Adult patients with moderate to severe plaque psoriasis and overweight or obesity who received ixekizumab plus tirzepatide were more likely to achieve simultaneous complete skin clearance and at least 10% weight reduction at 36 weeks compared with those receiving ixekizumab alone, according to a recent study.
In the 52-week, randomized, open-label, active-controlled phase IIIb TOGETHER-PsO clinical trial. researchers evaluated ixekizumab with or without tirzepatide in adult patients with moderate to severe psoriasis and overweight or obesity. The primary endpoint was simultaneous achievement of Psoriasis Area and Severity Index (PASI) 100 and at least 10% weight reduction at week 36. The trial was conducted at 72 sites across the United States from September 30, 2024, to January 8, 2026. Masked assessors evaluated psoriasis-related outcomes. The investigators analyzed the data from January to February 2026.
Eligible adults had moderate to severe plaque psoriasis for at least 6 months, a Static Physician Global Assessment score of 3 or greater, PASI of 12 or greater, at least 10% body surface area involvement, and either obesity or overweight with at least one weight-related comorbidity. The participants with prior treatment failure or intolerance to an interleukin (IL)-17 inhibitor or glucagon-like peptide-1 receptor agonist, prior ixekizumab or tirzepatide use, or inadequate response to more than three classes of advanced psoriasis therapy were excluded.
The researchers randomly assigned the participants 1:1 to receive ixekizumab plus tirzepatide or ixekizumab alone. Both groups received individualized diet and exercise counseling. Ixekizumab was administered as two 80-mg injections at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, and then every 4 weeks. Tirzepatide was started at 2.5 mg weekly and increased by 2.5 mg every 4 weeks to the maximum tolerated dose of 5 mg, 10 mg, or 15 mg by week 32.
Among 274 randomized participants in the modified intent-to-treat population, about 27% of those receiving ixekizumab plus tirzepatide achieved the primary endpoint vs 6% receiving ixekizumab alone, for a 21% absolute difference. Key secondary endpoints also favored the combination therapy: PASI 100 was achieved by 41% vs 29% of participants, simultaneous PASI 75 and at least 5% weight reduction by 80% vs 18%, and at least 10% weight reduction by 69% vs 9%, respectively.
Overall, 84% (n = 231) of the participants completed treatment through week 36. The mean age was about 46 years, mean body mass index was 39, mean psoriasis duration was nearly 15 years, and mean PASI was 20. The researchers noted that 97% of the participants had psoriasis affecting high-effect body sites, and 34% had prior experience with advanced psoriasis therapies.
Additional prespecified secondary outcomes showed greater numerical rates of PASI 75 and PASI 90 with ixekizumab plus tirzepatide, although these differences were not statistically significant. Dermatology Life Quality Index scores of 0 or 1 among participants with baseline scores greater than 1 occurred in 72% of participants receiving the combination therapy vs 58% of those receiving ixekizumab alone. Mean body weight decreased by 15% with ixekizumab plus tirzepatide vs 1% with ixekizumab alone. Cardiometabolic measures, including systolic and diastolic blood pressure, total cholesterol, triglycerides, and hemoglobin A1c, also showed greater reductions with the combination.
Treatment-emergent adverse events occurred in 71% of the participants receiving ixekizumab plus tirzepatide and 66% of those receiving ixekizumab alone, and most were mild or moderate. Gastrointestinal events were more common with ixekizumab plus tirzepatide, including nausea in 25% vs 2%, diarrhea in 15% vs 2%, constipation in 13% vs 0%, and vomiting in 9% vs 2%. Injection-site reactions occurred at similar rates between groups. Serious adverse events occurred in 4% of the participants receiving ixekizumab plus tirzepatide and 6% of those receiving ixekizumab alone. No mortality was reported.
The researchers noted several limitations, including the open-label design, more imputed data in the ixekizumab-only group compared with in the combination group, and the possibility that masked assessors could have inferred treatment assignment from weight change. The trial did not include a tirzepatide monotherapy group, limiting assessment of any direct effect of tirzepatide on psoriasis severity. The study also excluded patients with prior or current inadequate response to IL-17 inhibitors and was conducted only in the United States with 274 patients.
“Concomitant administration of [ixekizumab plus tirzepatide] was superior to [ixekizumab] alone in achieving key efficacy outcomes at 36 weeks of treatment, including complete skin clearance, with no new safety concerns,” wrote lead study author Mark Lebwohl, MD, of the Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York, and colleagues.
The trial was funded by Eli Lilly and Company. Full disclosures can be found in the published study.
Source: JAMA Dermatology
