More than half of the patients treated with the interleukin-17A antagonist, ixekizumab, achieved full resolution of skin plaques after a year of 2- to 4-week dosing, according to the latest analysis of data from the three UNCOVER trials of almost 4,000 patients with moderate to severe psoriasis.
The results of the three randomized, double-blind placebo-controlled pivotal trials were published online in the New England Journal of Medicine (doi: 10.1056/NEJMoa1512711).
Ixekizumab was approved in March for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy; it is marketed as Taltz by Eli Lilly. Some of the UNCOVER data have been previously reported. The UNCOVER studies were conducted at more than 100 sites in 21 countries.
Patients in the UNCOVER trials were randomized to 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg, 80 mg every 4 weeks after the same starting dose, or subcutaneous placebo injections, for 12 weeks.
In the UNCOVER-2 and UNCOVER-3 trials, additional cohorts were also randomized to twice-weekly etanercept (50 mg). All three trials also included a long-term extension period to 60 weeks, which was randomly assigned in UNCOVER-3 (where patients received 80 mg of ixekizumab every 4 weeks), or was implemented for all patients who responded to ixekizumab in the other two trials (where patients were randomized to 80 mg every 4 or 12 weeks, or placebo).
In the UNCOVER-1 trial in 1,296 patients, 89.1% of patients in the 2-week dosing group and 82.6% of the 4-week dosing group had achieved a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) by week 12, compared with 3.9% in the placebo group (P less than .0001 for all). Similarly, 35.3% of patients in the 2-week dosing group and 33.6% of those in the 4-week dosing group achieved a PASI score of 100 by week 12.
The high response rates seen during the induction period “were generally maintained during the long-term extension period in UNCOVER-3,” wrote Dr. Kenneth B. Gordon, professor of dermatology, Northwestern University, Chicago, and his coauthors. In the analysis of the long-term data from UNCOVER-3, the researchers reported that by week 60, 55% of patients receiving 80 mg of ixekizumab every 2 weeks during the induction period had achieved a PASI 100, and 52% of patients receiving ixekizumab every 4 weeks during the induction period had achieved a PASI 100.
Patients randomized to 80 mg of ixekizumab every 12 weeks after the first 12 weeks of treatment also showed significant long-term responses in the UNCOVER-1 and -2 trials. Nearly half (49.1%) of those who were initiated on 2-week dosing and 44.9% of those initiated on 4-week dosing achieved a PASI score of 75 on the 12-week dosing schedule, compared with 8%-9% of those randomized to placebo from week 12 through week 60.
The authors concluded that ixekizumab “provided high levels of clinical response at week 12 and through week 60,” adding, however, that “as with any treatment, the benefits need to be weighed against the adverse events, and the safety profile of longer-term treatment with ixekizumab should be examined.”
Although low serum IL-17 levels have previously been linked with cardiovascular disease, the study found no significant differences between the treatment and placebo groups in adverse cardiovascular events. Candidal infections were more common among those treated with ixekizumab, “a finding that is consistent with the role of IL-17A in the mucocutaneous defense against fungal infections,” they wrote.
There were 11 cases of inflammatory bowel disease reported among patients during treatment with ixekizumab and another three cases in patients receiving placebo during a randomized withdrawal period, who had received ixekizumab during the induction* period. These results “suggest that further evaluation is needed to understand the relationship between IL-17A inhibitors and inflammatory bowel disease,” the investigators said.
The authors of the study include Eli Lilly employees, several of whom also have stock options; the other authors declared a range of funding, advisory board positions, and speakers fees from pharmaceutical companies, including Eli Lilly. The UNCOVER studies were sponsored by Eli Lilly.
*A previous version of this article misstated the period during which three placebo patients received ixekizumab.