0 (0, 3.3) 15.2 (6.6, 30.4)
Treated Joint Bleeds
ABR (95% CI) * 0.8 (0.3, 2.2) 6.7 (2.0, 22.4)
% reduction (95% CI)p-value 89% (48%, 97.5%)0.0050
% patients with 0 bleeds (95% CI) 85.7 (69.7, 95.2) 50.0 (26.0, 74.0)
Median ABR (IQR) 0 (0, 0) 1 (0, 14.4)
Treated Target Joint Bleeds
ABR (95% CI) * 0.1 (0.03, 0.6) 3.0 (1.0, 9.1)
% reduction (95% CI)p-value 95% (77.3%, 99.1%)0.0002
% patients with 0 bleeds (95% CI) 94.3 (80.8, 99.3) 50.0 (26.0, 74.0)
Median ABR (IQR) 0 (0, 0) 1 (0, 6.5)

Descriptive analyses were conducted to assess HEMLIBRA prophylaxis once every week using 12-week treatment intervals up to Week 72. The descriptive mean ABRs for treated bleeds are shown in Table 9.

Table 9 Annualized Bleed Rate with HEMLIBRA Prophylaxis Once Every Week per 12-Week Intervals in Patients ≥ 12 Years of Age with Factor VIII Inhibitors
Endpoint Time Interval (Weeks)
1 – 12(N = 109) 13 – 24(N = 108) 25 – 36(N = 93) 37 – 48(N = 93) 49 – 60(N = 57) 61 – 72(N = 42)
ABR = annualized bleed rate; CI = confidence interval based on Poisson distribution; N = number of patients who contributed data for analyses at each time interval.
Treated Bleeds
Mean ABR (95% CI) 3.9(1.1, 10.2) 2.2(0.3, 7.6) 0.9(0, 5.5) 0.4(0, 4.4) 0.5(0, 4.7) 0.6(0, 4.9)

In the HAVEN 1 intra-patient analysis, HEMLIBRA prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (Table 10).

Table 10 Intra-Patient Comparison of Annualized Bleed Rate with HEMLIBRA Prophylaxis versus Previous Bypassing Agent Prophylaxis
Endpoint HEMLIBRA1.5 mg/kg once every week(N = 24) Previous Bypassing Agent Prophylaxis (N = 24)
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.
*
Based on negative binomial regression model.
Median Observation Period (weeks) 30.1 32.1
Treated Bleeds
ABR (95% CI) * 3.3 (1.3, 8.1) 15.7 (11.1, 22.3)
% reduction (95% CI)p-value 79% (51.4%, 91.1%)0.0003
% patients with 0 bleeds (95% CI) 70.8 (48.9, 87.4) 12.5 (2.7, 32.4)
Median ABR (IQR) 0 (0, 2.2) 12 (5.7, 24.2)

The HAVEN 1 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the Physical Health Score of the Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire for patients ≥ 18 years of age. The HEMLIBRA prophylaxis arm (Arm A) showed an improvement compared with the no prophylaxis arm (Arm B) in the Haem-A-QoL Physical Health Subscale score at the Week 25 assessment (Table 11). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25.

Table 11 Change in Haem-A-QoL Physical Health Score with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients (≥ 18 Years of Age) with Factor VIII Inhibitors at Week 25
Haem-A-QoL Scores at Week 25 HEMLIBRA1.5 mg/kg once every week(N = 25*) No Prophylaxis(N = 14*)
*
Number of patients ≥ 18 years who completed the Haem-A-QoL questionnaire.
Lower scores are reflective of better functioning.
Adjusted for baseline, and baseline by treatment group interaction.
Physical Health Score (range 0 to 100)
Adjusted mean 32.6 54.2
Difference in adjusted means (95% CI) 21.6 (7.9, 35.2)
p-value 0.0029

HAVEN 2 (Pediatric Patients)

The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical trial in pediatric males (age < 12 years, or 12 – 17 years who weigh < 40 kg) with hemophilia A with FVIII inhibitors. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once every week thereafter.

The study evaluated the efficacy of HEMLIBRA prophylaxis, including the efficacy of HEMLIBRA prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (NIS) prior to enrollment (intra-patient analysis).

At the time of the interim analysis, efficacy was evaluated in 59 pediatric patients who were < 12 years of age and had been receiving HEMLIBRA prophylaxis for at least 12 weeks, including 38 patients age 6 to < 12 years, 17 patients age 2 to < 6 years, and four patients age < 2 years.

Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 59 patients (Table 12). The median observation time for these patients was 29.6 weeks (range 18.4 – 63 weeks).

