Dual Joint-Weight Win Masks Single-Trial Limits and Dual-Cost Payer Hurdle

Lilly's TOGETHER-PsA Trial Shows Dual Therapy Efficacy in Psoriatic Arthritis

Eli Lilly and Company announced positive 52-week results from the Phase IIIb TOGETHER-PsA trial, evaluating Taltz (ixekizumab) combined with Zepbound (tirzepatide) for active psoriatic arthritis (PsA) in adults who are overweight or obese. The multicentre, randomised study, involving 271 patients, compared the combination therapy against Taltz monotherapy, both alongside calorie reduction and exercise. At week 36, the primary endpoint showed 39.2% of combination therapy patients achieved both an ACR50 response and at least a 10% weight reduction, significantly higher than 1.7% for monotherapy. Exploratory 52-week data further supported the dual therapy's benefits in disease control and weight management, with a safety profile consistent with known profiles of each drug.

• The TOGETHER-PsA trial's primary endpoint, assessed at week 36, demonstrated that 39.2% of patients receiving the Taltz and Zepbound combination achieved both an ACR50 response and at least a 10% body weight reduction. This was a substantial improvement compared to only 1.7% of patients on Taltz monotherapy, highlighting the synergistic effect of the dual treatment in addressing both PsA symptoms and weight.
• Exploratory 52-week results showed continued and robust benefits for the combination therapy. At one year, 43.7% of dual-therapy patients achieved an ACR50 response, versus 15.7% for monotherapy. Furthermore, 85.7% of combination patients achieved a 10% or greater weight reduction, compared to only 6.7% in the monotherapy group, indicating durable efficacy across key clinical measures.
• The trial reported adverse events that were mostly mild to moderate and consistent with the known safety profiles of Taltz and Zepbound, with no new safety signals identified. The study enrolled 271 adult patients with active PsA and a BMI of at least 30kg/m² (or 27-30kg/m² with comorbidity), reflecting the significant proportion of PsA patients who also experience overweight or obesity.

Addressing the Dual Burden of PsA and Comorbid Obesity

Psoriatic arthritis is a multi-domain, inflammatory disease impacting joints, soft tissues, and skin, and achieving sustained remission remains challenging despite multiple biologic and targeted synthetic disease-modifying antirheumatic drugs. Heterogeneous disease expression, comorbidities, and variable durability of response limit treatment effectiveness, with many patients still having suboptimal or unsustained response resulting in morbidity, structural damage and functional impairment.

• Tumor necrosis factor inhibitor inadequate response populations: Pragmatic evaluation of switching to a different mechanism of action versus cycling to another TNFi after initial TNFi failure, including guselkumab 100 mg every 4 weeks or at Week 0, Week 4, and every 8 weeks versus subcutaneous golimumab 50 mg every 4 weeks in EVOLUTION, bimekizumab 160 mg every 4 weeks in TNFi-IR patients in BE COMPLETE, upadacitinib 15 or 30 mg once daily in SELECT-PsA 2, and long-term tofacitinib efficacy and safety stratified by TNFi-IR versus bDMARD-naive status.

• Difficult-to-treat psoriatic arthritis: Operational definitions including failure of ≥1 csDMARD plus ≥2 b/tsDMARDs with different mechanisms of action, ≥2 b/tsDMARDs with different mechanisms of action within 12 months, or failure of >3 b/tsDMARDs with different mechanisms of action, associated with longer disease duration, higher activity, HLA-B27 positivity, comorbidities, extensive psoriasis, axial involvement, obesity, female gender, depression, and fibromyalgia.

• Psoriatic arthritis with concomitant inflammatory bowel disease: Retrospective matched cohort of PsA-IBD versus Only-PsA initiating TNF inhibitors or anti-IL-12/23 agents, with minimal disease activity and DAPSA remission/low disease activity achieved by 32.1% and 50.0% of PsA-IBD patients vs. 58.3% and 78.3% of Only-PsA patients at 6 months, and persistently higher VAS pain, PtGA, and HAQ-DI scores at 12 months.

• Nail psoriasis with joint involvement: Nail involvement affecting 57.5% of PsA patients in a multicenter study and 71.7% in a clinical and ultrasonographic study, associated with increased disease activity, lower quality of life, enthesitis, and distal interphalangeal joint enthesitis in 57% of digits with clinical nail involvement, with concurrent complete skin and nail clearance assessed as PASI 100 and mNAPSI 0.

• Psoriasis with early musculoskeletal symptoms at risk for progression: Retrospective multicentre evaluation of IL-23 inhibitors including guselkumab, risankizumab or tildrakizumab in moderate-to-severe psoriasis with early musculoskeletal involvement and enthesitis observed in 44.8% of patients with joint involvement, with no patients with enthesitis treated with guselkumab progressing to overt PsA.

TOGETHER-PsA: Promising 52-Week Efficacy for Taltz and Zepbound

In the phase III DISCOVER-2 trial in biologic-naive patients with active psoriatic arthritis, patients received guselkumab 100 mg every 4 weeks, guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks, or placebo with crossover to guselkumab 100 mg every 4 weeks beginning at week 24. Of the 739 randomized and treated patients, 652 (88%) completed treatment through week 100. At week 100, ACR20 response was 68-76%, ACR50 response was 48-56%, ACR70 response was 30-36%, Investigator's Global Assessment score of 0 was 55-67%, enthesitis resolution was 62-70%, and dactylitis resolution was 72-83%. Mean changes in the Sharp/van der Heijde modified score for PsA from weeks 52 to week 100 were range 0.13-0.75. Through week 112, 8% (5.8 per 100 patient-years) and 3% (1.9 per 100 patient-years) of the 731 guselkumab-treated patients had a serious adverse event or serious infection, respectively, and 1 death occurred (road traffic accident).

