Immunosuppressants, interleukin inhibitors. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Ustekinumab is a fully human IgG1κ monoclonal antibody that binds with specificity to the shared p40 protein subunit of human cytokines interleukin (IL) 12 and IL 23. Ustekinumab inhibits the bioactivity of human IL 12 and IL 23 by preventing p40 from binding to the IL-12Rβ1 receptor protein expressed on the surface of immune cells. Ustekinumab cannot bind to IL-12 or IL-23 that is already bound to IL 12Rβ1 cell surface receptors. Thus, ustekinumab is not likely to contribute to complement or antibody mediated cytotoxicity of cells with IL-12 and/or IL-23 receptors. IL-12 and IL-23 are heterodimeric cytokines secreted by activated antigen presenting cells, such as macrophages and dendritic cells, and both cytokines participate in immune functions; IL-12 stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype, IL-23 induces the T helper 17 (Th17) pathway. However, abnormal regulation of IL 12 and IL 23 has been associated with immune mediated diseases, such as psoriasis and psoriatic arthritis.
By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab may exert its clinical effects in both psoriasis and psoriatic arthritis through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology of these diseases.
During the long term extension of Psoriasis Study 2 (PHOENIX 2), patients treated with STELARA for at least 3.5 years mounted similar antibody responses to both pneumococcal polysaccharide and tetanus vaccines as a non-systemically treated psoriasis control group. Similar proportions of patients developed protective levels of anti-pneumococcal and anti-tetanus antibodies and antibody titers were similar among STELARA-treated and control patients.
Clinical Efficacy: Plaque Psoriasis:
The safety and efficacy of ustekinumab was assessed in 1,996 patients in two randomised, double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis and who were candidates for phototherapy or systemic therapy. In addition, a randomised, blinded assessor, active-controlled study compared ustekinumab and etanercept in patients with moderate to severe plaque psoriasis who had had an inadequate response to, intolerance to, or contraindication tociclosporin, MTX, or PUVA.
Psoriasis Study 1 (PHOENIX 1) evaluated 766 patients. 53% of these patients were either non-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 and followed by the same dose every 12 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16 followed by dosing every 12 weeks. Patients originally randomised to ustekinumab who achieved Psoriasis Area and Severity Index 75 response (PASI improvement of at least 75% relative to baseline) at both Weeks 28 and 40 were re-randomised to receive ustekinumab every 12 weeks or to placebo (i.e., withdrawal of therapy). Patients who were re-randomised to placebo at Week 40 reinitiated ustekinumab at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at Week 40. All patients were followed for up to 76 weeks following first administration of study treatment.
Psoriasis Study 2 (PHOENIX 2) evaluated 1,230 patients. 61% of these patients were either non-responsive, intolerant, or had a contraindication to other systemic therapy. Patients randomised to ustekinumab received 45 mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at 16 weeks. Patients randomised to receive placebo at Weeks 0 and 4 crossed over to receive ustekinumab (either 45 mg or 90 mg) at Weeks 12 and 16. All patients were followed for up to 52 weeks following first administration of study treatment.
Psoriasis Study 3 (ACCEPT) evaluated 903 patients with moderate to severe psoriasis who inadequately responded to, were intolerant to, or had a contraindication to other systemic therapy and compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept. During the 12-week active-controlled portion of the study, patients were randomised to receive etanercept (50 mg twice a week), ustekinumab 45 mg at Weeks 0 and 4, or ustekinumab 90 mg at Weeks 0 and 4.
Baseline disease characteristics were generally consistent across all treatment groups in PsoriasisStudies 1 and 2 with a median baseline PASI score from 17 to 18, median baseline Body Surface Area (BSA) ≥20, and median Dermatology Life Quality Index (DLQI) range from 10 to 12.
Approximately one third (Psoriasis Study 1) and one quarter (Psoriasis Study 2) of subjects had Psoriatic Arthritis (PsA). Similar disease severity was also seen in Psoriasis Study 3.
The primary endpoint in these studies was the proportion of patients who achieved PASI 75 response from baseline at Week 12 (see Tables 1 and 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In Psoriasis Study 1 maintenance of PASI 75 was significantly superior with continuous treatment compared with treatment withdrawal (p <0.001). Similar results were seen with each dose of ustekinumab. At 1 year (Week 52), 89% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 63% of patients re-randomised to placebo (treatment withdrawal) (p <0.001). At 18 months (Week 76), 84% of patients re-randomised to maintenance treatment were PASI 75 responders compared with 19% of patients re-randomised to placebo (treatment withdrawal). At 3 years (Week 148), 82% of patients re-randomised to maintenance treatment were PASI 75 responders. At 5 years (Week 244), 80% of patients re-randomised to maintenance treatment were PASI 75 responders.
