Summary

• Two phase 3, double-blind, placebo-controlled trials of adult patients with moderate to severe plaque psoriasis (PsO), PHOENIX 1 and PHOENIX 2, evaluated the efficacy and safety of STELARA administered subcutaneously (SC) via the following dosing regimens: two 45 mg or 90 mg doses 4 weeks apart followed by 45 or 90 mg every 12 weeks. In both trials, significantly more patients receiving 45 mg and 90 mg achieved the primary endpoint of ≥75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12 compared with placebo (P<0.001).^1,2

CLINICAL DATA

This document contains summarized clinical data through 5 years of follow up from PHOENIX 1 and PHOENIX 2.

PHOENIX 1

Leonardi et al (2008)¹ conducted the PHOENIX (A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial Evaluating the Efficacy and Safety of CNTO 1275 in the Treatment of Subjects with Moderate to Severe Plaque-type Psoriasis Followed by Longterm Extension) 1 study, a phase 3, double-blind, placebo-controlled, multicenter trial evaluating the efficacy and safety of STELARA in 766 adult patients with moderate to severe plaque PsO.

Study Design/Methods

• Adult patients with a diagnosis of plaque PsO for ≥6 months who were candidates for phototherapy or systemic therapy and had a baseline Psoriasis Area and Severity Index (PASI) score ≥12, and ≥10% of their body surface area (BSA) involved were eligible for enrollment.
• Subjects with non-plaque forms of PsO were ineligible.
• Eligible patients were randomized in equal proportions to 1 of 3 treatment groups:
  • STELARA 45 mg administered SC at weeks 0 and 4, and every 12 weeks.
  • STELARA 90 mg SC at weeks 0 and 4, and every 12 weeks.
  • Placebo at weeks 0 and 4, with half randomized to crossover to 45 mg and half to 90 mg at week 12.
• The primary endpoint was the proportion of patients achieving a PASI 75 response at week 12.
• Major secondary endpoints included the proportion of patients with a Physician's Global Assessment (PGA) score of cleared or minimal at week 12 and the time to loss of PASI 75 response in the patients receiving STELARA maintenance therapy compared with patients withdrawn from treatment at week 40 (randomized withdrawal phase).

Results

Efficacy

• PASI responses among patients at week 12 are described in Table: PHOENIX 1: Clinical Responses at Week 12.

• Maximum response was observed at about week 24, with 76.1% and 85.0% of patients in the respective 45 mg and 90 mg groups achieving a PASI 75 response.
• At week 28, more than 90% of patients in both STELARA groups achieved a ≥50% improvement from baseline in Psoriasis Area and Severity Index (PASI 50) response, and about half of the patients in both STELARA groups achieved a ≥90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) response, which were generally maintained through week 40.
• Patients randomized to placebo at baseline achieved similar response rates after crossover at week 12.
• PASI responses among patients randomized at week 40 are described in Table: PASI Responses at Week 52 Among Patients Randomized at Week 40.³
• A PASI 75 response was achieved within 12 weeks of reinitiating STELARA in 85.6% (167/195) of patients, with similar response rates observed in all treatment groups.

Safety

Placebo-Controlled Period

• Through week 12, at least 1 adverse event (AE) was reported in 57.6%, 51.4%, and 48.2% of patients in the 45 mg, 90 mg, and placebo groups, respectively.
• Serious adverse events (SAEs) were reported in 0.8% of patients (n=2) receiving 45 mg, 1.6% of patients (n=4) receiving 90 mg, and 0.8% of patients (n=2) receiving placebo.
• There were no malignancies reported during the placebo-controlled phase.

Through Week 76

• In the placebo-crossover and randomized-withdrawal phases, the most common SAEs included infections, malignancies, and cardiovascular (CV) events.
• The pattern and rate of AEs were comparable among patients in the placebo-crossover group (who did not undergo randomized withdrawal) and were similar before and after dose adjustment in patients who did not achieve PASI 75 at week 28 or week 40 and switched to every 8 week dosing.
• Antibodies to STELARA had developed in 38 (5.1%) of the 746 patients for whom data were available by week 76; these were predominantly low titer (<1/320) and not associated with injection site reactions.

