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Pharmacology: Pharmacodynamics: Mechanism of Action: STELARA 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. STELARA 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. STELARA cannot bind to IL-12 or IL-23 that is already bound to IL-12Rβ1 cell surface receptors. Thus, STELARA is not likely to contribute to complement or antibody mediated cytotoxicity of cells expressing 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. IL-12 stimulates natural killer (NK) cells and drives the differentiation of CD4+ T cells toward the T helper 1 (Th1) phenotype and stimulates interferon gamma (IFNγ) production. IL-23 induces the T helper 17 (Th17) pathway and promotes secretion of IL-17A, IL-21, and IL-22. Levels of IL-12 and IL-23 are elevated in the skin and blood of patients with psoriasis, and serum IL12/23p40 distinguishes patients with psoriatic arthritis from healthy individuals, implicating IL-12 and IL-23 in the pathophysiology of psoriatic inflammatory diseases. Genetic polymorphisms in IL23A, IL23R, and IL-12B genes confer susceptibility to these disorders. Additionally, IL-12 and IL-23 are highly expressed in lesional psoriatic skin, and IL-12-mediated induction of IFNγ correlates with psoriasis disease activity. IL-23 responsive T-cells have been found in the entheses in a mouse model of inflammatory arthritis, where IL-23 drives entheseal inflammation. In addition, there is pre-clinical evidence implicating IL-23 and downstream pathways in bone erosion and destruction through up-regulation of receptor activator of nuclear factor-κB ligand (RANKL), which activates osteoclasts.
In patients with Crohn's disease, IL-12 and IL-23 are elevated in the intestines and lymph nodes. This is accompanied by increases in serum IFNγ and IL-17A levels, suggesting that IL-12 and IL-23 promote Th1 and Th17 activation in Crohn's disease. Both IL-12 and IL-23 can also stimulate TNFα production by T cells, resulting in chronic intestinal inflammation and epithelial cell injury. Significant associations have been found between Crohn's disease and genetic polymorphisms in the IL23R and IL12B genes, suggesting a potential causal role for IL-12/23 signaling in the disease. This is supported by pre-clinical data demonstrating that IL-12/23 signaling is required for intestinal injury in mouse models of inflammatory bowel disease.
By binding the shared p40 subunit of IL-12 and IL-23, STELARA may exert its clinical effects in both psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis through interruption of the Th1 and Th17 cytokine pathways, which are central to the pathology of these diseases.
Pharmacodynamic Effects: Treatment with STELARA resulted in significant improvement in histological measures of psoriasis including epidermal hyperplasia and cell proliferation. These results are consistent with the clinical efficacy observed.
In patients with psoriasis and/or psoriatic arthritis, STELARA had no apparent effect on the percentages of circulating immune cell populations including memory and naive T cell subsets or circulating cytokine levels. Systemic markers of inflammation were measurable in the serum at baseline and 4 markers (MDC, VEGF, MCSF-1 and YKL-40) showed modest differences in concentration post-treatment in STELARA-treated patients as compared to placebo.
Treatment with STELARA resulted in a decrease in the gene expression of its molecular targets IL-12 and IL-23 as shown by analyses of mRNA obtained from lesional skin biopsies of psoriatic patients at baseline and up to 2 weeks post-treatment. In addition, STELARA down regulated the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8 in lesional skin biopsies. These results are consistent with the significant clinical benefit observed with STELARA treatment in psoriasis.
In psoriasis and psoriatic arthritis studies, clinical response (improvement in PASI or ACR measurements, respectively) appeared to be related to serum ustekinumab levels. Patients with psoriasis with higher PASI response had higher median serum concentrations of ustekinumab than those with lower clinical responses. In psoriasis studies, the proportion of patients who achieved PASI 75 response increased with increasing serum levels of ustekinumab. The proportion of patients who achieved PASI 75 response at Week 28 increased with increasing serum ustekinumab trough levels at Week 28. In psoriatic arthritis studies, patients achieving an ACR 20 response had higher median serum concentrations of ustekinumab than ACR 20 non-responders. The proportion of patients who achieved ACR 20 and ACR 50 response increased with increasing serum levels of ustekinumab.
In patients with Crohn's disease, treatment with STELARA resulted in a significant decrease in inflammatory markers including C-Reactive Protein (CRP) and fecal calprotectin. CRP was assessed during the study extension and the reductions observed during maintenance were generally sustained through week 252. Reductions in serum IFNγ and IL-17A, which are IL-12 and IL-23 regulated pro-inflammatory cytokines, were achieved and maintained in STELARA treated patients through Week 44 compared to placebo. Expression of genes such as IL-12Rβ1 and IL-23 was reduced in inflamed colon tissue from Crohn's disease patients, responders to STELARA treatment while no significant changes were observed in placebo treated patients at Week 6.
In patients with ulcerative colitis, treatment with STELARA resulted in a decrease in inflammatory markers including CRP and fecal calprotectin during the induction phase, which were maintained throughout the maintenance phase and study extension through week 92.
Immunization: During the long term extension of a Phase 3 psoriasis study (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 Studies: Clinical Efficacy - Plaque Psoriasis (Adults): The safety and efficacy of STELARA was assessed in 2 Phase 3, multicenter, randomized, double-blind, placebo-controlled studies in patients with moderate to severe plaque psoriasis (PHOENIX 1 and PHOENIX 2). A total of 1996 patients were enrolled in these studies.
The studies enrolled adults (≥ 18 years) with chronic (> 6 months) plaque psoriasis who had a minimum body surface area (BSA) involvement of 10%, and PASI score ≥ 12 and who were candidates for systemic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the studies. No concomitant antipsoriatic therapies were allowed during the study with the exception of low-potency topical corticosteroids on the face and groin after week 12.
The PASI is a composite score that assesses the fraction of body surface area involved with psoriasis and the severity of psoriatic changes within the affected regions (plaque thickness/induration, erythema, and scaling). PASI numeric scores range from 0 to 72, with higher scores representing more severe disease.
Patients achieving ≥ 75% improvement in PASI from baseline (PASI 75) were considered PASI 75 responders. Patients originally randomized to STELARA who were PASI 75 responders at both Weeks 28 and 40 were considered long-term PASI 75 responders. Patients achieving ≥ 90% improvement in PASI from baseline (PASI 90) were considered PASI 90 responders and patients with ≥ 50% improvement in PASI from baseline (PASI 50) were considered PASI 50 responders. Patients who achieved ≥ 50% but less than 75% improvement in PASI from baseline were considered partial responders. Patients with < 50% improvement in PASI from baseline were considered nonresponders.
Other key efficacy assessments included: The Physician's Global Assessment (PGA), a 6-category scale: 0 = cleared, 1 = minimal, 2 = mild, 3= moderate, 4 = marked and 5 = severe, that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. The PGA was assessed in PHOENIX 1 and 2.
The Dermatology Life Quality Index (DLQI), a dermatology-specific quality of life instrument designed to assess the impact of the disease on a patient's quality of life. DLQI scores range from 0 to 30, with a lower score representing a better quality of life. A decrease of 5 in the DLQI score from baseline is considered a clinically meaningful improvement. The DLQI was assessed in PHOENIX 1 and 2.
The SF-36, a health survey questionnaire consisting of multi-item scales measuring 8 health concepts. The SF-36 yields composite scores that provide a measure of disease impact on physical and mental health status. Higher SF-36 scores indicate a better quality of life. The SF-36 was assessed in PHOENIX 1.
The Nail Psoriasis Severity Index (NAPSI), a physician-assessed score that measures the severity of nail involvement. The scale consists of 4 components of nail matrix disease and 4 components of nail bed disease with scores from 0 to 8, with a lower scores representing milder disease. The NAPSI was assessed in PHOENIX 1.
The Hospital Anxiety and Depression Scale (HADS), a self-rating tool developed to evaluate psychological measures in patients with physical ailments. It consists of 2 subscales, one measuring anxiety (A-scale) and one measuring Depression (D-scale), which are scored separately. Lower HADS scores correspond to lesser psychological impairment. The HADS was assessed in PHOENIX 2.