In patients re-randomised to placebo, and who reinitiated their original ustekinumab treatment regimen after loss of ≥50% of PASI improvement 85% regained PASI 75 response within 12 weeks after re-initiating therapy.
In Psoriasis Study 1, at Week 2 and Week 12, significantly greater improvements from baseline were demonstrated in the DLQI in each ustekinumab treatment group compared with placebo. The improvement was sustained through Week 28. Similarly, significant improvements were seen in Psoriasis Study 2 at Week 4 and 12, which were sustained through Week 24. In Psoriasis Study 1, improvements in nail psoriasis (Nail Psoriasis Severity Index), in the physical and mental component summary scores of the SF-36 and in the Itch Visual Analogue Scale (VAS) were also significant in each ustekinumab treatment group compared with placebo. In Psoriasis Study 2, the Hospital Anxiety and Depression Scale (HADS) and Work Limitations Questionnaire (WLQ) were also significantly improved in each ustekinumab treatment group compared with placebo.
Psoriatic Arthritis (PsA):
Ustekinumab has been shown to improve signs and symptoms, physical function and health-related quality of life, and reduce the rate of progression of peripheral joint damage in adult patients with active PsA.
The safety and efficacy of ustekinumab was assessed in 927 patients in two randomised, double-blind, placebo-controlled studies in patients 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 no evidence 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 in both studies had enthesitis and dactylitis at baseline, respectively. Patients were randomised to receive treatment with ustekinumab 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).
In PsA Study 1 (PSUMMIT I) and PsA Study 2 (PSUMMIT II), 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In Study 1 previous treatment with anti-tumour necrosis factor (TNF)α agent was not allowed. In Study 2, the majority of patients (58%, n=180) had been previously treated with one or more anti-TNFα agent(s), of whom over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.
Signs and Symptoms:
Treatment with ustekinumab resulted in significant improvements in the measures of disease activity compared to placebo at Week 24. The primary endpoint was the percentage of patients who achieved American College of Rheumatology (ACR) 20 response at Week 24. The key efficacy results are shown in Table 3.
Click on icon to see table/diagram/image
ACR 20, 50 and 70 responses continued to improve or were maintained through Week 52 (PsA Study 1 and 2) and Week 100 (PsA Study 1). In PsA Study 1, ACR 20 responses at Week 100 were achieved by 57% and 64%, for 45 mg and 90 mg, respectively. In PsA Study 2, ACR 20 responses at Week 52 were achieved by 47% and 48%, for 45 mg and 90 mg, respectively.
The proportion of patients achieving a modified PsA response criteria (PsARC) response was also significantly greater in the ustekinumab groups compared to placebo at Week 24. PsARC responses were maintained through Weeks 52 and 100. A higher proportion of patients treated with ustekinumab who had spondylitis with peripheral arthritis as their primary presentation, demonstrated 50 and 70 percent improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores compared with placebo at Week 24.
Responses observed in the ustekinumab treated groups were similar in patients receiving and not receiving concomitant MTX, and were maintained through Weeks 52 and 100. Patients previously treated with anti-TNFα agents who received ustekinumab achieved a greater response at Week 24 than patients receiving placebo (ACR 20 response at Week 24 for 45 mg and 90 mg was 37% and 34%, respectively, compared with placebo 15%; p <0.05), and responses were maintained through Week 52.
For patients with enthesitis and/or dactylitis at baseline, in PsA Study 1 significant improvement in enthesitis and dactylitis score was observed in the ustekinumab groups compared with placebo at Week 24. In PsA Study 2 significant improvement in enthesitis score and numerical improvement (not statistically significant) in dactylitis score was observed in the ustekinumab 90 mg group compared with placebo at Week 24. Improvements in enthesitis score and dactylitis score were maintained through Weeks 52 and 100.
Structural damage in both hands and feet was expressed as change in total van der Heijde-Sharp score (vdH-S score), modified for PsA by addition of hand distal interphalangeal joints, compared to baseline. A pre-specified integrated analysis combining data from 927 subjects in both PsA Study 1 and 2 was performed. Ustekinumab demonstrated a statistically significant decrease in the rate of progression of structural damage compared to placebo, as measured by change from baseline to Week 24 in the total modified vdH-S score (mean ± SD score was 0.97 ± 3.85 in the placebo group compared with 0.40 ± 2.11 and 0.39 ± 2.40 in the ustekinumab 45 mg (p <0.05) and 90 mg (p <0.001) groups, respectively). This effect was driven by PsA Study 1. The effect is considered demonstrated irrespective of concomitant MTX use, and was maintained through Weeks 52 (integrated analysis) and 100 (PsA Study 1).