PHOENIX 1: LONG-TERM FOLLOW-UP THROUGH 5 YEARS

Kimball et al (2010 and 2012)^4,5 and Gordon et al (2011)⁶ reported results from PHOENIX 1 through 3 years of follow up.

Kimball et al (2013)⁷ evaluated the efficacy and safety of STELARA through 5 years in the PHOENIX 1 trial.

Results

Patient Characteristics

• This analysis included 766 patients with moderate to severe plaque PsO. Of the 753 patients who received at least 1 dose of STELARA, 68.7% (517/753) received STELARA through the last scheduled year 5 dose (at or before week 244) in the PHOENIX 1 trial.
• The overall study population included all patients who received ≥1 dose of STELARA (ie, week 40 responders, partial responders, and week 28 nonresponders who had their week 28 data carried forward [ie, no response] through week 244).
• Week 40 responders were comprised of patients who were randomized to STELARA at baseline, were PASI 75 responders at both weeks 28 and 40, and were rerandomized at week 40 to continue every 12 week maintenance treatment with STELARA.
• Partial responders (26% of the overall population) were comprised of patients with PASI 50 to <75 response at week 28 or <PASI 75 response at week 40 who were adjusted to every 8 week STELARA dosing. Results related to partial responders are not described in this document.
• No concomitant PsO treatments were allowed through Week 76; however, low and midpotency topical corticosteroids (Class III to VII), calcipotriene, and tazarotene were permitted after week 76.
• PASI and PGA were used to evaluate disease severity and treatment response through week 244 (the last year 5 dose). Safety parameters, including AEs and laboratory evaluations, were monitored through week 264 (the final year-5 visit). Serum samples collected through week 264 were tested for antibodies to STELARA using a bridging immunoassay.

Efficacy

Overall Study Population

• PASI 75 response rates at week 76 and week 244: week 76, 45 mg: 61.2%; 90 mg: 72.4% and week 244, 45 mg: 63.4%; 90 mg: 72.0%.
• PASI 90 response rates at week 244: 39.7% (45 mg) and 49.0% (90 mg).
• ≥100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100) response rates at week 244: 21.6% (45 mg) and 26.4% (90 mg).
• PGA score of 0 or 1 response rates at week 76 and week 244: week 76, 45 mg: 43.6%; 90 mg: 54.9% and week 244, 45 mg: 42.5%; 90 mg: 51.0%; the proportions of patients achieving these scores remained stable with maintenance dosing from week 76 to week 244.

Week 40 Responders Continuing Every 12 Week Dosing

• PASI 75 response rates through week 244: 79.1% in the 45 mg group and 80.8% in the 90 mg group.
• PASI 90 response rates at week 244: 47.8% (45 mg) and 58.9% (90 mg).
• PASI 100 response rates at week 244: 31.3% (45 mg) and 38.4% (90 mg).

