Summary Basis of Decision for Stelara

3.3.1 Pharmacodynamics

Clinical results of a Phase II study were used to determine the appropriate doses and dose regimens for drug evaluation in the Phase III studies.  A dose-response relationship in efficacy was demonstrated in the reduction of the Psoriasis Area and Severity Index (PASI), specifically the PASI 75 response (a reduction in score of at least 75% from baseline in PASI). Thirty-one of the 70 patients (44.3%) who were responding inadequately at Week 16 achieved a PASI 75 response with one additional dose at Week 16. This suggests that a maximum response may not be achieved until after 16 weeks of treatment. In the range of doses studied (45 mg to 360 mg), a dose-response relationship in safety was not apparent and the adverse events (AEs) did not increase with the increasing doses.

3.3.2 Pharmacokinetics

Absorption

Ustekinumab was absorbed slowly into the systemic circulation with a median time to reach the maximum serum concentration (t_max) occurring between 7.0 days (90 mg) and 13.5 days (45 mg) after a single SC administration in patients with psoriasis.

The C_max and AUC of ustekinumab appeared to increase proportionally with the 45 mg and 90 mg dose levels. Steady-state was achieved by Week 28 and there was no evidence of accumulation in ustekinumab concentrations over time when given every 12 weeks subcutaneously. The absolute bioavailability was approximately 57.2% in patients with psoriasis.

Serum ustekinumab concentrations appeared to be impacted by patient body weight. The median trough serum concentrations of ustekinumab in patients with higher body weight (>100 kg) in the 90 mg group were comparable to those in patients with lower body weight (≤100 kg) in the 45 mg group. When given the same dose, patients of higher body weight (>100 kg) had lower median serum ustekinumab concentrations compared with patients of lower body weight (≤100 kg).

Distribution

In patients with psoriasis, the median apparent volume of distribution during the terminal phase was 76 to 161 mL/kg following a single SC administration.

Metabolism

The exact metabolic pathway for ustekinumab is unknown. Like all proteins, ustekinumab is degraded in the lysozymes residing in the cells of all tissues.

Excretion

Ustekinumab was slowly eliminated from the circulation with a median half-life (t_1/2) of approximately 19.8 days (45 mg dose) to 21.2 days (90 mg dose), after a single SC administration in patients with psoriasis.

Immune Response

Antibodies to ustekinumab developed at a low incidence rate (approximately 5%) in patients that were treated with ustekinumab. The low incidence of antibody positive patients precludes definitive conclusions on the impact of antibody status on clinical response.

3.3.3 Clinical Efficacy

The safety and efficacy of Stelara (ustekinumab) were assessed in two multicentre, randomized, double-blind, placebo-controlled pivotal studies (PHOENIX 1 and PHOENIX 2) in patients 18 years of age and older with chronic (>6 months) plaque psoriasis who had a minimum body surface area involvement of 10%, and PASI score ≥12 and who were candidates for phototherapy or systemic therapy. Patients with other forms of psoriasis (guttate, erythrodermic, or pustular psoriasis) were excluded from the studies. No concomitant anti-psoriatic therapies were allowed during the study with the exception of low-potency topical corticosteroids on the face and groin after Week 12. A total of 1996 patients were enrolled in the two studies. Stelara and the placebo were administered by SC injection. In PHOENIX 1, the duration of treatment was 52 weeks or longer. In PHOENIX 2, the duration of treatment was 28 weeks. Patients randomized to receive 45 mg or 90 mg of Stelara, received Stelara at Weeks 0, 4, and 16. Patients randomized to placebo, received 45 mg or 90 mg Stelara at Weeks 12 and 16. In PHOENIX 1, subsequent dosing regimens were determined by each patient’s response status according to the study design.

For both studies, the primary endpoint was the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 12. The major secondary endpoint was the Physician’s Global Assessment (PGA) that indicated the physician’s overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling. The Dermatology Life Quality Index (DLQI) was also assessed in both studies. Other efficacy endpoints included the Nail Psoriasis Severity Index (NAPSI) and the Itch Visual Analog Scale (VAS) in PHOENIX 1; and the Hospital Anxiety and Depression Scale (HADS), and Work Limitations Questionnaire (WLQ) in PHOENIX 2.