Physical Function and Health-Related Quality of Life:
Ustekinumab-treated patients showed significant improvement in physical function as assessed by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) at Week 24. The proportion of patients achieving a clinically meaningful ≥0.3 improvement in HAQ-DI score from baseline was also significantly greater in the ustekinumab groups when compared with placebo. Improvement in HAQDI score from baseline was maintained through Weeks 52 and 100. There was significant improvement in DLQI scores in the ustekinumab groups as compared with placebo at Week 24, which was maintained through Weeks 52 and 100. In PsA Study 2 there was a significant improvement in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores in the ustekinumab groups when compared with placebo at Week 24. The proportion of patients achieving a clinically significant improvement in fatigue (4 points in FACIT-F) was also significantly greater in the ustekinumab groups compared with placebo. Improvements in FACIT scores were maintained through Week 52.
The median time to reach the maximum serum concentration (tmax
) was 8.5 days after a single 90 mg subcutaneous administration in healthy subjects. The median tmax
values of ustekinumab following a single subcutaneous administration of either 45 mg or 90 mg in patients with psoriasis were comparable to those observed in healthy subjects.
The absolute bioavailability of ustekinumab following a single subcutaneous administration was estimated to be 57.2% in patients with psoriasis.
Median volume of distribution during the terminal phase (Vz) following a single intravenous administration to patients with psoriasis ranged from 57 to 83 mL/kg.
The exact metabolic pathway for ustekinumab is unknown.
Median systemic clearance (CL) following a single intravenous administration to patients with psoriasis ranged from 1.99 to 2.34 mL/day/kg. Median half-life (t½
) of ustekinumab was approximately 3 weeks in patients with psoriasis and/or psoriatic arthritis, ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokinetic analysis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/day and 15.7 L, respectively, in patients with psoriasis. The CL/F of ustekinumab was not impacted by gender. Population pharmacokinetic analysis showed that there was a trend towards a higher clearance of ustekinumab in patients who tested positive for antibodies to ustekinumab.
The systemic exposure of ustekinumab (Cmax
and AUC) increased in an approximately dose-proportional manner after a single intravenous administration at doses ranging from 0.09 mg/kg to 4.5 mg/kg or following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis.
Single Dose versus Multiple Doses:
Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple subcutaneous dose administrations. Steady-state serum concentrations of ustekinumab were achieved by Week 28 after initial subcutaneous doses at Weeks 0 and 4 followed by doses every 12 weeks. The median steady-state trough concentration ranged from 0.21 μg/mL to 0.26 μg/mL (45 mg) and from 0.47 μg/mL to 0.49 μg/mL (90 mg) in patients with psoriasis. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
Impact of Weight on Pharmacokinetics:
In a population pharmacokinetic analysis using data from patients with psoriasis, body weight was found to be the most significant covariate affecting the clearance of ustekinumab. The median CL/F in patients with weight >100 kg was approximately 55% higher compared to patients with weight ≤100 kg. The median V/F in patients with weight >100 kg was approximately 37% higher as compared to patients with weight ≤100 kg. The median trough serum concentrations of ustekinumab in patients with higher weight (>100 kg) in the 90 mg group were comparable to those in patients with lower weight (≤100 kg) in the 45 mg group. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.
No pharmacokinetic data are available in patients with impaired renal or hepatic function. No specific studies have been conducted in elderly patients.
The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asian patients with psoriasis.
In the population pharmacokinetic analysis, there were no indications of an effect of tobacco or alcohol on the pharmacokinetics of ustekinumab.
Regulation of CYP450 Enzymes:
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; see Interactions).
Toxicology: Preclinical Safety Data:
Non-clinical data reveal no special hazard (e.g. organ toxicity) for humans based on studies of repeated-dose toxicity and developmental and reproductive toxicity, including safety pharmacology evaluations. In developmental and reproductive toxicity studies in cynomolgus monkeys, neither adverse effects on male fertility indices nor birth defects or developmental toxicity were observed. No adverse effects on female fertility indices were observed using an analogous antibody to IL-12/23 in mice.
Dose levels in animal studies were up to approximately 45-fold higher than the highest equivalent dose intended to be administered to psoriasis patients and resulted in peak serum concentrations in monkeys that were more than 100-fold higher than observed in humans.
Carcinogenicity studies were not performed with ustekinumab due to the lack of appropriate models for an antibody with no cross-reactivity to rodent IL-12/23 p40.