Hemlibra (Page 4 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals investigating the carcinogenic effects of emicizumab-kxwh have not been conducted. In vitro and in vivo testing of emicizumab-kxwh for genotoxicity was not conducted.

Animal fertility studies have not been conducted; however, emicizumab-kxwh did not cause any toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses of up to 30 mg/kg/week in subcutaneous general toxicity studies of up to 26-week duration and at doses of up to 100 mg/kg/week in a 4-week intravenous general toxicity study.

14 CLINICAL STUDIES

14.1 Hemophilia A without FVIII Inhibitors

The efficacy of HEMLIBRA for routine prophylaxis in patients with hemophilia A without FVIII inhibitors was evaluated in two clinical trials [adult and adolescent studies (HAVEN 3 and HAVEN 4)].

HAVEN 3 (Adult and Adolescent Patients)

The HAVEN 3 study (NCT02847637) was a randomized, multicenter, open-label, clinical trial in 152 adult and adolescent males (aged ≥ 12 years and ≥ 40 kg) with hemophilia A without FVIII inhibitors who previously received either episodic (on demand) or prophylactic treatment with FVIII. Patients received HEMLIBRA prophylaxis, 3 mg/kg once weekly for the first 4 weeks followed by either 1.5 mg/kg once every week [Arms A and D] or 3 mg/kg once every two weeks [Arm B] thereafter, or no prophylaxis (Arm C). Patients in Arm C could switch to HEMLIBRA prophylaxis (3 mg/kg once every two weeks) after completing at least 24 weeks without prophylaxis. For Arms A and B, 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). For Arm D patients, dose up-titration was allowed after the second qualifying bleed. During the study, five 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.

Eighty-nine patients previously treated with episodic (on demand) FVIII were randomized in a 2:2:1 ratio to receive HEMLIBRA prophylaxis 1.5 mg/kg once every week (Arm A), 3 mg/kg once every two weeks (Arm B), or no prophylaxis (Arm C), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Sixty-three patients previously treated with prophylactic FVIII were enrolled into Arm D to receive HEMLIBRA prophylaxis (1.5 mg/kg once every week).

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 (on-demand) FVIII who were randomized to HEMLIBRA prophylaxis 1.5 mg/kg once every week (Arm A) or 3 mg/kg once every two weeks (Arm B) compared with those receiving no prophylaxis (Arm C). The study also evaluated the randomized comparison of Arms A and C and Arms B and C for the efficacy of HEMLIBRA prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds.

The efficacy of HEMLIBRA prophylaxis compared with previous prophylactic FVIII was also evaluated in patients who had participated in a non-interventional study (NIS) prior to enrollment (Arm D). 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 3.

The efficacy results of HEMLIBRA prophylaxis (1.5 mg/kg once every week and 3 mg/kg once every two weeks) 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 5.

