Stelara (Ustekinumab) - Description and Clinical Pharmacology

DESCRIPTION

STELARA™ is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, STELARA™ is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. STELARA™ is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.

STELARA™ is available as: 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL. STELARA™ is supplied as a sterile solution in a single-use prefilled syringe with a 27 gauge fixed ½ inch needle, or a single-use 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that is manufactured using a dry natural rubber (a derivative of latex).

Each 45 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.

Each 90 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.

Each 45 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.

Each 90 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.

The STELARA™ solution is colorless to slightly yellow in appearance and has a pH of 5.7—6.3. STELARA™ does not contain preservatives.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ustekinumab is a human IgG1қ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the interleukin (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-12 β1.

Pharmacodynamics

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 psoriatic subjects.

Pharmacokinetics

Absorption

In psoriasis subjects, the median time to reach the maximum serum concentration (T_max) 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 T_max value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in psoriasis subjects. 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.

Distribution

Following subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to psoriasis subjects, 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.

Metabolism

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.

Elimination

The mean (± SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to psoriasis subjects 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.

Weight

When given the same dose, subjects weighing >100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing ≤100 kg.

Hepatic and Renal Impairment

No pharmacokinetic data are available in patients with hepatic or renal impairment.

Elderly

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.

Drug-Drug Interactions

Upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed [see Drug Interactions].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA™. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.

A male fertility study was conducted with only 6 male monkeys per group administered subcutaneous doses of 0, 22.5, or 45 mg/kg ustekinumab twice weekly prior to mating and during the mating period for 13 weeks, followed by a 13-week treatment-free period. Although fertility and pregnancy outcomes were not evaluated in mated females, there were no treatment-related effects on parental toxicity or male fertility parameters.

A female fertility study was conducted in mice using an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, beginning 15 days before cohabitation and continuing through GD 7. There were no treatment-related effects on maternal toxicity or female fertility parameters.

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.

CLINICAL STUDIES

Two multicenter, randomized, double-blind, placebo-controlled studies (STUDY 1 and 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.

STUDY 1 enrolled 766 subjects and 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 STUDY 1 and 40% of subjects in 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.

Clinical Response

The results of STUDY 1 and STUDY 2 are presented in Table 3 below.

Table 3. Clinical Outcomes STUDY 1 and STUDY 2

Week 12	STUDY 1			STUDY 2
		STELARA™			STELARA™
	Placebo	45 mg	90 mg	Placebo	45 mg	90 mg
Subjects randomized	255	255	256	410	409	411
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 4 below).

Table 4. Clinical Outcomes by Weight STUDY 1 and STUDY 2

	STUDY 1			STUDY 2
		STELARA™			STELARA™
	Placebo	45 mg	90 mg	Placebo	45 mg	90 mg
Subjects randomized	255	255	256	410	409	411
Week 12
PASI 75 response
≤ 100 kg	4%	74%	65%	4%	73%	78%
	6/166	124/168	107/164	12/290	218/297	225/289
>100 kg	2%	54%	68%	3%	49%	71%
	2/89	47/87	63/92	3/120	55/112	86/121
PGA of Cleared or Minimal
≤ 100 kg	4%	64%	63%	5%	74%	75%
	7/166	108/168	103/164	14/290	220/297	216/289
>100 kg	3%	49%	58%	3%	51%	69%
	3/89	43/87	53/92	4/120	57/112	84/121

Subjects in STUDY 1 were evaluated through Week 52. At Week 40, those who were PASI 75 responders at both Weeks 28 and 40 were re-randomized 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).