The Work Limitations Questionnaire (WLQ), a 25-item, self-administered questionnaire that was used to measure the impact of chronic health conditions on job performance and work productivity among employed populations. The WLQ assesses four aspects of work and productivity: Physical Demands, Time Management, Mental-Interpersonal Demand, and Output Demand. The four subscales range from 0-100 with the lower score indicating fewer work limitations. The WLQ was assessed in PHOENIX 2.
The Itch Visual Analog Scale, used to assess the severity of itch at the time of the assessment. Itch is assessed using a 10 cm horizontal line, or a Visual Analog Scale (VAS), representing the range of itch severity, from 0 (no itch at all) to 10 (severe itch). The Itch VAS was assessed in PHOENIX 1.
PHOENIX 1: PHOENIX 1 evaluated the safety and efficacy of STELARA versus placebo in 766 patients with plaque psoriasis and the efficacy of every 12 week dosing for patients who were PASI 75 responders.
Patients randomized to STELARA received 45 mg or 90 mg doses at Weeks 0 and 4 followed by the same doses every 12 weeks. Patients 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 followed by the same dose every 12 weeks.
Maintenance Dosing (every 12 weeks): To evaluate the therapeutic benefit of maintenance dosing with STELARA, patients originally randomized to STELARA who were PASI 75 responders at both Weeks 28 and 40 were re-randomized to either maintenance dosing of STELARA every 12 weeks or to placebo (ie, withdrawal of therapy). Patients who were re-randomized to placebo at Week 40 reinitiated STELARA at their original dosing regimen when they experienced at least a 50% loss of their PASI improvement obtained at Week 40.
Dose Adjustment (every 8 weeks): At Week 28, patients who were nonresponders discontinued treatment and patients who were partial responders were adjusted to every-8-week dosing.
PASI 75 responders at week 28 who became partial responders or nonresponders at Week 40 were adjusted to every-8-week dosing.
All patients were followed for up to 76 weeks following first administration of study treatment.
PHOENIX 2: PHOENIX 2 evaluated the safety and efficacy of STELARA versus placebo in 1230 patients with plaque psoriasis. Patients randomized to STELARA received 45 mg or 90 mg doses at Weeks 0 and 4 followed by an additional dose at Week 16. Patients 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 followed by the same dose every 12 weeks.
Dose Adjustment (every 8 weeks): At Week 28, patients who were nonresponders discontinued treatment and patients who were partial responders were re-randomized to continue every-12-week dosing or switch to every-8-week dosing.
PASI 75 responders at week 28 who became partial responders or nonresponders at Week 40 were adjusted to every-8-week dosing.
All patients were followed for up to 52 weeks following first administration of study agent.
Baseline Disease Characteristics: PHOENIX 1 and 2: Baseline disease characteristics across PHOENIX 1 and 2 were similar (Table 1). (See Table 1.)
Click on icon to see table/diagram/imageEfficacy at the Primary Endpoint, PHOENIX 1 and 2: In both the PHOENIX 1 and PHOENIX 2 studies, a significantly greater proportion of patients randomized to treatment with STELARA were PASI 75 responders compared with placebo at Week 12 (Table 2). In the PHOENIX 1 study, 67% and 66% of patients receiving STELARA 45 mg and 90 mg, respectively, achieved a PASI 75 response at Week 12 compared with 3% of patients receiving placebo. In the PHOENIX 2 study, 67% and 76% of patients receiving STELARA 45 mg and 90 mg respectively achieved a PASI 75 response at Week 12 compared with 4% of patients receiving placebo.
All 3 components of the PASI (plaque thickness/induration, erythema, and scaling) contributed comparably to the improvement in PASI.
The efficacy of STELARA was significantly superior (p<0.001) to placebo across all subgroups defined by baseline demographics, clinical disease characteristics (including patients with a history of psoriatic arthritis) and prior medication usage. While pharmacokinetic modeling suggested a trend towards higher CL/F in patients with diabetes, a consistent effect on efficacy was not observed.
Other Efficacy Measures at Week 12: In both PHOENIX 1 and PHOENIX 2, compared with placebo, significantly greater proportions of patients randomized to 45 mg or 90 mg STELARA achieved a cleared or minimal PGA score, and significantly greater proportions of patients randomized to 45 mg or 90 mg STELARA were PASI 90 and PASI 50 responders at Week 12 (Table 2). In the PHOENIX 1 study, 59% and 61% of the patients treated with 45 mg and 90 mg STELARA, respectively, achieved PGA scores of cleared or minimal compared with 4% of placebo-treated patients. In PHOENIX 2, 68% and 73% of patients receiving 45 mg or 90 mg STELARA, respectively, had cleared or minimal PGA scores compared with 4% of the placebo patients. In PHOENIX 1, PASI 90 was achieved by 42% and 37% of the patients treated with 45 mg and 90 mg STELARA, respectively, compared with 2% of placebo-treated patients. In PHOENIX 2, the percentage of patients achieving PASI 90 was 42% in the 45 mg STELARA group, 51% in the 90 mg STELARA group and 1% in the placebo group. The percentage of patients achieving PASI 50 in PHOENIX 1 was 84% and 86% in the 45 mg and 90 mg STELARA groups, respectively, compared with 10% in the placebo group. Similarly, 84% of patients treated with 45 mg STELARA, 89% of patients treated with 90 mg STELARA and 10% of patients treated with placebo reached PASI 50 in PHOENIX 2 (Table 2). (See Table 2.)
Click on icon to see table/diagram/imageResponse Over Time: In PHOENIX 1, significantly greater proportions of STELARA-treated patients had PASI 50 responses (9% and 10% for the 45 mg and 90 mg groups, respectively) compared with placebo (2%) by Week 2 (p< 0.001). Significantly greater proportions of patients treated with STELARA achieved PASI 75 responses (9% and 12% for the 45 mg and 90 mg STELARA groups, respectively) compared with placebo (0.4%) by Week 4 (p< 0.001). Maximum response was generally achieved by Week 24 in the 45 mg and 90 mg-STELARA treatment groups, and response rates were generally sustained through Week 36 (Figure 1). In PHOENIX 1, PASI 75 rates at Week 24 were 76% for the 45 mg group, and 85% for the 90 mg group. Higher response rates were observed in patients receiving STELARA 90 mg than in those receiving STELARA 45 mg by Week 16 and these higher response rates were sustained through Week 36 (Figure 1). Similar results were observed in the PHOENIX 2 study through Week 28.
In pre-specified analyses of efficacy by body weight in PHOENIX 1 and PHOENIX 2, no consistent pattern of dose response was seen in patients ≤ 100 kg. In patients who weighed >100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 2). (See Figure 1.)
Click on icon to see table/diagram/imageTherapeutic Benefit of Long-term Continuous Use: At Week 40 in PHOENIX 1, 162 patients were randomized to receive STELARA (maintenance) and 160 were randomized to receive placebo (treatment withdrawal). 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 STELARA (Figure 2). At 1 year (Week 52), 89% of patients re-randomized to maintenance treatment were PASI 75 responders compared with 63% of patients re-randomized to placebo (treatment withdrawal) (p<0.001). At 18 months (Week 76), 84% of patients re-randomized to maintenance treatment were PASI 75 responders compared with 19% of patients re-randomized to placebo (treatment withdrawal). At 3 years (Week 148), 82% of patients re-randomized to maintenance treatment were PASI 75 responders. At 5 years (Week 244), 80% of patients re-randomized to maintenance treatment were PASI 75 responders. (See Figure 2.)
Click on icon to see table/diagram/imageEfficacy of Retreatment: In PHOENIX 1, after withdrawal from therapy, patients reinitiated their original STELARA treatment regimen after loss of ≥ 50% of PASI improvement. Retreatment with STELARA resulted in 71% of evaluated patients regaining PASI 75 response within 8 weeks after reinitiating therapy and 85% of evaluated patients regaining PASI 75 response within 12 weeks after reinitiating therapy.
