for 57% of time and above 1% for 83% of time.
Table 5:Estimation of steady-state peak and trough FVIII activity and time to 5% FVIII activity for ESPEROCT
Dose regimen
Age range
60 IU/kg
(50–75 IU/kg)
twice weekly
<12 years
50 IU/kg
twice weekly
≥12 years
50 IU/kg
Q4D
≥12 years
75 IU/kg
Q7D
≥12 years
Peak FVIII activity (%) 110/112* 133/138* 132 194
Trough FVIII activity (%) 2.8/0.8* 8.6/3.6* 3.5 0.3
Time to 5% FVIII activity (days) 2.5/2.5* 3.6/3.6* 3.6 4.0
% of time in dosing interval
above 5% FVIII activity 72 95 90 57
*Twice weekly values are shown as 3 day/4 day. Only 50 IU/kg data are used for the analysis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis, mutagenesis, and impairment of fertility studies in animals have not been performed.
13.2 Animal Toxicology and/or Pharmacology
No adverse effects were observed in immune-deficient rats intravenously injected with ESPEROCT (50-1200 IU/kg/injection), once every 4th day for 52 weeks. No evidence of polyethylene glycol accumulation was detected byimmunohistochemical staining of brain tissue, including the choroid plexus.
14 CLINICAL STUDIES
The safety and efficacy of ESPEROCT have been eva luated in five multinational, open-label trials in male subjects withsevere hemophilia A (<1% endogenous Factor VIII activity). One trial was subsequently partially randomized to eva luate twodifferent prophylaxis regimens. All subjects were previously treated, which was defined as having received other Factor VIIIproducts for ≥150 exposure days for adolescents and adults, and ≥50 exposure days for pediatric subjects. The key exclusioncriteria across trials included known or suspected hypersensitivity to trial or related products and known history of FactorVIII inhibitors or current inhibitor ≥0.6 Bethesda units (BU).
The efficacy eva luation included 254 subjects, who received at least one dose of ESPEROCT, in the following trials:
• Adolescent/adult trial: This trial included 186 subjects, 161 adults (18 to 65 years old) and 25 adolescents (12 to <18years old); it consisted of a Main Phase and optional Extension Phase. During the Main Phase, 175 subjects received theprophylaxis regimen which consisted of 50 IU/kg every 4 days (Q4D), while 12 adults chose to be treated on-demand.
(One subject changed from on-demand to prophylaxis and is counted in both groups.) Thirteen (7%) of 175 adults in theprophylaxis arm modified their dosing regimen to Q3-4D dosing for ease of use. All subjects received at least one doseof ESPEROCT and are eva luable for safety and efficacy. A total of 165 subjects (91%) completed the Main Phase of thistrial.
o Extension: This extension compared two dose regimens: 75 IU/kg every 7 days (Q7D) and 50 IU/kg Q4D. Therandomization was open to subjects who experienced 2 or fewer bleeds during the last 6 months in the Main Phase.
• Pediatric trial: This trial included 68 subjects who were evenly divided with 34 in each age group, 0–<6 and 6–<12 yearsof age. All subjects received the same prophylaxis regimen of approximately 65 IU/kg (50–75 IU/kg) twice weekly. Atotal of 63 subjects (93%) completed the Main Phase.
• Surgery trial: In the surgery trial, 33 previously treated adolescents/adults underwent 45 major surgeries. The dose level
of ESPEROCT was chosen so that FVIII activity at least as recommended by World Feder |
