"The US Food and Drug Administration (FDA) has approved a foam containing calcipotriene and betamethasone dipropionate (Enstilar, Leo Pharma Inc) for topical treatment of plaque psoriasis in adults 18 years of age and older, according to a "...
Mechanism Of Action
Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.
In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with psoriasis.
In subjects with psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with psoriasis. Following multiple subcutaneous doses of STELARA® , the steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Following subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to subjects with psoriasis, the mean (±SD) apparent volume of distribution during the terminal phase (Vz/F) was 161 ± 65 mL/kg and 179 ± 85 mL/kg, respectively. The mean (±SD) volume of distribution during the terminal phase (Vz) following a single intravenous administration to subjects with psoriasis ranged from 56.1 ± 6.5 to 82.1 ± 23.6 mL/kg.
The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The mean (±SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to subjects with psoriasis ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.
When given the same dose, subjects with psoriasis or psoriatic arthritis weighing > 100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing ≤ 100 kg. The median trough serum concentrations of ustekinumab in subjects of higher weight ( > 100 kg) in the 90 mg group were comparable to those in subjects of lower weight ( ≤ 100 kg) in the 45 mg group.
Hepatic and Renal Impairment
No pharmacokinetic data are available in patients with hepatic or renal impairment.
A population pharmacokinetic analysis (N=106/1937 subjects greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of in vitro data has not been established [see DRUG INTERACTIONS].
Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to antiTNFα agents in patients with psoriatic arthritis.
Animal Toxicology And/Or Pharmacology
In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.
Two multicenter, randomized, double-blind, placebo-controlled studies (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥ 12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.
Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16.
In both studies, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.
In both studies, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of study subjects had a history of psoriatic arthritis.
The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 2 below.
Table 2. Clinical Outcomes
Ps STUDY 1 and Ps STUDY 2
|Week 12||Ps STUDY 1||Ps STUDY 2|
|45 mg||90 mg||45 mg||90 mg|
|PASI 75 response||8 (3%)||171 (67%)||170 (66%)||15 (4%)||273 (67%)||311 (76%)|
|PGA of Cleared or Minimal||10 (4%)||151 (59%)||156 (61%)||18 (4%)||277 (68%)||300 (73%)|
Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.
In subjects who weighed ≤ 100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed > 100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 3 below).
Table 3: Clinical Outcomes by Weight Ps STUDY 1 and Ps
|Ps STUDY 1||Ps STUDY 2|
|45 mg||90 mg||45 mg||90 mg|
|PASI 75 response at Week 12*|
|≤ 100 kg||4%||74%||65%||4%||73%||78%|
|> 100 kg||2%||54%||68%||3%||49%||71%|
|PGA of Cleared or Minimal at Week 12*|
|≤ 100 kg||4%||64%||63%||5%||74%||75%|
|> 100 kg||3%||49%||58%||3%||51%||69%|
|*Patients were dosed with study medication at Weeks 0 and 4.|
Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
The safety and efficacy of STELARA® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA ( ≥ 5 swollen joints and ≥ 5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline.
Patients were randomized to receive treatment with STELARA® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX ( ≤ 25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24.
In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the patients had been previously treated with an anti-TNFα agent, of whom over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.
In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 4). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in Study 2. Responses were similar in patients regardless of prior TNFα exposure.
Table 1: ACR 20, ACR 50, ACR 70 and PASI 75 responses
in PsA STUDY 1 and PsA STUDY 2 at Week 24
|PsA STUDY 1||PsA STUDY 2|
|Placebo||45 mg||90 mg||Placebo||45 mg||90 mg|
|Number of patients randomized||206||205||204||104||103||105|
|ACR 20 response, N (%)||47 (23%)||87 (42%)||101 (50%)||21 (20%)||45 (44%)||46 (44%)|
|ACR 50 response, N (%)||18 (9%)||51 (25%)||57 (28%)||7 (7%)||18 (17%)||24 (23%)|
|ACR 70 response, N (%)||5 (2%)||25 (12%)||29 (14%)||3 (3%)||7 (7%)||9 (9%)|
|Number of patients with ≥ 3% BSAa||146||145||149||80||80||81|
|PASI 75 response, N (%)||16 (11%)||83 (57%)||93 (62%)||4 (5%)||41 (51%)||45 (56%)|
|aNumber of patients with ≥ 3% BSA psoriasis skin involvement at baseline The percent of patients achieving ACR 20 responses by visit is shown in Figure 1.|
Figure 1: Percent of patients achieving ACR 20
response through Week 24
The results of the components of the ACR response criteria are shown in Table 5.
Table 5: Mean change from baseline in ACR components
at Week 24
|PsA STUDY 1|
|Number of swollen jointsa|
|Mean Change at Week 24||-3||-5||-6|
|Number of tender joints b|
|Mean Change at Week 24||-4||-8||-9|
|Patient's assessment of painc|
|Mean Change at Week 24||-0.5||-2||-2.6|
|Patient global assessmentc|
|Mean Change at Week 24||-0.5||-2||-2.5|
|Physician global assessmentc|
|Mean Change at Week 24||-1.4||-2.6||-3.1|
|Disability index (HAQ)d|
|Mean Change at Week 24||-0.1||-0.3||-0.4|
|Mean Change at Week 24||0.01||-0.5||-0.8|
|aNumber of swollen joints counted (0-66)
bNumber of tender joints counted (0-68)
cVisual analogue scale; 0= best, 10=worst.
dDisability Index of the Health Assessment Questionnaire; 0 = best, 3 = worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity.
eCRP: (Normal Range 0.0-1.0 mg/dL)
An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24.
STELARA® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders ( ≥ 0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24.
Last reviewed on RxList: 3/18/2014
This monograph has been modified to include the generic and brand name in many instances.
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