ILUMYA Solution for injection Ref.[27742] Active ingredients: Tildrakizumab

No formal pharmacodynamics studies have been conducted with ILUMYA.

Tildrakizumab pharmacokinetics increases proportionally over a dose range from 50 mg to 200 mg (0.5 to 2 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of tildrakizumab at Weeks 0, 4, and every 12 weeks thereafter. At the 100 mg dose at Week 16, the mean (± SD) steady-state trough concentrations ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state C_max was 8.1 mcg/mL (34%).

Absorption

The absolute bioavailability of tildrakizumab was estimated to be 73-80% following subcutaneous injection. The peak concentration (C_max) was reached by approximately 6 days.

Distribution

The geometric mean (CV%) volume of distribution is 10.8 L (24%).

Elimination

The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was approximately 23 days (23%).

Metabolism

The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Specific Populations

No clinically significant differences in the pharmacokinetics of tildrakizumab were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of tildrakizumab.

Body Weight

Tildrakizumab concentrations were lower in subjects with higher body weight.

Drug Interaction Studies

Cytochrome P450 Substrates

The AUC_inf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUC_inf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed.

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of ILUMYA.

No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison). The monkeys were not mated to evaluate fertility.

In two multicenter, randomized, double-blind, placebo-controlled trials (Trial 2 [NCT01722331] and Trial 3 [NCT01729754]), 926 subjects were treated with ILUMYA 100 mg (N=616) or placebo (N=310). Subjects had a Physician Global Assessment (PGA) score of ≥3 (moderate) on a 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.

In both trials, subjects were randomized to either placebo or ILUMYA (100 mg at Week 0, Week 4, and every twelve weeks thereafter [Q12W]) up to 64 weeks.

Trials 2 and 3 assessed the changes from baseline to Week 12 in the two co-primary endpoints:

• PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score.
• PGA of 0 (“cleared”) or 1 (“minimal”), the proportion of subjects with a PGA of 0 or 1 and at least a 2-point improvement.

Other evaluated outcomes in Trials 2 and 3 included the proportion of subjects who achieved a reduction from baseline in PASI score of at least 90% (PASI 90) and a reduction of 100% in PASI score (PASI 100) at Week 12 and maintenance of efficacy up to Week 64.

In both trials, subjects in the ILUMYA 100 mg and placebo treatment groups were predominantly men (69%) and White (80%), with a mean age of 46 years. At baseline, these subjects had a median affected BSA of 27%, a median PASI score of 17.8, and approximately 33% had a PGA score of 4 (“marked”) or 5 (“severe”). Approximately 34% had received prior phototherapy, 39% had received prior conventional systemic therapy, and 18% had received prior biologic therapy for the treatment of psoriasis. Approximately 16% of subjects had a history of psoriatic arthritis.

Clinical Response at Week 12

The results of Trials 2 and 3 are presented in Table 2.

Table 2. Efficacy Results at Week 12 in Adults with Plaque Psoriasis in Trials 2 and 3 (NRI*):

^* NRI = Non-Responder Imputation
^† Co-Primary Endpoints
^‡ PGA score of 0 (“cleared”) or 1 (“minimal”)

Examination of age, gender, race, and previous treatment with a biologic did not identify differences in response to ILUMYA among these subgroups at Week 12.

Maintenance of Response and Durability of Response

In Trial 2, subjects originally randomized to ILUMYA and who were responders at Week 28 (i.e., PASI 75) were re-randomized to an additional 36 weeks of either maintaining the same dose of ILUMYA Q12W (every twelve weeks) or placebo.

At Week 28, 229 (74%) subjects treated with ILUMYA 100 mg were PASI 75 responders. At Week 64, 84% of subjects who continued on ILUMYA 100 mg Q12W maintained PASI 75 compared to 22% of subjects who were re-randomized to placebo. In addition, for subjects who were re-randomized and also had a PGA score of 0 or 1 at Week 28, 69% of subjects who continued on ILUMYA 100 mg Q12W maintained this response (PGA 0 or 1) at Week 64 compared to 14% of subjects who were re-randomized to placebo.

For PASI 75 responders at Week 28 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of PASI 75 was approximately 20 weeks.

In addition, for subjects who were re-randomized to placebo and also had a PGA score of 0 or 1 at Week 28, the median time to loss of PGA score of 0 or 1 was approximately 16 weeks.