Dosing Interval Adjustment: In PHOENIX 1, Week 28 and Week 40 Partial Responders and Week 40 Nonresponders were adjusted from every 12 week to every 8 week dosing. Approximately 40%-50% of Week 28 Partial Responders to every 12 week dosing achieved PASI 75 response after adjustment to every 8 week dosing and this proportion of PASI 75 responders was maintained through Week 52. A similar proportion of patients who were PASI 75 responders at Week 28 and subsequently became partial responders or nonresponders at Week 40 achieved PASI 75 response following a dosing interval adjustment to every 8 weeks.
Quality of Life: In PHOENIX 1 and 2, the mean baseline DLQI scores ranged from 11 to 12. In PHOENIX 1, the mean baseline SF-36 Physical Component ranged from 47-49 and the mean baseline SF-36 Mental Component was approximately 50. Quality of life improved significantly in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo as evaluated by DLQI in PHOENIX 1 and 2 and SF-36 in PHOENIX 1 (Tables 3 and 4). Quality of life improvements were significant as early as 2 weeks in patients treated with STELARA and these improvements were maintained over time with continued dosing. (See Tables 3 and 4.)
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Click on icon to see table/diagram/imageNail Psoriasis: In PHOENIX 1, the median baseline NAPSI score for nail psoriasis was 4.0 and the median number of fingernails involved with psoriasis was 8.0. Nail psoriasis improved significantly in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo when measured by the NAPSI score (Tables 5 and 6). Nail psoriasis continued to improve over time through Week 52 in patients treated with STELARA. (See Tables 5 and 6.)
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Click on icon to see table/diagram/imageHospital Anxiety and Depression Scale: At baseline in PHOENIX 2, the mean HADS anxiety and depression scores were 6.9 and 5.1, respectively. Both anxiety and depression scores were reduced significantly in patients randomized to 45 mg or 90 mg STELARA at Week 12 compared with patients randomized to placebo (Table 7). HADS improvements were maintained through Week 24 (Table 8). (See Tables 7 and 8.)
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Click on icon to see table/diagram/imageWork Limitations Questionnaire: The Work Limitations Questionnaire obtained at baseline showed impaired work productivity among patients with psoriasis evaluated in PHOENIX 2 for the Physical Demands, Time Management, Mental-Interpersonal and Output Demands component scores. Work productivity improved significantly more in patients randomized to STELARA at Week 12 compared with patients randomized to placebo as measured by the four WLQ subscales (Physical Demands, Time Management, Mental-Interpersonal, and Output Demands; Table 9). (See Table 9.)
Click on icon to see table/diagram/imageItch VAS: Itch associated with psoriasis improved significantly (p<0.001) at Week 12 in patients randomized to 45 mg or 90 mg STELARA compared with patients randomized to placebo as evaluated by Itch VAS in PHOENIX 1 (Table 10). (See Table 10.)
Click on icon to see table/diagram/imageACCEPT: In addition, a multicenter, randomized, single-blind, active-controlled study (ACCEPT) compared the safety and efficacy of ustekinumab and etanercept in patients 18 years of age and older with chronic (>6 months) plaque psoriasis who had a minimum BSA involvement of 10%, PASI score ≥12, Physician Global Assessment (PGA) score ≥ 3, who were candidates for phototherapy or systemic therapy, and who had had an inadequate response to, intolerance to, or contraindication to cyclosporine, MTX, or PUVA therapy. A total of 903 patients were enrolled in the study.
The ACCEPT trial compared the efficacy of ustekinumab to etanercept and evaluated the safety of ustekinumab and etanercept in patients with moderate to severe psoriasis. The active-controlled portion of the study was from Week 0 to Week 12, during which patients were randomized 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. This trial was powered to test the superiority of each ustekinumab dose to etanercept on the primary endpoint of the proportion of patients who achieved a PASI 75 at week 12.
Significantly greater proportions of subjects treated with ustekinumab 45 mg (67%; p = 0.012) or 90 mg (74%; p < 0.001) were PASI 75 responders at Week 12 compared with the etanercept group (57%). PASI 90 response was observed in 36% and 45% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared with 23% of patients receiving etanercept (p<0.001 for each comparison versus etanercept). PASI 100 response was observed in 12% and 21% of patients in the ustekinumab 45 mg and 90 mg groups, respectively, compared to 6% of patients receiving etanercept (Table 11). In addition, a greater proportion of patients in the ustekinumab 45 mg and 90 mg treatment groups achieved a PGA score of "cleared" or "minimal" (65% and 71%, respectively) compared with patients in the etanercept treatment group (49%) (p<0.001 for each comparison versus etanercept).
In pre-specified analyses of efficacy by body weight in ACCEPT, minimal dose response to ustekinumab was evident in patients ≤ 100 kg. In patients who weighed >100 kg, higher PASI 75 response rates were seen with 90 mg dosing compared with 45 mg dosing, and a higher proportion of patients receiving 90 mg dosing had PGA scores of cleared or minimal compared with patients receiving 45 mg dosing (Table 11). (See Table 11.)
Click on icon to see table/diagram/imageClinical Efficacy – Pediatric Plaque Psoriasis: Adolescent patients (12 to 17 years of age): The efficacy of STELARA was studied in 110 pediatric patients 12 to 17 years of age, in a multicenter, Phase 3, randomized, double blind, placebo controlled study (CADMUS). Patients were randomized to receive either placebo (n=37), or the recommended dose of STELARA (n=36) (see Dosage and Administration) or half the recommended dose of STELARA (n=37) by subcutaneous injection at Weeks 0 and 4 followed by every 12 week (q12w) dosing. At Week 12, placebo treated patients crossed over to receive STELARA. Efficacy observed in patients treated with the recommended dose of STELARA is presented as follows.
The baseline disease characteristics of randomized subjects are summarized in Table 12. Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemic or phototherapy, were eligible for the study. Approximately half of the patients had prior exposure to conventional systemic or biologic therapy. (See Table 12.)
Click on icon to see table/diagram/imageThe primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) at Week 12. Secondary endpoints included PASI 75, PASI 90, change from baseline in Children's Dermatology Life Quality Index (CDLQI), change from baseline in the total score of PedsQL (Pediatric Quality of Life Inventory) at Week 12. At Week 12, subjects treated with STELARA showed significantly greater improvement in their psoriasis and health related quality of life compared with placebo (Table 13). (See Table 13.)
Click on icon to see table/diagram/imageAll patients were followed for efficacy for up to 52 weeks following first administration of study agent. The proportion of patients with a PGA score of cleared (0) or minimal (1) and the proportion achieving PASI 75 showed separation between the STELARA treated group and placebo at the first post-baseline visit at Week 4 reaching a maximum at Week 8. Improvements in PGA, PASI, CDLQI and PedsQL were maintained through Week 52. The PGA scores of cleared (0) or minimal (1)over time through Week 52 are summarized in Figure 3 as follows. (See Figure 3.)
Click on icon to see table/diagram/imagePediatric Patients (Children 6 to 11 years of age)The efficacy of STELARA was studied in 44 pediatric patients 6 to 11 years of age with moderate to severe plaque psoriasis in an open label, single-arm, multicenter, Phase 3 study (CADMUS Jr.). Patients were treated with the recommended dose of STELARA (n=44) (see Dosage and Administration) by subcutaneous injection at Weeks 0 and 4 followed by every 12 week (q12w) dosing.
The baseline disease characteristics of enrolled patients are summarized in Table 14. Patients with PASI ≥ 12, PGA ≥ 3 and BSA involvement of at least 10%, who were candidates for systemic therapy or phototherapy, were eligible for the study. Approximately 23% of the patients had prior exposure to conventional systemic therapy or biologic therapy. (See Table 14.)
