Mechanism Of Action
Tildrakizumab is a humanized IgG1/k monoclonal antibody
that selectively binds to the p19 subunit of IL-23 and inhibits its interaction
with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved
in inflammatory and immune responses. Tildrakizumab inhibits the release of
proinflammatory cytokines and chemokines.
No formal pharmacodynamics studies have been conducted
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 Cmax was 8.1 mcg/mL (34%).
The absolute bioavailability of tildrakizumab was
estimated to be 73-80% following subcutaneous injection. The peak concentration
(Cmax) was reached by approximately 6 days.
The geometric mean (CV%) volume of distribution is 10.8 L
The geometric mean (CV%) systemic clearance was 0.32
L/day (38%) and the half-life was approximately 23 days (23%).
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.
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.
Tildrakizumab concentrations were lower in subjects with
higher body weight.
Drug Interaction Studies
Cytochrome P450 Substrates
The AUCinf 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 AUCinf of
caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19
substrate), and midazolam (CYP3A4 substrate) were observed.
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*)
||Trial 2 (NCT01722331)
||Trial 3 (NCT01729754)
|ILUMYA 100 mg
(N=309) n (%)
(N=154) n (%)
|ILUMYA 100 mg
(N=307) n (%)
(N=156) n (%)
|PGA of 0 or 1†‡
|* 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 rerandomized 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.