Safety

• STELARA was generally well tolerated without evidence of cumulative toxicity with increased duration of exposure through 5 years in 753 patients (3104 patient years [PY]) of follow-up; the average duration of follow-up was 214 weeks in the combined group.
• There were 32 serious infections (13 in the 45 mg group and 19 in the 90 mg group) reported in 30 patients.
• Nonmelanoma skin cancers (NMSCs) were reported in 14 patients (10 in the 45 mg group and 4 in the 90 mg group), with a ratio of basal cell carcinoma to squamous cell carcinoma of 13:1.
• Other malignancies were reported in 15 patients (9 in the 45 mg group and 6 in the 90 mg group) and include:
  • Five patients with prostate cancer, 3 with melanoma (2 in situ and 1 invasive), and 1 patient each with breast cancer, colon cancer, lymphoma, metastatic pancreatic carcinoma, head and neck cancer, thyroid cancer, and transitional cell carcinoma.
• There were 10 cases of major adverse cardiovascular events (MACE; 8 in the 45 mg group and 2 in the 90 mg group) reported in 10 patients; all patients with MACE had at least 3 established CV risk factors.
• Five deaths (1 in the 45 mg group and 4 in the 90 mg group) were reported during the study: sleep apnea presumed to be CV in origin (45 mg); complications from bilateral pneumonia; perforated bowel resulting from trauma; suicide; and cervical vertebral fracture secondary to a fall. One additional death was reported after the study ended in a patient (90 mg group) who had previously discontinued study treatment due to metastatic pancreatic cancer.
• Cumulative rates of overall AEs, AEs leading to discontinuation, SAEs, infections, malignancies, and MACE were generally comparable between patients receiving STELARA 45 and 90 mg.
• Rates of AEs per 100 PY (all rates reported are per 100 PY) in the 45 mg, 90 mg, and combined groups were 220.92, 209.05, and 214.94, respectively.
• Rates of AEs leading to discontinuation in the 45 mg, 90 mg, and combined groups were 2.03, 2.26, and 2.13, respectively.
• Rates of SAEs in the 45 mg, 90 mg, and combined groups were 5.26, 5.43, and 5.35, respectively.
• Rates of infections in the 45 mg, 90 mg, and combined groups were 83.71, 81.64, and 82.66, respectively.
  • Rates of infections requiring treatment in the 45 mg, 90 mg, and combined groups were 28.44, 30.37, and 29.41, respectively.
  • Rates of serious infections in the 45 mg, 90 mg, and combined groups were 0.84, 1.21, and 1.03, respectively.
• Rates of malignant neoplasms in the 45 mg, 90 mg, and combined groups were 1.24, 0.64, and 0.93, respectively.
  • Rates of NMSCs in the 45 mg, 90 mg, and combined groups were 0.65, 0.26, and 0.45, respectively.
  • Rates of other malignancies (excluding NMSCs) in the 45 mg, 90 mg, and combined groups were 0.59, 0.38, and 0.48, respectively.
• Rates of MACE in the 45 mg, 90 mg, and combined groups were 0.52, 0.13, and 0.32, respectively.
• No cases of active tuberculosis or other infections of interest (eg, atypical mycobacterial, systemic fungal, or salmonella) were reported through year 5. One potential opportunistic infection (disseminated cutaneous herpes zoster) was reported early in the study.
• No cases of anaphylaxis or serum sickness-like reactions associated with STELARA were observed.

PHOENIX 2

Papp et al (2008)² conducted the PHOENIX 2 study, which was a phase 3, multicenter, double-blind, placebo-controlled trial evaluating the efficacy and safety of STELARA in 1230 adult patients with moderate to severe plaque PsO.

Study Design/Methods

• Adult patients with a diagnosis of plaque PsO for ≥6 months who were candidates for phototherapy or systemic therapy, and had a baseline PASI score ≥12, and ≥10% of their BSA involved were eligible for enrollment.
• Subjects with non-plaque forms of PsO were ineligible.
• The trial was divided into 3 phases: placebo-controlled phase (weeks 0-12), placebo crossover and active treatment phase (weeks 12-28), and a randomized dose intensification phase (weeks 28-52).
• At baseline, eligible patients were randomized in a 1:1:1 ratio to 1 of 3 treatment groups as in PHOENIX 1.
• The primary endpoint was the proportion of patients who achieved a PASI 75 response at week 12.
• Major secondary endpoints included the proportion of patients with a PGA score of cleared or minimal at week 12 and the number of visits with PASI 75 response between weeks 40 and 52 in the group receiving STELARA every 8 weeks compared with the group receiving STELARA every 12 weeks.

Results

Efficacy

• PASI responses among patients at week 12 are described in Table: PHOENIX 2: Clinical Responses at Week 12.

Safety: Placebo-Controlled Period

• Through week 12, at least 1 AE was reported in 53.1% and 47.9% of patients in the 45 mg and 90 mg groups, respectively, compared with 49.8% of placebo-treated patients.
• SAEs were reported in 2.0% of patients (n=8) receiving 45 mg, 1.2% of patients (n=5) receiving 90 mg, and 2.0% of patients (n=8) receiving placebo through week 12.
• In addition, 1 case of squamous cell carcinoma in the placebo group and 1 case of basal cell carcinoma in the 90 mg group were reported.
• No differences were seen in liver aminotransferase concentrations, fasting glucose, or hemoglobin A1c levels between treatment groups.

PHOENIX 2: LONG-TERM FOLLOW-UP THROUGH 5 YEARS

Langley et al (2015)⁸ evaluated the safety and efficacy of STELARA through 5 years in the PHOENIX 2 trial.