Click on icon to see table/diagram/imageThe primary endpoint was the proportion of patients who achieved a PGA score of cleared (0) or minimal (1) at Week 12. Secondary endpoints included PASI 75, PASI 90, and change from baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 12. At Week 12, patients treated with STELARA showed clinically meaningful improvements in their psoriasis and health related quality of life (Table 15). (See Table 15.)
Click on icon to see table/diagram/imageAll patients were followed for efficacy for up to 52 weeks following first administration of study agent. Efficacy measured by PGA score of 0 or 1 was observed as early as the first post-baseline visit at Week 4 and increased through Week 16 and then remained relatively stable through Week 52.Improvements in PGA, PASI, and CDLQI were maintained through Week 52.
Clinical Efficacy - Psoriatic arthritis (PsA): The safety and efficacy of STELARA was assessed in two multicenter, randomized, double-blind, placebo-controlled, Phase 3 studies, PSUMMIT I and PSUMMIT II, in patients with active psoriatic arthritis. Patients were randomized to receive treatment with either STELARA 45 mg, 90 mg, or placebo subcutaneous injections at Weeks 0 and 4 followed by every 12 week (q12w) dosing. The primary endpoint in these studies was the reduction in the signs and symptoms of psoriatic arthritis (PsA) as measured by the percentage of ACR 20 responders at Week 24. Secondary endpoints included change from baseline in Disability Index of the Health Assessment Questionnaire (HAQ-DI), PASI 75, ACR 50, ACR 70 and change from baseline in total radiographic scores of the hands and feet, at Week 24. Efficacy data were collected and analyzed through Week 52 for both studies and through Week 100 for PSUMMIT I. These studies included 927 (PSUMMIT I, n=615; PSUMMIT II, n=312) adult patients (≥18 years) who had active psoriatic arthritis (≥5 swollen joints and ≥5 tender joints, despite disease modifying antirheumatic (DMARD) and/or nonsteroidal anti-inflammatory (NSAID) therapy). Methotrexate use was allowed during the studies but was not mandatory. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). In PSUMMIT I and PSUMMIT II, 80% and 86% of the patients, respectively, had been previously treated with DMARDs.
In PSUMMIT I patients, who had been previously treated with anti-TNFα therapy, prior to the first study dose, were excluded. In PSUMMIT II, the majority of patients (58%, n=180) had been previously treated with one or more anti-TNFα agent(s) for at least 8 weeks (14 weeks with infliximab) or had discontinued anti-TNFα for intolerance at any time. Among the patients who had been previously treated with an anti-TNFα agent, over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance.
Patients with each subtype of psoriatic arthritis were enrolled, including polyarticular arthritis with no evidence of rheumatoid nodules (39%, N=362), spondylitis with peripheral arthritis (28%, N=255), asymmetric peripheral arthritis (21%, N=193), distal interphalangeal (DIP) arthritis (12%, N=112) and arthritis mutilans (0.5%, N=5). Over 70% and 40% of the patients in both studies had enthesitis and dactylitis at baseline, respectively.
In both studies, a significantly greater proportion of patients achieved ACR 20 and ACR 50 responses at Week 24 in the STELARA 45 mg and 90 mg groups compared to placebo (see Table 16). In PSUMMIT I, a significantly greater proportion of patients and in PSUMMIT II a numerically greater proportion of patients (p=NS) achieved ACR 70 responses in the STELARA 45 mg and 90 mg groups compared to placebo (see Table 16).
In both studies, the proportion of patients achieving a modified PsA response criteria (PsARC) or a Disease Activity Index Score 28 using C-reactive protein (DAS28-CRP) response was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT I the proportion of patients achieving DAS28-CRP remission was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, the proportion of patients who achieved DAS28-CRP remission was significantly greater in the STELARA 90 mg group compared to placebo (see Table 17). DAS28-CRP and PsARC responses were maintained through Week 52 in both studies and through Week 100 in PSUMMIT I. (See Table 16.)
Click on icon to see table/diagram/imageThe time course for ACR 20 response rates during the first 24 weeks in both studies for patients receiving STELARA or placebo are summarized in Figure 4. ACR 20 responses showed improvement at the first assessment (Week 4). ACR 20, 50 and 70 responses continued to improve or were maintained through Week 52 (see Table 17). In PSUMMIT I, ACR responses were maintained through Week 100. (See Figure 4 and Table 17.)
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Click on icon to see table/diagram/imageIn PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 153 continued the same dose and were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 99 (64.7%), 57 (37.3%) and 34 (22.2%) subjects respectively. Of 204 subjects randomized to STELARA 90 mg, 185 were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 120 (64.9%), 74 (40%) and 41 (22.2%) subjects respectively.
In PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 138 continued the same dose and were available for evaluation at Week 100. Among those, ACR 20, 50 and 70 responses were achieved by 89 (64.5%), 63 (45.7%) and 41 (29.7%) subjects respectively. Of 204 subjects randomized to STELARA 90 mg, 166 were available for evaluation at Week 100. Among those, ACR 20, 50 and 70 responses were achieved by 116 (69.9%), 84 (50.6%) and 41 (24.7%) subjects respectively.
In PSUMMIT II, of 103 subjects randomized to STELARA 45 mg, 68 continued the same dose and were available for evaluation at Week 52. Among those, ACR 20, 50, and 70 responses were achieved by 41 (60.3%), 23 (33.8%) and 11 (16.2%) subjects respectively. Of 105 subjects randomized to STELARA 90 mg, 83 were available for evaluation at Week 52. Among those, ACR 20, 50 and 70 responses were achieved by 49 (59%), 26 (31.3%) and 17 (20.5%) subjects respectively.
Additionally, within each weight group (≤100 kg and >100 kg), ACR 20, ACR 50 and ACR 70 responses were consistently higher in the STELARA 45 and 90 mg groups than in the placebo group (see Table 18).
Click on icon to see table/diagram/imageSTELARA treatment resulted in significantly greater improvement compared with placebo for each ACR component (see Table 19).
Click on icon to see table/diagram/imageMethotrexate Use: The proportion of patients achieving ACR responses were consistently greater in patients treated with STELARA than those treated with placebo regardless of concomitant MTX use (see Table 20). Responses observed in the STELARA groups were similar in patients receiving or not receiving concomitant MTX. ACR responses were maintained through Week 52 in PSUMMIT I and II and through Week 100 in PSUMMIT I. (See Table 20.)
Click on icon to see table/diagram/imagePrior Anti-TNFα therapy: PSUMMIT II evaluated 180 patients who were previously treated with one or more anti-TNFα agents for at least 8 weeks (14 weeks with infliximab), or had documented intolerance of anti-TNFα therapy at any time in the past.
Among patients previously treated with anti-TNFα agents, a significantly greater proportion of STELARA-treated patients achieved an ACR 20 response at Week 24 compared to placebo (see Table 21). ACR 20, 50 and 70 responses were generally maintained through Week 52. (See Table 21.)
Click on icon to see table/diagram/imageEnthesitis and Dactylitis: For patients with enthesitis and/or dactylitis at baseline, in PSUMMIT I, a significant improvement in enthesitis and dactylitis score was observed in the STELARA 45 mg and 90 mg groups compared to placebo. In PSUMMIT II, a significant improvement in enthesitis score and numerical improvement in dactylitis score were observed in the 90 mg group (p=NS) compared with the placebo group (see Table 22). In both studies, improvement in enthesitis score and dactylitis score were maintained at Week 52. In PSUMMIT I, the improvement in enthesitis score and dactylitis score was maintained through Week 100. (See Table 22.)
Click on icon to see table/diagram/imageA higher proportion of patients treated with STELARA, that have spondylitis with peripheral arthritis as their primary presentation, demonstrated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 and 70 percent improvement in BASDAI scores at Week 24 compared with placebo (see Table 23).
