Ixekizumab With or Without Tirzepatide in Adults With Psoriasis and Overweight or Obesity: A Phase 3b Randomized Clinical Trial.

IMPORTANCE: Overweight and obesity affect 60% to 78% of patients with psoriasis, affecting disease severity, treatment response, and clinical outcomes. However, no large, randomized, active-controlled clinical trial has evaluated a treatment strategy that addresses both diseases simultaneously. OBJECTIVE: To evaluate the efficacy and safety of ixekizumab with or without tirzepatide in participants with psoriasis and overweight or obesity. DESIGN, SETTING, AND PARTICIPANTS: This phase 3b, randomized, open-label, 52-week clinical trial was conducted at 72 sites in the US in adults with moderate to severe plaque psoriasis who have overweight with 1 or more weight-related comorbidities or obesity. The trial started on September 30, 2024, and completed the week 36 primary end point on January 8, 2026. Data were analyzed from January to February 2026. INTERVENTIONS: Participants were randomized (1:1) to ixekizumab plus tirzepatide or ixekizumab as adjunct to diet and exercise in both treatment arms. MAIN OUTCOMES AND MEASURES: At week 36, the primary end point was simultaneous achievement of Psoriasis Activity and Severity Index (PASI) 100 and 10% or greater weight reduction. Key secondary end points were PASI 100 and simultaneous PASI 75 and 5% or greater weight reduction, as well as 10% or greater weight reduction. RESULTS: Among the 274 randomized participants (mean [SD] age, 45.6 [12.7] years; 123 [44.9%] women and 151 [55.1%] men; mean [SD] screening body mass index [calculated as weight in kilograms divided by height in meters squared], 39.2 [9.1]; mean [SD] duration of psoriasis, 14.6 [13.0] years; mean [SD] PASI, 19.7 [8.1]), 231 (84.3%) completed the treatment through week 36. Overall, 27.1% of participants simultaneously achieved PASI 100 and a 10% or greater weight reduction with ixekizumab plus tirzepatide vs 5.8% with ixekizumab (risk difference [RD], 21.2%; 95% CI, 12.8%-29.7%; P < .001). Also, 40.6% vs 29.0% of participants achieved PASI 100 (RD, 11.6%; 95% CI, 0.3%-22.9%; P = .04), 79.9% vs 17.9% simultaneously achieved PASI 75 and a 5% or greater weight reduction (RD, 62.0%; 95% CI, 51.7%-72.2%; P < .001), and 69.2% vs 9.1% achieved a 10% or greater weight reduction (RD, 60.0%; 95% CI, 50.4%-69.7%; P < .001), respectively. Adverse events were generally consistent with established drug safety profiles, the most common being gastrointestinal tract events and injection site reactions. Gastrointestinal tract events occurred more frequently with ixekizumab plus tirzepatide vs ixekizumab. CONCLUSIONS AND RELEVANCE: The trial results suggest that concomitant ixekizumab and tirzepatide produced clinically meaningful, statistically significant improvements in skin clearance and reductions in weight in participants with moderate to severe psoriasis, with no new safety concerns, while providing additional cardiometabolic benefits and a potential to elevate care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06588283.