The TOGETHER-PsA trial (NCT06588296) is a 52-week, randomized, multicenter, assessor-blinded, open-label Phase 3b study evaluating the efficacy and safety of concomitant subcutaneous ixekizumab (Taltz, an IL-17A inhibitor) and tirzepatide (Zepbound, a dual GIP/GLP-1 receptor agonist) compared to ixekizumab monotherapy in 271 adults with active psoriatic arthritis (PsA) and obesity (BMI ≥30 kg/m²) or overweight (BMI 27-29.9 kg/m² with ≥1 weight-related comorbidity). Participants had high baseline disease burden (mean DAPSA score 58.65, HAQ-DI 1.3) and mean BMI 37.6 kg/m²; over 60% had prior advanced therapy exposure. Both arms included lifestyle counseling for reduced-calorie diet and physical activity.
At week 36, the primary composite endpoint—ACR50 response (≥50% improvement in tender/swollen joint counts and ≥3 of 5 core measures) plus ≥10% weight reduction—was met by 31.7% of patients receiving combination therapy versus 0.8% on monotherapy (p<0.001), using a hypothetical efficacy estimand in the modified intent-to-treat population. In a key secondary endpoint, ACR50 response alone occurred in 33.5% of the combination arm versus 20.4% with monotherapy, representing a 64% relative increase (p<0.05). This suggests that pharmacologic treatment of obesity directly improves PsA disease activity beyond the effects of IL-17A inhibition.
Adverse events were mild to moderate and aligned with individual drug profiles. In the combination arm, common events (≥5%) included nausea, diarrhea, constipation, and injection site reactions; monotherapy commonly reported injection site reactions and upper respiratory infections.
These findings represent the first controlled evidence that integrating obesity management with incretin-based therapy enhances outcomes in PsA, a condition where an estimated 65% of U.S. patients have comorbid obesity/overweight. The results support a potential paradigm shift toward comprehensive treatment addressing both inflammation and metabolic burden. Detailed data will be presented at upcoming medical meetings and submitted to regulators. A similar trial (TOGETHER-PsO) in plaque psoriasis is ongoing, with topline results expected in the first half of 2026.