Click on icon to see table/diagram/imagePASI Response: In PSUMMIT I and PSUMMIT II, the proportion of patients with psoriasis involvement of ≥3% BSA at baseline who achieved a ≥75% improvement in the PASI assessment at Week 24 was significantly greater in the STELARA 45 mg and 90 mg groups compared with the placebo group (see Table 25). In both studies the proportion of patients achieving the PASI 75 response was maintained through Week 52 (PSUMMIT I, STELARA 45 mg-70.1% and 90 mg-68.1%; PSUMMIT II, STELARA 45 mg-56.5% and 90 mg-64.4%). In PSUMMIT I, the PASI 75 response was maintained through Week 100.
The proportion of patients who achieved both a PASI 75 response and an ACR 20 response was evaluated for those patients with ≥3% BSA psoriasis skin involvement at baseline. A significantly higher proportion of patients achieved the combined response in the STELARA 45 mg and 90 mg groups compared with the placebo group at Week 24 (see Table 24). In both studies the proportion of patients achieving both a PASI 75 response and an ACR20 response was maintained through Week 52 (PSUMMIT I, STELARA 45 mg-44.8% and 90 mg-44.3%; PSUMMIT II, STELARA 45 mg-36.8% and 90 mg-43.1%). In PSUMMIT I, the proportion of patients achieving the combined PASI 75 and ACR20 response was maintained through Week 100. (See Table 24.)
Click on icon to see table/diagram/imageAdditionally, within each weight group (≤100 kg and >100 kg), PASI 75, 90 and 100 responses were consistently higher in the STELARA 45 and 90 mg groups than in the placebo group (see Table 25).
Click on icon to see table/diagram/imageMethotrexate Use: In both studies, the proportion of patients who achieved a PASI 75 response at Week 24 was consistently higher in STELARA 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use. PASI 75 responses were maintained through Week 52 in both PSUMMIT I and II. In PSUMMIT I, PASI 75 response was maintained at Week 100.
Prior Anti-TNFα Therapy: In PSUMMIT II, the proportion of patients who achieved a PASI 75 response at Week 24 was significantly greater in STELARA 45 mg and 90 mg groups compared with placebo in patients previously treated with an anti-TNFα agent.
Radiographic Response: Structural damage in both hands and feet was assessed by readers unaware of treatment group and order of visits, and expressed as change in total van der Heijde-Sharp score (vdH-S score), modified for PsA by addition of hand distal interphalangeal (DIP) joints, compared to baseline. A pre-specified integrated analysis combining data from 927 subjects in both PSUMMIT I & II was performed. At Week 24, based on this integrated analysis, the STELARA 45 mg or 90 mg treatment significantly inhibited progression of structural damage, when compared to placebo (see Table 26). Beyond Week 24, STELARA treatment continued to inhibit the progression of structural damage through Week 52. The mean change from Week 24 to 52 in total modified vdH-S score (0.18 and 0.26 in the STELARA 45 mg and 90 mg groups respectively) was less than the mean change from Week 0 to 24 (see Table 26). In PSUMMIT I, the effect of STELARA on inhibition of structural damage progression was maintained through Week 100. Among subjects treated with STELARA 45 mg and 90 mg with no radiographic progression from baseline to Week 52 (n=103, and 113, respectively), 81.5% and 88.8% continued to show no radiographic progression at Week 100. (See Table 26.)
Click on icon to see table/diagram/imageAt Week 24, patients treated with STELARA demonstrated less progression of structural damage compared to placebo, irrespective of concomitant MTX use.
The effect of STELARA on progression of structural damage in patients with prior anti-TNFα experience has not been established although it has not been adequately studied.
Physical Function and Health-Related Quality of Life: In PSUMMIT I and PSUMMIT II, physical function and health-related quality of life were assessed using the Disability Index of the Health Assessment Questionnaire (HAQ-DI), Dermatology Life Quality Index (DLQI) and the SF-36 health survey.
Patients treated with STELARA showed significant improvement in physical function as assessed by the HAQ-DI at Week 24. The proportion of patients achieving a clinically meaningful ≥0.3 improvement in HAQ-DI score from baseline at Week 24 was also significantly greater in the STELARA groups when compared with placebo (see Table 27). Improvement was observed at the first assessment (Week 4), reached maximum at Week 12 and was maintained through Week 24. Improvement in HAQ-DI score from baseline was maintained in both studies at Week 52 and through Week 100 in PSUMMIT I.
In both studies, the improvement in HAQ-DI at Week 24 was consistently greater in the STELARA 45 mg and 90 mg groups compared with placebo regardless of concomitant MTX use.
In PSUMMIT II, the improvement in HAQ-DI at Week 24 was significantly greater in the STELARA 45 mg and 90 mg groups compared with placebo in patients previously treated with anti-TNFα agents. (See Table 27.)
Click on icon to see table/diagram/imageIn PSUMMIT I, of 205 subjects randomized to STELARA 45 mg, 153 continued the same dose and were available for evaluation at Week 52. Among those, the HAQ-DI response was achieved by 83 (54.2%) subjects. Of 204 subjects randomized to STELARA 90 mg, 185 were available for evaluation at Week 52. Among those, HAQ-DI response was achieved by 102 (55.1%) subjects.
In PSUMMIT II, of 103 subjects randomized to STELARA 45 mg, 68 continued the same dose and were available for evaluation at Week 52. Among those, the HAQ-DI response was achieved by 29 (42.6%) subjects. Of 105 subjects randomized to STELARA 90 mg, 83 were available for evaluation at Week 52. Among those, HAQ-DI response was achieved by 44 (53%) subjects.
The DLQI was assessed by comparing the change in DLQI scores from baseline for those patients with ≥3% BSA at baseline. In both studies at Week 24, there was a significant improvement from baseline in DLQI scores in both the STELARA 45 mg and 90 mg groups as compared with placebo (see Table 28) and the improvement was maintained at Week 52. In PSUMMIT I, the improvement from baseline in DLQI scores was maintained through Week 100.
In both PSUMMIT I and PSUMMIT II, at Week 24, the change from baseline in the SF-36 physical component summary (PCS) scores was significantly greater in the STELARA 45 mg and 90 mg groups compared with the placebo group. In both studies, the change from baseline in the SF-36 mental component summary (MCS) scores at Week 24 was greater in both STELARA groups compared with the placebo group (p<0.001 for PSUMMIT I - 90 mg group, p=NS for other groups) (see Table 28). The change from baseline in the SF-36 PCS and MCS scores was maintained at Week 52 in both studies, and at Week 100 in PSUMMIT I.
In PSUMMIT II, a significant change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores was observed at Week 24 in the STELARA 45 mg and 90 mg groups compared with the placebo group (median improvement, all 3.0 vs 0.0; p<0.007). Similarly, the percentage of patients with clinically significant improvement in fatigue from baseline (4 points in FACIT-F) was significantly greater in the STELARA 45 mg (49% [p<0.001]) and 90 mg groups (49% [p<0.001]) compared with the placebo group (25.8%). The change from baseline in the FACIT-F scores was maintained at Week 52. (See Table 28.)
Click on icon to see table/diagram/imageHealth Economics: Health economics data on time lost from work, employability, and daily productivity at work, school, or home were collected through questionnaires at baseline and Week 24. To assess productivity, patients were asked to indicate how much their disease affected their productivity at work, school or at home in the past 4 weeks, using a 10 cm Visual Analogue Scale (VAS) (not at all affected [0] to affected very much [10]).
The improvement in self-reported productivity was significantly greater in the STELARA 45 mg and 90 mg groups compared to placebo at Week 24. The improvement in self-reported productivity was maintained in both studies at Week 52 and through Week 100 in PSUMMIT I.
Clinical Efficacy - Crohn's Disease: The safety and efficacy of STELARA were evaluated in three randomized, double-blind, placebo-controlled clinical trials in adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450). The clinical development program consisted of two 8-week IV induction studies (UNITI-1 and UNITI-2) followed by a 44-week subcutaneous randomized withdrawal maintenance study (IM-UNITI) representing 52 weeks of therapy.