Study Design/Methods

• PASI and PGA were used to evaluate treatment response through week 244. Safety endpoints were monitored through week 264.
• The overall study population included all patients who received at least 1 dose of STELARA.
• Results related to partial responders who were early adjusters (PASI 50 to <75 response at week 28 or <PASI 75 response at week 40 and had their dosing interval reduced from every 12 to every 8 weeks) or late adjusters (had their dosing interval adjusted after week 52) are not described in this document.

Results

• This analysis included 1212 patients who received at least 1 dose of STELARA in the PHOENIX 2 trial. Of these, 849 (70%) completed study treatment at year 5.

Efficacy at Week 244: Overall Population

• PASI 75 response rates: STELARA 45 mg: 76.5%, STELARA 90 mg: 78.6%.
• PASI 90 response rates: STELARA 45 mg: 50.0%, STELARA 90 mg: 55.5%.
• PASI 100 response rates: STELARA 45 mg: 28.1%, STELARA 90 mg: 31.3%.
• PGA score of 0/1: STELARA 45 mg: 54.0%, STELARA 90 mg: 58.6%.

Safety Through Week 264

• Cumulative rates of AEs and SAEs were generally comparable between patients receiving STELARA 45 and 90 mg in the overall population and between nonadjusters and adjusters.
• There were no cases of active tuberculosis or infections of interest (atypical mycobacterial, systemic fungal, or salmonella).
• The most common serious infections included diverticulitis (n=7), cellulitis (n=5), and cholecystitis (n=3).
• There were no reported cases of anaphylaxis or serum sickness-like reactions.

ADDITIONAL ANALYSES FROM PHOENIX 1 AND PHOENIX 2

Additional subanalyses of the data from PHOENIX 1 and 2 showed comparable efficacy and safety in patients previously treated with conventional systemic therapies or phototherapy,⁹ psoriatic arthritis at baseline,¹⁰ or with specific baseline demographic characteristics (gender, age, body mass index [BMI], and geographic region).¹¹

Lebwohl et al (2010)¹² evaluated pooled serum concentration data from PHOENIX 1 (n=766) and PHOENIX 2 (n=1230) at week 28 to examine the impact of weight on STELARA efficacy, safety, and pharmacokinetics. Groups of patients were defined by 10 kg increments of body weight.

Results

Patient Characteristics

• At baseline, the mean weights of patients in PHOENIX 1 and PHOENIX 2 were 93.9 kg and 91.0 kg, respectively.
• Among patients enrolled in PHOENIX 1 and PHOENIX 2, 50.4% and 48.3% were obese (BMI ≥30), and 34.2% and 31.7% were overweight but not obese (BMI ≥25 to <30), respectively.

Efficacy

• At week 28, the PASI 75 response rates were approximately 20% higher in the STELARA 90 mg group than in the 45 mg group for the subpopulation of patients weighing >100 kg (74.2% [155/209] and 54.6% [107/196], respectively; P<0.0001).
• In addition, the PASI 75 response rates at week 28 were similar between the STELARA 90 mg and 45 mg groups (80.8% [350/433] and 76.9% [347/451]; P=0.1823) for the subpopulation weighing ≤100 kg, respectively.
• Additionally, there was an impact of weight on response when measured by a PASI 90 response from baseline or a PGA of cleared or minimal (score of 0 or 1, respectively).
  • At week 28, better responses across studies with the 90 mg group were observed than with the 45 mg group in the subpopulation of patients weighing >100 kg, however, responses were similar between the 45 mg and 90 mg groups in the subpopulation of patients weighing ≤100 kg.
• Ustekinumab serum concentrations were affected by weight, with lower serum concentrations observed in heavier patients at both doses.
• The median ustekinumab serum concentrations in patients weighing >100 kg in the 90 mg group were similar over time to those in patients weighing ≤100 kg in the 45 mg group.

Safety

• Weight had no effect on the safety of STELARA. Regardless of baseline weight, approximately half of the patients experienced ≥1 AE in each treatment group.
• During the placebo-controlled period (weeks 0-12), the rates and types of SAEs, infections, and AEs leading to discontinuation were similar in the subpopulation of patients weighing <100 kg and ≥100 kg.
• The overall incidences of antibodies to STELARA were reported to be higher in patients weighing ≥100 kg with the 45 mg group compared to the 90 mg group (18.4% vs 2.2% in PHOENIX 1) and (13.6% vs 6.7% in PHOENIX 2).

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 01 October 2024.