The proportion of patients who achieved the primary efficacy endpoint (PASI 75 response at Week 12) was significantly greater in each of the Stelara groups (45 mg and 90 mg) compared to the placebo group in both pivotal studies (PHOENIX 1 and PHOENIX 2). In PHOENIX 1, the PASI 75 response at Week 12 was 67% and 66% for the patients that received 45 mg and 90 mg of Stelara, respectively, compared to 3% for those that received placebo. In PHOENIX 2, the same efficacy endpoint was 67% and 76% for patients that received 45 mg and 90 mg of Stelara, respectively, compared to 4% for those that received placebo.

In both studies, treatment with Stelara, administered as 45 mg or 90 mg SC injections, led to rapid, substantial, significant, clinically meaningful improvements in psoriasis and was generally well-tolerated. The improvements in psoriasis were generally consistent with each Stelara group. A dose response in efficacy was observed with generally higher response rates observed in the 90 mg group versus the 45 mg group. Treatment with Stelara resulted in significantly improved Quality Of Life (QOL), as measured by the PGA and DLQI in both studies. The other endpoints (NAPSI, VAS, HADS, and WLQ) also supported the primary endpoint. In PHOENIX 1, the dose response began to emerge at Week 16, reached a maximum around Week 24, and was generally maintained through Week 40. In PHOENIX 2, the dose response reached its maximum around Week 16, and was generally maintained through Week 28. In both studies, clinical efficacy was affected by patient weight. In patients ≤100 kg, efficacy was similar with 45 mg or 90 mg dosing, whereas in patients >100 kg, higher levels of efficacy were observed with 90 mg compared to 45 mg dosing. Clinical response was generally associated with serum ustekinumab concentrations. Patients with a higher clinical response (as measured by PASI response) had higher median serum concentration of ustekinumab than those with a lower clinical response.

In addition, a multicentre, randomized, 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 body surface area involvement of 10%, PASI score ≥12, PGA score ≥3, who were candidates for phototherapy or systemic therapy, and who had an inadequate response to, intolerance to, or contraindication to cyclosporine, methotrexate, or Psoralen and Ultraviolet A (PUVA) therapy. A total of 903 patients were enrolled in the study. The percentages of patients that achieved a PASI 75 response at Week 12 were 67% and 74% for the 45 mg and 90 mg Stelara groups, respectively; compared to 57% for the etanercept group.

Overall, patients with moderate to severe psoriasis who were treated with Stelara 45 mg or 90 mg showed significant improvement in psoriasis.

3.3.4 Clinical Safety

The clinical safety of Stelara was primarily assessed from the two pivotal studies PHOENIX 1 and PHOENIX 2, described in 3.3.3 Clinical Efficacy. Additional safety data from a Phase III clinical study, ACCEPT, (also described in 3.3.3 Clinical Efficacy) provided supportive data to the original drug submission.

In both pivotal studies, Stelara was generally well-tolerated. The AE rates, AE profiles, and rates of AEs in the 45 mg and 90 mg Stelara groups were generally comparable to that observed in the placebo groups. The rates of discontinuation due to the study drug were generally comparable in the 45 mg and 90 mg groups. The rate of serious adverse events (SAEs) was low. No dose response in SAE rates or profile was apparent. The proportions of patients experiencing markedly abnormal values in haematology and chemistry laboratory test results were low and generally comparable between the placebo and Stelara groups. The incidence of injection site reactions with Stelara was low and generally mild in nature. The low incidence of antibody-positive subjects precludes definitive conclusions on the impact of antibody status on the development of injection site reactions. There was no apparent association between the development of antibodies to Stelara and the development of injection site reactions.

Stelara is a selective immunomodulator. Immunomodulating agents have the potential to increase the risk of infections and malignancies.