Induction of Clinical Response and Remission: UNITI-1 and UNITI-2 studies included 1409 (UNITI-1, n=769; UNITI-2, n=640) patients. In both studies, patients were permitted to concomitantly receive oral 5-ASA compounds, immunomodulators, corticosteroids, and/or antibiotics. Patients were randomized to receive a single IV administration of either 130 mg STELARA, or approximately 6 mg/kg STELARA designed as a tiered dose based on patient body weight (Table 27) or placebo at Week 0. The primary endpoint was clinical response (defined as a reduction in CDAI score of ≥100 points or CDAI score <150) at Week 6. Secondary endpoints included clinical remission at Week 8, clinical response at Week 8, 70-point response at Week 3, and 70-point response at Week 6. Efficacy data were collected and analyzed through Week 8 for both studies.
In UNITI-1, patients had failed or were intolerant to prior anti-TNFα therapy. At baseline, approximately 46% (n=340) patients were receiving corticosteroids (including budesonide) and 31.4% of patients were receiving immunomodulators. Approximately 48% had failed 1 prior anti-TNFα therapy and 52% had failed 2 or 3 prior anti-TNFα therapies (40.8% and 10.4%, respectively). In this study, 29.1% patients had an inadequate initial response (primary non responders), 69.4% responded but subsequently lost response (secondary non-responders), and 36.4% were intolerant to anti-TNFα therapies.
Patients in UNITI-2 had failed at least one conventional therapy (corticosteroids or immunomodulators) and were either anti-TNFα naive (68.6%) or had previously received but not failed anti-TNFα therapy (31.4%). At baseline, approximately 40% patients were receiving corticosteroids (including budesonide) and 35% patients were receiving immunomodulators.
In these induction studies, efficacy was higher and better sustained in the tiered dose group compared to the 130 mg dose group, and tiered dosing is therefore the recommended IV induction dose. In both UNITI-1 and UNITI-2, a significantly greater proportion of patients were in clinical response and remission in the group treated with STELARA, compared to placebo (Table 29, Figure 5). Clinical response and remission were significant as early as Week 3 in STELARA treated patients and continued to improve through Week 8 (Figure 5). (See Table 29 and Figure 5.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageMaintenance of Response and Remission: The maintenance study (IM-UNITI) evaluated 388 patients who achieved clinical response (≥100 point reduction in CDAI score) at Week 8 of induction with STELARA in UNITI-1 or UNITI-2. Of those, approximately 60% of the patients entered the maintenance study in remission. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg STELARA every 8 weeks, 90 mg STELARA every 12 weeks or placebo for 44 weeks.
Concomitant doses of oral 5-ASA compounds, immunomodulators corticosteroids and antibiotics were permitted. Corticosteroids were tapered at the start of the maintenance trial. The primary endpoint was clinical remission (CDAI < 150) at Week 44. Secondary endpoints assessed at Week 44 included clinical response, clinical remission among STELARA treated patients in clinical remission after induction, corticosteroid-free remission, and clinical remission in the subset of patients who were refractory or intolerant to anti-TNFα treatment.
Significantly higher proportions of patients maintained clinical remission and response in the STELARA treated groups as compared to placebo at Week 44 (Table 30, Figure 6). A higher proportion of STELARA treated patients compared to placebo achieved sustained clinical remission (clinical remission at Week 36, 40 and 44). (See Table 30 and Figure 6.)
Click on icon to see table/diagram/imageClick on icon to see table/diagram/imageDelayed Response: Patients who were not in clinical response to STELARA induction received a 90 mg subcutaneous injection of STELARA upon entry into the maintenance study. Eight weeks later, 50.5% of the patients achieved clinical response and continued to receive maintenance dosing every 8 weeks; among these patients with continued maintenance dosing, a majority achieved levels of response (68.1%) and remission (50.2%) similar to the patients who initially responded to STELARA induction.
Dosing in Patients with a Lower Inflammatory Burden: In patients with a lower inflammatory burden as reflected by CRP ≤ 10 mg/L at initiation of induction or initiation of maintenance therapy, the efficacy of the every 12 week dosing regimen was similar to that of the every 8 week dosing regimen.
Dosing Frequency Adjustment: In IM-UNITI, patients who did not maintain response to STELARA when treated every 12 weeks were allowed to increase the frequency of dosing and receive STELARA every 8 weeks. Loss of response was defined as a CDAI score ≥ 220 points and a ≥ 100 point increase from the CDAI score at baseline. In these patients, clinical remission was achieved in 41.4% of patients 16 weeks after dosing frequency adjustment.
Resumption of Treatment: Patients that responded to STELARA induction and who were randomized to the placebo group at the start of the maintenance study received 90 mg STELARA subcutaneously every 8 weeks at time of loss of response. Of these patients, 70.6% achieved clinical response and 39.2% achieved clinical remission 16 weeks after receiving the first subcutaneous dose of STELARA.
Long-Term Maintenance: In IM-UNITI, patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension, clinical remission and response were generally maintained through week 92. Results were consistent between patients who failed TNF-therapies versus those who did not.
No new safety concerns were identified in this study extension with up to 2 years of treatment in patients with Crohn's Disease.
Corticosteroid Use in Maintenance: In patients that were in clinical response to STELARA induction therapy, a greater proportion of patients in the STELARA treated group were in remission and corticosteroid-free compared to the placebo group after 44 weeks of maintenance treatment (Table 25). In addition, a higher proportion of patients were in clinical response and not receiving corticosteroids in the STELARA treated group compared to placebo.
Endoscopic Healing of the Mucosa: Endoscopic healing of the mucosa was evaluated in 252 patients with baseline endoscopic disease activity in a substudy. At Week 8, after a single IV induction dose, reduction in mucosal inflammation, as measured by the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), was greater in patients treated with STELARA (n=83) compared with patients treated with placebo (n=97) (-3.0 vs -0.7, p=0.009). Similar reductions in histologic inflammation were also observed.
Reduction in endoscopic and histologic inflammation was observed in patients treated with STELARA in maintenance. However, due to the small number of patients, the efficacy of STELARA in the maintenance of endoscopic healing could not be definitively established.
Fistula Response: In patients with draining fistulas at baseline (8.8%), a numerically greater proportion of STELARA treated patients achieved a fistula response (defined as ≥ 50% reduction from baseline of the induction study in the number of draining fistulas) compared with placebo over 44 weeks (p=NS). The proportion of patients in fistula response at Week 44 was 45.5% (5/11) for placebo group, 71.4% (5/7) for STELARA 90 mg every 12 week dosing group, and 87.5% (7/8) for STELARA 90 mg every 8 week dosing group.
Health-Related Quality of Life Measures: Improvement in general and disease specific health-related quality of life was assessed using the SF-36 and Inflammatory Bowel Disease Questionnaire (IBDQ) respectively.
SF-36: A higher proportion of patients treated with STELARA showed clinically meaningful improvements in SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and these improvements were significantly greater at week 8 compared with the placebo group in UNITI-1 (MCS) and UNITI-2 (PCS, MCS and all subscores). These improvements in the PCS and MCS scores were maintained in STELARA treated patients in the IM-UNITI maintenance study through Week 44.
IBDQ: At Week 8 in UNITI-1 and UNITI-2, significant improvement from baseline in the inflammatory bowel disease questionnaire (IBDQ) total score and all subscales, was observed in the patients treated with STELARA compared to placebo. In both studies, a higher proportion of patients with clinically meaningful improvement in IBDQ total scores were observed in patients treated with STELARA compared to placebo. These improvements in the IBDQ total scores were maintained in STELARA treated patients in the IM-UNITI maintenance study through Week 44.
Long-term Maintenance of Health-related Quality of Life Measures: Improvement in health related quality of life as measured by IBDQ and SF-36 was generally maintained during the extension through week 252.
Clinical Efficacy – Ulcerative Colitis: The safety and efficacy of ustekinumab was assessed in two randomized, double-blind, placebo-controlled, multicenter studies in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥2 based on central review of the endoscopy). The clinical development program consisted of one intravenous induction study (referred to as UNIFI-induction) with treatment of up to 16 weeks followed by a 44-week subcutaneous randomized withdrawal maintenance study (referred to as UNIFI-maintenance) representing at least 52 weeks of therapy.
