Risankizumab More Effective in Psoriasis Than Ustekinumab in Early Trial
Selective inhibition of interleukin (IL)-23 with the investigational drug risankizumab may be more effective in treating psoriasis than ustekinumab, a less specific drug, a phase 2 study suggests.
Results were published online April 20 in the New England Journal of Medicine.
"Although these findings are preliminary, the data suggest that selective blockade of [IL]-23 through the inhibition of the p19 subunit rather than p40 provides a more complete inhibition of [IL]-23 activity, potentially resulting in greater efficacy in the treatment of plaque psoriasis at the doses used," Kim Papp, MD, PhD, from Clinical Research and Probity Medical Research, Waterloo, Ontario, Canada, and colleagues write.
Risankizumab is a humanized monoclonal antibody that targets the p19 subunit unique to IL-23, resulting in disrupted signaling. In contrast, ustekinumab targets the p40 subunit, which is shared between IL-12 and IL-23, resulting in inhibition of both cytokines. Some studies have suggested that blockade of just IL-23 may be the primary reason for risankizumab's efficacy in psoriasis.
The head-to-head phase 2 trial took place at 32 sites in North America and Europe and evaluated how selective inhibition of IL-23 compares with blockade of both IL-12 and IL-23. The study included 166 adults with moderate to severe chronic plaque psoriasis affecting 10% or more of the body surface area. Researchers randomly assigned participants to receive subcutaneous injections of risankizumab (a single 18-mg dose at week zero [n = 43] or 90-mg [n = 41] or 180-mg [n = 42] doses at weeks 0, 4, and 16) or ustekinumab (n = 40; 45 or 90 mg, depending on body weight at weeks 0, 4, and 6). The primary endpoint was 90% or more reduction in Psoriasis Area and Severity Index score from baseline.
After 12 weeks, pooled results from the 90- and 180-mg risankizumab groups showed that 77% achieved the primary endpoint compared with 40% in the ustekinumab groups (P < .001).
Similarly, at week 12, pooled results for the risankizumab groups showed that 45% of participants had complete clearance of lesions compared with 18% in the ustekinumab group (P < .001).
The risankizumab group also showed faster onset of action and maintained efficacy for up to 20 weeks after the final dose. In contrast, efficacy in the ustekinumab group began to wane 8 weeks after the last dose.
"Showing a very effective response with the more specific drug provides more evidence that IL-23 and not IL-12 is probably the key cytokine in psoriasis," James Elder, MD, PhD, told Medscape Medical News. Dr Elder, who was not involved in the study, is a professor of dermatology at the University of Michigan, Ann Arbor, and conducts research about genetics, the immune system, and psoriasis.
"That's not to say that IL-12 may not be important, but really the choke point in the process seems to have more to do with IL-23 and its signaling," he added.
In a sense, IL-23 appears to serve as the main "gas pedal" for the pro-inflammatory cytokine IL-17. IL-23 plays a role in the expansion of a class of T cells that make IL-17, he explained. Inhibiting IL-23 ultimately affects the pathway that leads to IL-17, and may produce a much better clinical response than targeting IL-17 itself.
However, psoriasis drugs on the market are already very effective, he said, although some patients still show varying treatment responses. No good biomarkers exist to help predict response to one drug vs another.
"One would hope that adding another competitor in the field would lead to some progress. One of the most difficult parts of all these drugs is their expense," he said. An additional competitor could conceivably help drive down prices, he speculated.
Further Safety Research Needed
Before that can happen, the results will need confirmation in larger, randomized controlled trials. Safety issues will also need to be assessed.
Serious adverse events were slightly higher with risankizumab 18 mg (12%) and 90 mg (15%) compared with ustekinumab (8%). No serious adverse events occurred in the 180-mg risankizumab group.
Two basal cell carcinomas and one major adverse cardiovascular event occurred in the risankizumab group.
Nasopharyngitis represented the most common adverse event and occurred in more than 10% of all groups.
Although the results showed slightly higher rates of serious adverse events with risankizumab compared with ustekinumab, Dr Elder said the adverse effects did not appear particularly concerning. However, the short study duration, lack of control arm, and small study size mean the study could not fully evaluate safety issues.
On the basis of its mechanism of action, possible adverse effects with risankizumab could include flare-ups in patients with underlying Crohn's disease or increased fungal infections such as oral candidiasis. The study did not report on these outcomes.
The study was funded by Boehringer Ingelheim. Seven coauthors are employees of Boehringer Ingelheim. One or more coauthors report a variety of financial relationships including personal fees, grant support, other support from one or more of the following: Boehringer Ingelheim, Amgen, AbbVie, Celgene, Dermira, Genentech, GlaxoSmithKline, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Sandoz, Sanofi, Genzyme, Sun Pharmaceutical, UCB, Valeant, DUSA Pharmaceuticals, Merck, Allergan, Galderma, Centocor, LEO Pharma, MedImmune, Kyowa Hakko Kirin Pharma, Roche, Takeda Pharmaceuticals USA, UCB, Biogen Idec, Serono, BMS, Innovaderm, Kadmon, grants from Paraxel, Sun Pharma, Confluence Life Scientific, Akros, GLG, GSK, Vitae, Escalier, EMD Serono, Eli Lilly, Kineta, Provectus, Merck Sharp & Dohme, Bristol-Myers Squibb, Astellas, Baxalta, VBL Therapeutics, Maruho, Almirall, Biogen Idec, and Mundipharma. Dr Elder has disclosed no relevant financial relationships.
N Engl J Med. 2017;376:1551-1560.
Risankizumab More Effective in Psoriasis Than Ustekinumab in Early Trial. Medscape. April 20, 2017.
Find out what women really need.