Sustainability of ustekinumab established in patients with psoriatic arthritis

Rochester, N.Y. - The human interleukin-12 and interleukin-23 (IL-12/IL-23) inhibitor ustekinumab (Stelara, Janssen) is effective and is well tolerated in patients who have active psoriatic arthritis.

Analyses of data collected through one year of follow-up in two phase 3 clinical trials demonstrated that ustekinumab was associated with significantly greater improvements in joint, tissue and skin manifestations after 24 weeks compared with placebo, had durable or increasing efficacy with ongoing quarterly injections, and provided benefit for individuals previously treated with a tumor necrosis factor-alpha (TNF-alpha) inhibitor.

“There is a major unmet need for alternative therapies in patients with psoriatic arthritis who cannot take or fail an anti-TNF-alpha agent. The phase 3 study results provide an evidence basis supporting use of ustekinumab in this patient population,” says Christopher T. Ritchlin, M.D., M.P.H., study investigator and professor of medicine, allergy/immunology, and rheumatology, University of Rochester School of Medicine and Dentistry, Rochester, N.Y.

He adds, “We are looking forward to findings from radiologic data that are now being analyzed. In addition, while the safety of ustekinumab in patients with psoriatic arthritis has been favorable so far, data from longer follow-up are needed.”

The phase 3 studies, known as PSUMMIT 1 (n=615) and PSUMMIT 2 (n=312), randomized patients to induction therapy with subcutaneous injections of ustekinumab 45 mg, ustekinumab 90 mg, or placebo at weeks zero and four; further injections were given every 12 weeks. Patients previously treated with an IL-12/23 inhibitor were excluded from both studies. Only patients who were naïve to TNF-alpha inhibitor treatment were enrolled in PSUMMIT 1; 180 patients in PSUMMIT 2 had prior treatment with one or more TNF-alpha inhibitors.

Good response at both doses

The proportion of patients achieving a ≥ 20 percent improvement in joint signs and symptoms according to the American College of Rheumatology criteria (ACR 20 responder rate) at week 24 was analyzed as the primary efficacy endpoint. The results showed statistically significant differences favoring both ustekinumab 45 mg and 90 mg compared with placebo in both PSUMMIT 1 (42.4 percent and 49.5 percent vs. 22.8 percent) and PSUMMIT 2 (43.7 percent and 43.8 percent vs. 20.2 percent).

ACR 20 responder rates for PSUMMIT 2 patients naïve to anti-TNF-alpha treatment were similar to those observed in the PSUMMIT 1 population, but higher than for PSUMMIT 2 patients with a history of anti-TNF-alpha treatment who had more active disease at baseline. Among anti-TNF-alpha-experienced patients, the ACR 20 response rate was higher among those who had received a single anti-TNF-alpha agent versus more than one, although the population with the latter history was small.

Psoriasis Area Severity Index 75 (PASI 75) responder rates at week 24 (assessed in patients with ≥ 3 percent body surface area involvement with psoriasis at entry) were significantly higher for the ustekinumab 45 and 90 mg versus placebo in both PSUMMIT 1 (57.2 percent and 62.4 percent vs. 11 percent) and PSUMMIT 2 (51.3 percent and 55.6 percent vs. 5.0 percent).

Analyses of secondary efficacy endpoints related to joint symptoms (ACR 50 and ACR 70 response rates, 28-joint disease activity score based on CRP, improvements and enthesitis and dactylitis scores), also consistently showed significant differences favoring ustekinumab versus placebo, as did changes in the Health Assessment Questionnaire-Disability Index (HAQ-DI).

Assessing AEs

In the two studies, patients with a < 5 percent improvement in tender and swollen joint counts at week 16 were considered nonresponders in the primary efficacy analysis and switched to ustekinumab 45 mg if they were receiving placebo or to ustekinumab 90 mg if they were receiving the lower dose. All patients still on placebo at week 24 were crossed over to ustekinumab. Analyses of data collected through week 52 showed ustekinumab treatment benefits were generally sustained or improved.

Adverse event rates were similar in the ustekinumab and control groups at the end of the 16-week placebo-controlled period. Rates of serious adverse events were low and also similar for ustekinumab and placebo. There were no deaths or opportunistic infections in the studies, and during follow-up from week 24 to 52, there were five myocardial infarctions and 1 cerebrovascular accident.

“It is difficult to know the impact of ustekinumab on cardiovascular risk based on these events since they did not occur during the placebo-controlled period and do not appear to be dose-related,” Dr. Ritchlin says.

Dr. Ritchlin also observed that the benefits of ustekinumab in the PSUMMIT and psoriasis trials taken together with the fact that neither it nor anti-IL-17 antibodies or anti-IL-17R antibody demonstrated efficacy for rheumatoid arthritis provide some insights on pathophysiology.

“These findings support a disease pathogenesis model for psoriasis and psoriatic arthritis that includes both a Th1 and Th17 immune response where IL-23, IL-17, and possibly other cytokines released by Th17 cells, such as IL-22, are of central importance,” he says.

The one-year results were recently published for PSUMMIT 1 (McInnes IB, Kavanaugh A, Gottlieb AB, et al. Lancet. 2013 Jun 12. Epub ahead of print) and reported for PSUMMIT 2 at the 2013 Annual European Congress of Rheumatology.  Janssen submitted a biologic license application seeking approval for ustekinumab for the treatment of active psoriatic arthritis in December 2012.

Disclosures: Dr. Ritchlin is a consultant to and receives grant/research support from Janssen and other companies marketing or developing products for the treatment of psoriatic arthritis.