In both pivotal studies, the infection rates and the profile of infections observed through Week 12 were similar in the placebo and Stelara groups; and the infection rates and profiles were similar in the 45 mg and 90 mg groups. The most common AEs were nasopharyngitis and other upper respiratory tract infections. Most were considered mild and did not necessitate drug discontinuation. Rates of serious infections were generally low. No cases of tuberculosis were reported. One serious potential opportunistic infection of cutaneous disseminated herpes zoster was reported in the Stelara 90 mg group.

In PHOENIX 1, no malignancies were reported through Week 12. However, through the end of the reporting period (Week 52) malignancies occurred in 9 patients. Four non-cutaneous solid tumour malignancies (one case each: breast, prostate, thyroid cancer, and a malignant kidney neoplasm) were reported in 4 patients in the 45 mg group, and basal cell skin carcinomas were reported in 5 patients (2 patients in the placebo who later went to the 45 mg group, 1 patient in the 45 mg group, and 2 patients in the 90 mg group). In PHOENIX 2, through Week 28, 8 malignancies occurred in 7 patients. Non-melanoma skin carcinomas were reported in 6 Stelara-treated subjects. One solid tumour (hepatic neoplasm) was reported in a patient in the placebo group.

The ACCEPT study provided additional data related to the incidence of malignancies. In this study, 209 patients received 45 mg of ustekinumab, 347 patients received 90 mg of ustekinumab, and 347 patients received etanercept, for the treatment of moderate to severe plaque psoriasis. Four (0.7%) subjects in the ustekinumab groups had a treatment-emergent malignancy. Three subjects had a basal and/or squamous cell skin cancer detected in areas of psoriasis that had cleared with treatment. One subject with a familial history of breast cancer was diagnosed with breast cancer. No malignancies were observed in the etanercept group.

Longer term follow-up is required to better define the safety profile of Stelara. Changes have been made to the Product Monograph to reflect the identified safety concerns, particularly the theoretical concern that products such as Stelara might foster the development of malignancies. The sponsor has agreed to provide additional safety data as outlined in section 3.3.5 Additional Issues.

3.3.5 Additional Issues

The following commitments were requested by Health Canada and were accepted by the sponsor:

• Provide Health Canada with a detailed Canadian Risk Management Plan (RMP) for evaluation by December 24th, 2008 and work with Health Canada to revise the RMP based on their feedback, as appropriate.
• Perform all post-marketing activities listed in the Response to Clarifax dated October 17, 2008, including but not limited to: Pharmacovigilance Activities (Adverse Event Collection and Single Case Processing, Aggregate Reports, Safety Surveillance and Signal Detection); Evaluation of Safety Data from Clinical Trials and Post-Marketing Studies; and Medical Education Plan.
• Submit to Health Canada, in accordance with Canadian Regulations, all serious adverse events including malignancies, other autoimmune diseases, serious infections, et cetera (etc.). that occur in the ongoing clinical trials with Stelara.
• Submit to Health Canada the Stelara Medical Educational materials for comments and feedback by December 19, 2008.
• Provide Health Canada with Periodic Safety Update Reports (PSUR) for Stelara every six months for the first two years post approval. Include in each PSUR an analysis of all Adverse Drug Events that may be related to the immunogenicity profile of Stelara (for example [e.g.], ADEs related to Immune System Disorder, Skin and Subcutaneous Tissue Disorders, etc.); malignancies, serious infections; blood glucose abnormalities.
• Include Canadian patients receiving Stelara in a patient registry program, either in the international Public Service Appointment Regulations (PSOLAR) registry program or in a Canadian registry program, as will be indicated in the Canadian RMP.
• File a Supplemental New Drug Submission as soon as the final study reports of the two pivotal studies that led to the market authorization of Stelara by Health Canada become available.
• Submit to Health Canada any reports or correspondence regarding the PSOLAR registry program as well as the ongoing clinical trials or any other sources.
• Provide all reports pertaining to post-approval commitments as made to major Regulatory Authorities.