Efficacy results presented for UNIFI-induction and UNIFI-maintenance were based on central review of endoscopies.
UNIFI-induction included 961 patients. The primary endpoint for the induction study was the proportion of patients in clinical remission (defined as a Mayo score ≤2 points, with no individual subscore >1) at Week 8. Patients were randomized to receive a single intravenous administration of either the recommended tiered dose of approximately 6 mg/kg (see Table 33; Initial IV dosing of STELARA), a fixed dose of 130 mg ustekinumab, or placebo at Week 0.
Concomitant use of oral corticosteroids, immunomodulators, and aminosalicylates were permitted and 90% of patients continued to receive at least one of these medications. Enrolled patients had to have failed conventional therapy (corticosteroids or immunomodulators) or at least one biologic (a TNFα antagonist and/or vedolizumab). 49% of patients had failed conventional therapy, but not a biologic (of which 94% where biological-naïve). 51% of patients had failed or were intolerant to a biologic. Approximately 50% of the patients had failed at least 1 prior anti-TNFα therapy (of which 48% were primary non-responders) and 17% had failed at least 1 anti-TNFα therapy and vedolizumab.
In UNIFI-induction a significantly greater proportion of patients were in clinical response and remission in the ustekinumab treated group compared to placebo (Table 31). As early as Week 2, the earliest scheduled study visit, and at each visit thereafter, a higher proportion of ustekinumab patients had no rectal bleeding or achieved normal stool frequency (defined as a stool frequency subscore of 0 or 1) as compared with placebo patients. Significant differences in partial Mayo score and symptomatic remission were observed between ustekinumab and placebo as early as Week 2. Efficacy was higher in the tiered dose group (6 mg/kg) compared to the 130 mg dose group in select endpoints, and tiered dosing is therefore the recommended intravenous induction dose. (See Table 31.)
Click on icon to see table/diagram/imageUNIFI-maintenance evaluated 523 patients who achieved clinical response with single IV administration of ustekinumab in UNIFI-induction. Patients were randomized to receive a subcutaneous maintenance regimen of either 90 mg ustekinumab every 8 weeks, 90 mg ustekinumab every 12 weeks or placebo for 44 weeks.Significantly greater proportions of patients were in clinical remission at Week 44 and maintained clinical response through Week 44 in both ustekinumab treated groups compared to the placebo group (see Table 32).
Click on icon to see table/diagram/imageThe beneficial effect of ustekinumab on clinical response, mucosal healing and clinical remission was observed in induction and in maintenance both in patients who failed conventional therapy but not a biologic therapy, as well as in those who had failed at least one prior TNFα antagonist therapy, and/or vedolizumab including in patients with a primary non-response to TNFα antagonist therapy.
Delayed Responders to Ustekinumab Induction: Ustekinumab treated patients who were not in response at Week 8 of UNIFI-induction received an administration of 90 mg SC ustekinumab at Week 8 (36% of patients). Of those patients, 9% of patients who were initially randomized to the recommended induction dose achieved clinical remission and 58% achieved clinical response at Week 16. When combining the delayed responders with the initial responders, 80% of subjects randomized to the recommended induction dose in UNIFI-I achieved clinical response and 18% achieved clinical remission within 16 weeks after initiating treatment with ustekinumab.
Patients who were not in clinical response to ustekinumab induction at Week 8 of the UNIFI-induction study but were in response at Week 16 (157 patients) entered in the non-randomized portion of UNIFI-maintenance and continued to receive maintenance dosing every 8 weeks; among these patients, a majority (62%) maintained response and 30% achieved remission at Week 44.
Long-Term Maintenance: In UNIFI (UCO3001), patients who completed the study through week 44 were eligible to continue treatment in a study extension. Among patients who entered the study extension, symptomatic remission was generally maintained through week 92 for patients who failed conventional therapy (but not a biologic therapy) and those who failed biologic therapy, including those who failed both anti-TNF and vedolizumab.
No new safety concerns were identified in this study extension with up to 2 years of treatment in patients with ulcerative colitis.
Endoscopic Normalization: Normalization of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0 and was observed as early as Week 8 of UNIFI-induction. At Week 44 of UNIFI-maintenance, it was achieved in 24% and 29% of patients treated with ustekinumab every 12 or 8 weeks, respectively, as compared to 18% of patients in the placebo group.
Histologic & Histo-Endoscopic Mucosal Healing: Histologic healing (defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue) was assessed at Week 8 of UNIFI-induction and Week 44 of UNIFI-maintenance. At Week 8, after a single intravenous induction dose, significantly greater proportions of patients in the recommended dose group achieved histologic healing (36%) compared with patients in the placebo group (22%). At Week 44 maintenance of this effect was maintained with significantly more patients in histologic healing in the every 12 week (54%) and every 8 week (59%) ustekinumab groups as compared to placebo (33%).
A combined endpoint of histo-endoscopic mucosal healing defined as subjects having both mucosal healing and histologic healing was evaluated at week 8 of UNIFI-induction and Week 44 of UNIFI-maintenance. Patients receiving ustekinumab at the recommended dose showed significant improvements on the histo-endoscopic mucosal healing endpoint at Week 8 in the ustekinumab group (18%) as compared to the placebo group (9%). At Week 44, maintenance of this effect was observed with significantly more patients in histo-endoscopic mucosal healing in the every 12 week (39%) and every 8 week (46%) ustekinumab groups as compared to placebo (24%).
Health-related quality of life: Health-related quality of life was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), SF-36 and EuroQoL-5D (EQ-5D) questionnaires. At Week 8 of UNIFI-induction, patients receiving ustekinumab showed significantly greater and clinically meaningful improvements on IBDQ total score, EQ-5D and EQ-5D VAS, and SF-36 Mental Component Summary Score and SF-36 Physical Component Summary Score when compared to placebo. These improvements were maintained in ustekinumab-treated patients in UNIFI-maintenance through Week 44.
Patients receiving ustekinumab experienced significantly more improvements in work productivity as assessed by greater reductions in overall work impairment and in activity impairment as assessed by the WPAI-GH questionnaire than patients receiving placebo.
Long-term maintenance of health-related quality of life measures: Improvement in health related quality of life as measured by IBDQ and SF-36 was generally maintained during the extension through week 92.
Hospitalizations and Ulcerative Colitis related surgeries: Through Week 8 of UNIFI-induction, the proportions of subjects with ulcerative colitis disease related hospitalizations were significantly lower for subjects in the ustekinumab recommended dose group (1.6%, 5/322) compared with subjects in the placebo group (4.4%, 14/319) and no subjects underwent ulcerative colitis disease related surgeries in subjects receiving ustekinumab at the recommended induction dose compared to 0.6% (2/319) subjects in the placebo group.
Through Week 44 of UNIFI-maintenance, a significantly lower number of ulcerative colitis disease related hospitalizations was observed in subjects in the combined ustekinumab group (2.0%, 7/348) as compared with subjects in the placebo group (5.7%, 10/175). A numerically lower number of subjects in the ustekinumab group (0.6%, 2/348) underwent ulcerative colitis disease related surgeries compared with subjects in the placebo group (1.7%, 3/175) through Week 44.
Pharmacokinetics: Absorption: 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 that observed in healthy subjects.
The absolute bioavailability of ustekinumab following a single subcutaneous administration was estimated to be 57.2% in patients with psoriasis. Following the recommended intravenous induction dose, median peak serum ustekinumab concentration was 126.1 mcg/mL in patients with Crohn's disease, and 127.0 mcg/mL in patients with ulcerative colitis.
Distribution: 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. In a population pharmacokinetic analysis of ustekinumab, the volume of distribution at steady-state was 4.62 L in patients with Crohn's disease and 4.44 L in patients with ulcerative colitis.
Metabolism: The exact metabolic pathway for ustekinumab is unknown.