Table 12 Annualized Bleed Rate with HEMLIBRA Prophylaxis 1.5 mg/kg Once Every Week in Pediatric Patients < 12 Years of Age with Factor VIII Inhibitors (Interim Analysis)
Endpoint ABR * (95% CI)N = 59 Median ABR (IQR)N = 59 % Zero Bleeds (95% CI)N = 59
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.
*
Based on negative binomial regression model.
Treated Bleeds 0.3 (0.1, 0.5) 0 (0, 0) 86.4 (75, 94)
All Bleeds 3.8 (2.2, 6.5) 0 (0, 3.4) 55.9 (42.4, 68.8)
Treated Spontaneous Bleeds 0 (0, 0.2) 0 (0, 0) 98.3 (90.9, 100)
Treated Joint Bleeds 0.2 (0.1, 0.4) 0 (0, 0) 89.8 (79.2, 96.2)
Treated Target Joint Bleeds 0.1 (0, 0.7) 0 (0, 0) 96.6 (88.3, 99.6)

In the intra-patient analysis, 18 pediatric patients who had participated in the NIS had an ABR for treated bleeds of 19.8 (95% CI [15.3, 25.7]) on previous bypassing agent treatment (prophylactic treatment in 15 patients and on-demand treatment for 3 patients). HEMLIBRA prophylaxis resulted in an ABR for treated bleeds of 0.4 (95% CI [0.2, 0.9]) based on negative binomial regression, corresponding to a 98% reduction in bleed rate. On HEMLIBRA prophylaxis, 14 patients (77.8%) had zero treated bleeds.

The HAVEN 2 study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement) using the Physical Health Score of the Hemophilia-specific Quality of Life Short Form (Haemo-QoL-SF) questionnaire for patients ≥ 8 to < 12 years of age. HEMLIBRA prophylaxis showed improvement from baseline in the Haemo-QoL-SF Physical Health Subscale score at the Week 25 assessment.

HAVEN 4 (Adult and Adolescent Patients)

The HAVEN 4 study (NCT03020160) was a single-arm, multicenter, open-label, clinical trial in 41 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A with or without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII or bypassing agents. Patients received HEMLIBRA prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 6 mg/kg once every four weeks thereafter.

Efficacy was evaluated in a subgroup of 5 patients with hemophilia A with FVIII inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. The median observation time was 26.1 weeks (range 24.4 – 28.6 weeks). HEMLIBRA prophylaxis resulted in an ABR (95% CI) for treated bleeds of 1.2 (0.1, 14.8) based on negative binomial regression. On HEMLIBRA prophylaxis, 4 patients had zero treated bleeds.

The efficacy results of HEMLIBRA prophylaxis (1.5 mg/kg once every week, 3 mg/kg once every two weeks, and 6 mg/kg once every four weeks) with respect to rate of treated bleeds are shown in Table 13.

Table 13 Annualized Bleed Rate (Treated Bleeds) with HEMLIBRA Prophylaxis in Patients with or without Factor VIII Inhibitors
Endpoint HAVEN 1 HAVEN 2 HAVEN 3 HAVEN 4
HEMLIBRA 1.5 mg/kg once every week (N = 35) No Prophylaxis(N = 18) HEMLIBRA 1.5 mg/kg once every week(N = 59) HEMLIBRA 1.5 mg/kg once every week(N = 36) HEMLIBRA 3 mg/kg once every two weeks(N = 35) No Prophylaxis(N = 18) HEMLIBRA 6 mg/kg once every four weeks(N = 41)
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile; HAVEN 1 = adult and adolescent patients with factor VIII inhibitors; HAVEN 2 = pediatric patients with factor VIII inhibitors; HAVEN 3 = adult and adolescent patients without factor VIII inhibitors; HAVEN 4 = adult and adolescent patients with or without factor VIII inhibitors.
*
Based on negative binomial regression model.
Median Efficacy Period (weeks) 29.3 24 29.6 29.6 31.3 24 25.6
ABR(95% CI) * 2.9(1.7, 5) 23.3(12.3, 43.9) 0.3(0.1, 0.5) 1.5(0.9, 2.5) 1.3(0.8, 2.3) 38.2(22.9, 63.8) 2.4(1.4, 4.3)
% reduction vs no prophylaxis (95% CI),p-value 87% (72.3%, 94.3%)< 0.0001 96% (92.5%, 98%)< 0.0001 97% (93.4%, 98.3%)< 0.0001
% patients with 0 bleeds(95% CI) 62.9(44.9, 78.5) 5.6(0.1, 27.3) 86.4(75, 94) 55.6(38.1, 72.1) 60(42.1, 76.1) 0(0, 18.5) 56.1(39.7, 71.5)
% patients with 0 — 3 bleeds (95% CI) 85.7(69.7, 95.2) 11.1(1.4, 34.7) 100(93.9, 100) 91.7(77.5, 98.2) 94.3(80.8, 99.3) 5.6(0.1, 27.3) 90.2(76.9, 97.3)
Median ABR (IQR) 0(0, 3.7) 18.8(13, 35.1) 0(0, 0) 0(0, 2.5) 0(0, 1.9) 40.4(25.3, 56.7) 0(0, 2.1)

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