Guselkumab(Wincal Biopharm)

Introduction: Medical therapy for Crohn's disease (CD) is directed at controlling intestinal inflammation to prevent development of disease-related complications. Not all patients will respond to currently available treatments and thus, novel therapies are needed. The interleukin (IL)-23 cytokine axis is implicated in CD pathogenesis and so targeting this pathway has become an important focus for drug development.Areas covered: This review summarizes the role of the IL23 cytokine pathway in CD pathogenesis and appraises phase I and II clinical trial data for novel IL23p19 specific monoclonal antibodies for the treatment of CD. The evidence for risankizumab (BI655066/ABBV066), brazikumab (MEDI2070, formerly AMG139), guselkumab (CNTO1959), tildrakizumab (MK3222), and mirikizumab (LY3074828) is reviewed; moreover, future applications for these agents are considered.Expert opinion: Targeting the specific p19 subunit of IL23 is a promising strategy in CD. Two multicenter, randomized, placebo-controlled phase II clinical trials have evaluated risankizumab and brazikumab. Both studies indicate that IL23-specific blockade is likely to be a safe and effective alternative to current biologics, including the TNF antagonists vedolizumab and ustekinumab. Confirmatory Phase 3 studies are underway. Ultimately, comparative effectiveness trials will be necessary to define the role of IL23-specific antagonists in CD treatment algorithms.

Little is known about the effect of specific anti-interleukin-23 therapy, as compared with established anti-tumor necrosis factor therapies, for the treatment of moderate-to-severe plaque psoriasis.

In a 52-week, phase 2, dose-ranging, randomized, double-blind, placebo-controlled, active-comparator trial, we compared guselkumab (CNTO 1959), an anti-interleukin-23 monoclonal antibody, with adalimumab in patients with moderate-to-severe plaque psoriasis. A total of 293 patients were randomly assigned to receive guselkumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter, 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at weeks 0 and 4 and every 12 weeks thereafter) through week 40, placebo, or adalimumab (standard dosage for psoriasis). At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. The primary end point was the proportion of patients with a Physician's Global Assessment (PGA) score of 0 (indicating cleared psoriasis) or 1 (indicating minimal psoriasis) at week 16.

At week 16, the proportion of patients with a PGA score of 0 or 1 was significantly higher in each guselkumab group than in the placebo group: 34% in the 5-mg group, 61% in the 15-mg group, 79% in the 50-mg group, 86% in the 100-mg group, and 83% in the 200-mg group, as compared with 7% in the placebo group (P≤0.002 for all comparisons). Moreover, the proportion was significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (58%) (P<0.05 for all comparisons). At week 16, the proportion of patients with at least a 75% improvement in Psoriasis Area and Severity Index scores was significantly higher in each guselkumab group than in the placebo group (P<0.001 for all comparisons). At week 40, the proportion of patients with a PGA score of 0 or 1 remained significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (71%, 77%, and 81%, respectively, vs. 49%) (P<0.05 for all comparisons). Between week 0 and week 16, infections were observed in 20% of the patients in the guselkumab groups, 12% in the adalimumab group, and 14% in the placebo group.

The results of this phase 2 trial suggest that guselkumab may be an effective therapy for plaque psoriasis and that control of psoriasis can be achieved with specific anti-interleukin-23 therapy. (Funded by Janssen Research and Development; X-PLORE ClinicalTrials.gov number, NCT01483599.).