The anti-interleukin-23 monoclonal antibody guselkumab performed significantly better than the anti-tumor necrosis factor therapy adalimumab in the treatment of plaque psoriasis. The results of the phase 2 randomized, placebo-controlled trial were published in the July 9 issue of the New England Journal of Medicine. Experts caution that more data are needed to evaluate the safety profile, however.

At week 16 of the multisite trial, patients who received 50 mg or more of guselkumab had the best response, with greater doses generally leading to a greater numbers of trial participants achieving a Physician's Global Assessment (PGA) score of 0, meaning cleared psoriasis, or 1, meaning minimal psoriasis. The optimal performance was among patients receiving 100 mg every 8 weeks, with 86% of participants scoring a 0 or 1. Among patients in the adalimumab group, 58% scored a 0 or 1 at 16 weeks; 7% of those in the placebo group scored 0 or 1 (P ≤ .002 for all comparisons).

"Guselkumab has more robust efficacy than does adalimumab and has a mechanism of action that is more specifically targeted to psoriasis than does ustekinumab," the authors write. "Larger and longer-term phase 3 trials...are under way to examine the safety and comparative efficacy of guselkumab for the treatment of moderate-to-severe psoriasis."

52-Week Randomized Trial

Kenneth B. Gordon, MD, professor, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, and colleagues conducted a 52-week, randomized, double-blind trial comparing guselkumab (CNTO 1959), an anti-interleukin-23 monoclonal antibody, with adalimumab, a monoclonal antibody against tumor necrosis factor, or placebo in 293 patients with moderate to severe plaque psoriasis. The study defined moderate to severe plaque psoriasis as 10% or more of the total body surface involvement at baseline, a PGA score of 3 or higher, and a score of 12 or higher on the Psoriasis Area and Severity Index.

The primary trial endpoint was the share of patients with a PGA score of 0 or 1 at week 16.

For the first 40 weeks, 43 patients were randomly assigned to a standard dose of adalimumab (80 mg at week 0 and 40 mg week 1 and every other week thereafter through week 39), a placebo (42 patients), or guselkumab (208 patients). The researchers randomly assigned patients in the guselkumab group to various doses: 5 mg per week for first 4 weeks and every 12 weeks thereafter (41 patients), 15 mg every 8 weeks (41 patients), 50 mg per week through week 4 and every 12 weeks thereafter (42 patients), 100 mg every 8 weeks (42 patients), or 200 mg per week through week 4 and every 12 weeks thereafter (42 patients). At week 16, patients in the placebo group were given 100 mg guselkumab every 8 weeks. Administration of adalimumab was not blinded, but the evaluator conducting efficacy assessments was unaware of study group assignments.

At week 40, the share of patients with PGA scores of 0 or 1 remained greater in the 50 mg (71%), 100 mg (77%), and 200 mg (81%) guselkumab groups compared with the adalimumab group (49%; P < .05 for all comparisons), and greater in all dose levels of the guselkumab groups than in the placebo group. Most patients in the 100-mg guselkumab group had completely cleared psoriasis, with 62% having a PGA score of 0 and 100% improvement from baseline in Psoriasis Area and Severity Index scores among 54% of patients after 40 weeks.

Guselkumab efficacy dropped slightly near the end of 12-week dosing regimens compared with in those patients on 8-week dosing.

Too Early to Tell on Safety

"This is an interesting drug," Guy Webster, MD, PhD, clinical professor, Department of Dermatology, Jefferson Medical College, Philadelphia, Pennsylvania, told Medscape Medical News. The study was well done, he said, but it is too early to judge its safety. "It's a small phase 2 study, so the extent of in-human experience is small. What seems like a benign safety profile could greatly change when it gets into more people for a longer time. Remember that Raptiva [Genentech] looked safe for a few years after it was introduced."

"It seems significantly better for psoriasis than adalimumab (in this small study). Is it so much better that the risk of unknown adverse events is outweighed by the greater efficacy? That's a judgment call," Dr Webster continued. "Adalimumab is a fine drug with a long record of safety that takes good care of many patients," he said. "A bigger study will follow. Let's see if the results hold up."

At week 16, adverse events were similar among all three treatment groups, at 52% in the placebo group, 50% in the guselkumab groups, and 56% in the adalimumab group. There was no evidence of a dose–response relationship in the rate of adverse events in the guselkumab groups, the researchers note. Twenty percent of patients in the guselkumab groups had infections in the first 16 weeks compared with 12% in the adalimumab group and 14% in the placebo group. Infection rates for guselkumab and adalimumab were similar in weeks 16 to 52, with infections in 30% of the guselkumab groups and 37% in the adalimumab group.

In weeks 16 through 52, patients in the adalimumab group had a somewhat higher proportion of adverse events than those in the guselkumab groups (61% vs 49%). Throughout the trial, infection was the most commonly reported adverse event, seen in about 30% of patients. No patients in the guselkumab groups reported a serious infection; one in the adalimumab group did.

Three of the 235 patients in the guselkumab groups discontinued treatment as a result of adverse events over the course of 40 weeks; one patient in the adalimumab group discontinued treatment. Four patients in the guselkumab groups had serious adverse events compared with one in the adalimumab group. Three patients in the guselkumab groups experienced a major cardiovascular event; none in the adalimumab group did. One patient in the guselkumab groups was diagnosed with cervical cancer; no patients in the adalimumab group were diagnosed with cancer.

The authors note that the relatively small sample size in the several treatment groups was one limitation of the study. In addition, baseline patient characteristics were not balanced among the groups. They further note that it was "difficult to interpret" the significance of three major cardiovascular events in the guselkumab groups.

The study was funded by Janssen Research & Development. Dr Gordon and several coauthors report having served as consultants, receiving research funding, or receiving speaking fees from one or more of the following companies: AbbVie, Amgen, Janssen, Celgene, Eli Lilly, Galderma, Incyte, Leo Pharma, Merck, Novartis, Tribute, Pfizer, Xenoport, Bristol-Myers Squibb, Medac, Abbott Laboratories, Actelion Pharmaceuticals, Biogen-Idec, Forward Pharma, GlaxoSmithKline, Ocean Pharma, Regeneron, Takeda, Vertex. Outside commenter Dr Webster serve or served as a director, officer, partner, employee, adviser, consultant, or trustee for Dermira, Galderma Laboratories LP, Valeant Pharmaceuticals International, Cutanea Life Sciences, GlaxoSmithKline, Vitae Pharmaceuticals, Sienna Technologies, SolGel Technologies, Ranbaxy Pharmaceuticals Inc, Aclaris; Lalumiere LLC, and Xenon Pharmaceuticals Inc.

N Engl J Med. 2015;373:136-144. Abstract