Table 5 Annualized Bleed Rate with HEMLIBRA Prophylaxis versus No Prophylaxis in Patients ≥ 12 Years of Age without Factor VIII Inhibitors
Endpoint HEMLIBRA1.5 mg/kg once every week (N = 36) HEMLIBRA3 mg/kg once every two weeks (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) * 1.5 (0.9, 2.5) 1.3 (0.8, 2.3) 38.2 (22.9, 63.8)
% reduction (95% CI)p-value 96% (92.5%, 98%)< 0.0001 97% (93.4%, 98.3%)< 0.0001
% patients with 0 bleeds (95% CI) 55.6 (38.1, 72.1) 60 (42.1, 76.1) 0 (0, 18.5)
Median ABR (IQR) 0 (0, 2.5) 0 (0, 1.9) 40.4 (25.3, 56.7)
All Bleeds
ABR (95% CI) * 2.5 (1.6, 3.9) 2.6 (1.6, 4.3) 47.6 (28.5, 79.6)
% reduction (95% CI)p-value 95% (90.1%, 97%)< 0.0001 94% (89.7%, 97%)< 0.0001
% patients with 0 bleeds (95% CI) 50 (32.9, 67.1) 40 (23.9, 57.9) 0 (0, 18.5)
Median ABR (IQR) 0.6 (0, 3.9) 1.6 (0, 4) 46.9 (26.1, 73.9)
Treated Spontaneous Bleeds
ABR (95% CI) * 1.0 (0.5, 1.9) 0.3 (0.1, 0.8) 15.6 (7.6, 31.9)
% reduction (95% CI)p-value 94% (84.9%, 97.5%)< 0.0001 98% (94.4%, 99.4%)< 0.0001
% patients with 0 bleeds (95% CI) 66.7 (49.0, 81.4) 88.6 (73.3, 96.8) 22.2 (6.4, 47.6)
Median ABR (IQR) 0 (0, 1.3) 0 (0, 0) 10.8 (2.1, 26)
Treated Joint Bleeds
ABR (95% CI) * 1.1 (0.6, 1.9) 0.9 (0.4, 1.7) 26.5 (14.7, 47.8)
% reduction (95% CI)p-value 96% (91.5%, 98.1%)< 0.0001 97% (93%, 98.5%)< 0.0001
% patients with 0 bleeds (95% CI) 58.3 (40.8, 74.5) 74.3 (56.7, 87.5) 0 (0, 18.5)
Median ABR (IQR) 0 (0, 1.9) 0 (0, 1.3) 21.3 (14.5, 41.3)
Treated Target Joint Bleeds
ABR (95% CI) * 0.6 (0.3, 1.4) 0.7 (0.3, 1.6) 13 (5.2, 32.3)
% reduction (95% CI)p-value 95% (85.7%, 98.4%)< 0.0001 95% (85.3%, 98.2%)< 0.0001
% patients with 0 bleeds (95% CI) 69.4 (51.9, 83.7) 77.1 (59.9, 89.6) 27.8 (9.7, 53.5)
Median ABR (IQR) 0 (0, 1.4) 0 (0, 0) 12.8 (0, 39.1)

In the HAVEN 3 intra-patient analysis, HEMLIBRA prophylaxis resulted in a statistically significant (p < 0.0001) reduction (68%) in bleed rate for treated bleeds compared with previous FVIII prophylaxis collected in the NIS prior to enrollment (see Table 6).

Table 6 Intra-Patient Comparison of Annualized Bleed Rate with HEMLIBRA Prophylaxis versus Previous FVIII Prophylaxis
Endpoint HEMLIBRA1.5 mg/kg once every week(N = 48) Previous FVIII Prophylaxis(N = 48)
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) 33.7 30.1
Treated Bleeds
ABR (95% CI) * 1.5 (1, 2.3) 4.8 (3.2, 7.1)
% reduction (95% CI)p-value 68% (48.6%, 80.5%)< 0.0001
% patients with 0 bleeds (95% CI) 54.2 (39.2, 68.6) 39.6 (25.8, 54.7)
Median ABR (IQR) 0 (0, 2.1) 1.8 (0, 7.6)

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 36 patients with hemophilia A without FVIII inhibitors based on the bleed rate for bleeds requiring treatment with coagulation factors. The study also evaluated the efficacy of HEMLIBRA prophylaxis on all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds.

The efficacy results of HEMLIBRA prophylaxis 6 mg/kg once every four weeks with respect to rate of treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds, and treated target joint bleeds are shown in Table 7. The median observation time was 25.6 weeks (range 24.1 – 29.4 weeks).

Table 7 Annualized Bleed Rate with HEMLIBRA Prophylaxis 6 mg/kg Once Every Four Weeks in Patients ≥ 12 Years of Age without Factor VIII Inhibitors
Endpoint ABR * (95% CI)N = 36 Median ABR (IQR)N = 36 % Zero Bleeds (95% CI)N = 36
ABR = annualized bleed rate; CI = confidence interval; IQR = interquartile range, 25th percentile to 75th percentile.
*
Based on negative binomial regression model.
Treated Bleeds 2.6 (1.5, 4.7) 0 (0, 2.1) 52.8 (35.5, 69.6)
All Bleeds 4.8 (3.2, 7.1) 2.1 (0, 6.1) 27.8 (14.2, 45.2)
Treated Spontaneous Bleeds 0.6 (0.2, 1.6) 0 (0, 0) 83.3 (67.2, 93.6)
Treated Joint Bleeds 1.8 (0.8, 4) 0 (0, 1.9) 69.4 (51.9, 83.7)
Treated Target Joint Bleeds 1.1 (0.4, 3.7) 0 (0, 0) 83.3 (67.2, 93.6)

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