Elimination: 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 Crohn's disease, psoriasis and/or psoriatic arthritis ranging from 15 to 32 days across all psoriasis and psoriatic arthritis studies. In a population pharmacokinetic analysis of ustekinumab, the clearance was 0.19 L/day while the half-life was approximately 19 days in patients with Crohn's disease and ulcerative colitis.
Dose Linearity: 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 vs. Multiple Doses: Serum concentration-time profiles of ustekinumab were generally predictable after single or multiple subcutaneous dose administrations. In patients with psoriasis, 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 mcg/mL to 0.26 mcg/mL (45 mg) and from 0.47 mcg/mL to 0.49 mcg/mL (90 mg).
Following the recommended IV induction dose, median peak serum ustekinumab concentration was 126.1 mcg/mL in patients with Crohn's disease and 127.0 mcg/mL in patient with ulcerative colitis. Starting at Week 8, subcutaneous maintenance dosing of 90 mg ustekinumab was administered every 8 or 12 weeks. Steady state ustekinumab concentration was achieved by the start of the second maintenance dose. There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 8 or 12 weeks.
Following subcutaneous maintenance dosing of 90 mg ustekinumab every 8 weeks, median steady-state trough concentrations ranged from 1.97 mcg/mL to 2.24 mcg/mL in patients with Crohn's disease and 2.69 mcg/mL to 3.09 mcg/mL in patients with ulcerative colitis. Following subcutaneous maintenance dosing of 90 mg ustekinumab every 12 weeks, median steady state trough concentrations ranged from 0.61 mcg/mL to 0.76 mcg/mL in patients with Crohn's disease and 0.92 mcg/mL to 1.19 mcg/mL in patients with ulcerative colitis. The steady-state trough ustekinumab levels resulting from 90 mg ustekinumab every 8 weeks were associated with higher clinical remission rates as compared to the steady state trough levels following 90 mg every 12 weeks.
Dosing Frequency Adjustment: In patients with Crohn's disease and ulcerative colitis, based on observed data and population PK analyses, randomized subjects who lost response to treatment had lower serum ustekinumab concentrations over time compared with subjects who did not lose response. In Crohn's disease, dose adjustment from 90 mg every 12 weeks to 90 mg every 8 weeks was associated with an increase in trough serum ustekinumab concentrations and an accompanying increase in efficacy. In ulcerative colitis, population PK model based simulations demonstrated that adjusting dosing from 90 mg every 12 weeks to every 8 weeks would be expected to result in a 3-fold increase in steady-state trough ustekinumab concentrations. Additionally on the basis of clinical trial data in patients with ulcerative colitis, a positive exposure-response relationship was established between trough concentrations and clinical response, clinical remission, and mucosal healing.
Impact of Weight on Pharmacokinetics: Serum ustekinumab concentrations were affected by weight in patients with psoriasis and/or psoriatic arthritis. Within each dose (45 mg or 90 mg), patients of higher weight (> 100 kg) had lower median serum ustekinumab concentrations compared with those in patients of lower weight (≤ 100 kg). However, across doses, 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.
Population Pharmacokinetic Analysis: In a population pharmacokinetic analysis using data from patients with psoriasis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.465 L/d and 15.7 L, respectively, and the t½ was approximately 3 weeks in patients with psoriasis. The CL/F of ustekinumab was not impacted by sex, age, or race. The CL/F was impacted by body weight, with a trend toward higher CL/F in patients with higher body weight. The median CL/F in patients with weight > 100 kg was approximately 55% higher compared with patients with weight ≤ 100 kg. The median V/F in patients with weight > 100 kg was approximately 37% higher as compared with patients with weight ≤ 100 kg. Similar results were obtained from a confirmatory population pharmacokinetic analysis using data from patients with psoriatic arthritis.
In the population pharmacokinetic analysis using data from patients with psoriasis, the effect of comorbidities (past and current history of diabetes, hypertension, and hyperlipidemia) on pharmacokinetics of ustekinumab was evaluated. The pharmacokinetics of ustekinumab were impacted by the comorbidity of diabetes, with a trend towards higher CL/F in patients with diabetes. The mean CL/F in patients with diabetes was approximately 29% higher compared with patients without diabetes.
Population pharmacokinetic analysis showed that there was a trend towards a higher clearance of ustekinumab in patients with positive immune response.
No specific drug-drug interaction studies have been conducted in healthy subjects or patients with psoriasis, psoriatic arthritis, Crohn's disease or ulcerative colitis.
In the population pharmacokinetic analyses, the effect of the most frequently used concomitant medications in patients with psoriasis (including paracetamol/acetaminophen, ibuprofen, acetylsalicylic acid, metformin, atorvastatin, naproxen, levothyroxine, hydrochlorothiazide, and influenza vaccine) on pharmacokinetics of ustekinumab was explored and none of the concomitant medications exerted significant impact. The pharmacokinetics of ustekinumab was not impacted by the prior use of MTX, cyclosporine, or other biological therapeutics for the treatment of psoriasis. The pharmacokinetics of ustekinumab was not impacted by concomitant use of NSAIDs or prior exposure to anti-TNFα agents in patients with psoriatic arthritis; or by the use of MTX, oral corticosteroids, 6-MP, AZA in patients with psoriatic arthritis or Crohn's disease, or by prior exposure to biologics (i.e. anti-TNFα agents and/or vedolizumab) in patients with ulcerative colitis.
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).
Special Populations: Pediatrics 6 to 17 years of age: The pharmacokinetics of ustekinumab in pediatric psoriasis patients, 6 to 17 years of age, treated with the recommended dose was generally comparable to that in the adult psoriasis population. No pharmacokinetic data are available in pediatric patients with Crohn's disease or ulcerative colitis.
Elderly (65 years of age and older): No specific studies have been conducted in elderly patients. The population pharmacokinetic analysis indicated there were no apparent changes in CL/F and V/F estimates in patients ≥ 65 years.
Renal impairment: No pharmacokinetic data are available in patients with renal insufficiency.
Hepatic impairment: No pharmacokinetic data are available in patients with impaired hepatic function.
Other populations: The pharmacokinetics of ustekinumab were generally comparable between Asian and non-Asian patients with psoriasis, Crohn's disease, or ulcerative colitis.
The pharmacokinetics of ustekinumab were not impacted by the use of tobacco or alcohol.
Toxicology: NON-CLINICAL INFORMATION: In repeated-dose toxicity studies in juvenile cynomolgus monkeys, ustekinumab was well-tolerated following IV doses up to 45 mg/kg/week for up to 1 month and following twice-weekly SC doses up to 45 mg/kg for 6 months. There were no ustekinumab-related findings in the immunotoxicity and cardiovascular safety pharmacology evaluations. In histopathology evaluations there were no preneoplastic changes observed.
There were no adverse effects in monkeys at exposures that were 179-fold higher than the peak serum concentration in humans following 90 mg weekly subcutaneous injection and 29-fold higher than the peak serum concentration in humans following 6 mg/kg IV administration.
Carcinogenicity and Mutagenicity: 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.
Reproductive Toxicology: Three developmental toxicity studies were conducted in cynomolgus monkeys. No ustekinumab-related maternal toxicity, abortions, still-births, embryotoxicity, developmental delays, malformations or birth defects were observed at doses up to 45 mg/kg following weekly or twice weekly administration of ustekinumab via the IV or SC routes, respectively. In neonates born from pregnant monkeys treated with ustekinumab no adverse effects on growth or functional development were observed and no deficits were observed in immunotoxicity evaluations. In a male fertility study in cynomolgus monkeys no ustekinumab-related effects on mating behavior, sperm parameters, or serum concentrations of male hormones were observed following twice weekly subcutaneous administration of ustekinumab at doses up to 45 mg/kg.
A female fertility toxicity study was conducted in mice using an analogous antibody that binds to and inhibits IL-12 and IL-23 activity in mice. Twice weekly subcutaneous administration of the anti-mouse IL-12/23 antibody was well tolerated at doses up to 50 mg/kg and no adverse effects on female fertility parameters were observed.
