Conference Coverage
Brodalumab met all primary endpoints against its first-in-class rival, ustekinumab, and against placebo in two phase III trials of more than 3,700 patients with moderate to severe plaque psoriasis, investigators reported in the New England Journal of Medicine.
The results of the two studies, AMAGINE-2 and AMAGINE-3, were published on Sept. 30 (N Eng J Med. 2015;373:1318-28).
Dr. Mark Lebwohl
“The data for brodalumab are the best data we’ve seen. It literally is twice as effective at achieving PASI [Psoriasis Area Severity Index] 100 as ustekinumab, which is a spectacular drug,” lead investigator Dr. Mark Lebwohl said in an interview. “More than two-thirds of patients achieved PASI 90. We’ve never seen data like this before,” said Dr. Lebwohl, professor and chairman of the department of dermatology at Icahn School of Medicine at Mount Sinai, New York.
Dermatologists and patients have closely followed brodalumab, an investigational interleukin-17 receptor A inhibitor, which, in March 2015, was reported to have doubled the PASI 100 response rate of ustekinumab in the AMAGINE-2 trial. But 2 months later, Amgen pulled funding and ended its partnership with AstraZeneca on the biologic in the wake of suicides of two patients who had recently completed brodalumab treatment. At the time, Amgen stated that it was concerned that brodalumab would receive restrictive labeling related to suicidal ideation and behavior. An Amgen spokeswoman on Sept. 29 declined to elaborate.
On Sept. 1, however, Valeant Pharmaceuticals announced that it was partnering with AstraZeneca to continue with plans to develop and commercialize brodalumab and that regulatory submissions in the United States and the European Union were planned for the 4th quarter of 2015.
In the interview, Dr. Lebwohl said he did not know of a mechanism by which blocking the IL-17 receptor might increase the risk of depression or suicide. “But psoriasis is certainly associated with depression,” he added. “Two out of more than 3,700 patients committed suicide over more than a year, and that could certainly be attributable to the depression associated with the underlying skin disease.”
AMAGINE-2 and AMAGINE-3 were replicate phase III, double-blind, randomized, controlled trials of 3,712 patients with moderate to severe plaque psoriasis. In the two studies, week 12 PASI 75 rates were about 85% with 210 mg of brodalumab, about 68% for 140 mg of brodalumab, and 6%-8% for placebo (P less than .001). Moreover, week 12 PASI 100 response rates with 210 mg of brodalumab were 37% and 44%, compared with 19% and 22% for ustekinumab (P less than .001), the investigators reported.
Median time to PASI 75 on 210 mg of brodalumab was 4 weeks – about twice as fast as for ustekinumab. Rates of static Physician’s Global Assessment (sPGA) scores of 0 or 1 (clear or almost clear skin) also were significantly higher for brodalumab, compared with placebo (P less than .001).
Mild to moderate candidiasis was more common during induction of brodalumab, compared with ustekinumab or placebo, underscoring the role of interleukin-17A in microbial surveillance, Dr. Lebwohl and his associates pointed out. They estimated that 1-1.3 serious infections occurred for every 100 patient-years of exposure to brodalumab, through 52 weeks.
The investigators reported but did not comment on the suicides, stating only that the study populations were large enough to assess common adverse events but “may have been inadequate for the detection of rare adverse events, which would require longer follow-up of large numbers of patients to provide a full understanding of the safety profile of brodalumab.”
Ustekinumab is marketed as Stelara.
Amgen funded the AMAGINE-2 and AMAGINE-3 studies. Dr. Lebwohl reported having received grant support from Amgen, AbbVie, Janssen Biotech, UCB Pharma, Pfizer, Celgene, Eli Lilly, and Novartis outside the submitted work. Twenty-four coauthors reported grant support or personal fees from Amgen, Abbvie, Merck, Janssen, and several other pharmaceutical companies. The other investigators declared no competing interests.