In the phase 3 SELECT-PsA 1 study, patients received upadacitinib 15 mg or 30 mg once daily, or adalimumab 40 mg every other week, through week 104. Of 1704 patients, 25.4% discontinued the study drug by week 104. Proportions of patients achieving ≥20%/50%/70% improvement in American College of Rheumatology criteria, ≥75%/90%/100% improvement in Psoriasis Area and Severity Index, or minimal disease activity were maintained through week 104, with greater responses by nominal P value observed with upadacitinib 15 mg and 30 mg versus adalimumab for ACR20/50/70 and minimal disease activity. Mean change from baseline in modified total Sharp/van der Heijde Score was similar across groups and to week 56 results. Rates of serious infection, herpes zoster, anemia, neutropenia, lymphopenia, and elevated creatine phosphokinase remained numerically higher with upadacitinib 15 mg and/or 30 mg versus adalimumab, while rates of malignancies excluding non-melanoma skin cancer, major adverse cardiovascular events, and venous thromboembolism were similar across groups and rates of non-melanoma skin cancer were higher with upadacitinib versus adalimumab. Two deaths were reported with upadacitinib 15 mg, one with upadacitinib 30 mg, and one with adalimumab.

In OPAL Balance, a 36-month open-label long-term extension study with a 12-month methotrexate withdrawal substudy, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1. Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and 453 [66%] of 686 completed the long-term extension study or substudy. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0.1 patients with events [95% CI 0.0-0.3] per 100 person-years). Incidences as number of patients with events per 100 person-years included 1.7 (1.2-2.5) for herpes zoster, 1.0 (0.6-1.6) for serious infections, 0.4 (0.1-0.8) for opportunistic infections, 0.7 (0.4-1.2) for malignancies excluding non-melanoma skin cancer, 0.9 (0.5-1.5) for non-melanoma skin cancer, 0.2 (0.1-0.6) for major adverse cardiovascular events, 0.1 (0.0-0.3) for pulmonary embolism, and 0.4 (0.1-0.8) for arterial thromboembolism, with no deep vein thromboses occurring. Efficacy was sustained up to month 36.

Safety Profile and Clinical Impact of Taltz-Zepbound Combination

Long-term integrated safety data for ixekizumab in adults with psoriasis, psoriatic arthritis and axial spondyloarthritis include 8228 patients with an ixekizumab exposure of 20 895.9 PY from 21 clinical trials, and 6892 adult patients with PsO, 1401 with PsA, and 932 with axSpA with a cumulative IXE exposure of 22,371.1 PY from 25 randomized clinical trials. Additional psoriasis-specific pooling reported total ixekizumab exposure of 17,003.4 p-y (N = 5898) with 2749 patients having ≥4 years of exposure, and 6892 adult patients with a cumulative exposure of 18,025.7 PY with up to 5 years of exposure. The most common TEAEs were nasopharyngitis, upper respiratory tract infection and injection-site reactions, with the most commonly reported TEAE across indications reported as nasopharyngitis (IRs per 100 PY: 8.8 (PsO), 9.0 (PsA), 8.4 (axSpA)). In psoriatic arthritis-specific pooling, total exposure reached 1822.2 PY (1118 patients) and 1,373.4 patient-years, with the most common TEAEs reported as upper respiratory tract infection (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 IR), and bronchitis (4.5 IR).

Across populations, IRs were low for AEs leading to discontinuation (IRs ≤5.1 per 100 PY), serious AEs (IRs ≤6.0 per 100 PY) and death (IRs ≤0.3 per 100 PY), with SAEs reported by 969 patients with PsO (IR 5.4), 134 patients with PsA (IR 6.0), and 101 patients with axSpA (IR 4.8), and forty-five deaths reported (PsO, n = 36, IR 0.2; PsA, n = 6, IR 0.3; axSpA, n = 3, IR 0.1). IRs per 100 PY of discontinuation from IXE due to AE were 2.9 (PsO), 5.1 (PsA), and 3.1 (axSpA), and IRs per 100 PY of injection site reactions were 5.9 (PsO), 11.6 (PsA) and 7.4 (axSpA). The most reported TEAEs of special interest were infections (IRs ≤35.8 per 100 PY), with serious infections IR 1.3, Candida IR 1.9 (PsO), 2.0 (PsA), and 1.2 (axSpA), and candidiasis reported in 327 patients (IR 1.9/100 p-y) with the majority identified as mucocutaneous. Patients rarely reported malignancies (IR ≤0.8), IBD including ulcerative colitis and Crohn's disease (IR ≤0.8) and major adverse cardiovascular events (IR ≤0.5), with adjudicated IRs per 100 PY of inflammatory bowel disease ≤0.8 across indications (0.1 [PsO]; 0.1 [PsA]; 0.8 [axSpA]), depression, major adverse cerebro-cardiovascular events and malignancies ≤1.6 across all indications, and IBD events uncommon with 31 patients (IR 0.2) having confirmed IBD (ulcerative colitis, n = 18; Crohn disease, n = 13). TEAEs were most commonly reported the first 2 years of exposure with ixekizumab and IR decreased over the years (infections, injection-site reactions and depression) or remained constant over the entire treatment period (serious infections, major adverse cardiovascular events, malignancies and IBD), with TEAEs not increasing during IXE exposure: IRs per 100 PY, PsO: 88.9 to 63.2 (year 0-1 to 4-5), PsA: 87 to 67.3 (year 0-1 to 2-3), axSpA: 82.1 to 55.4 (year 0-1 to >=2).

For tirzepatide, a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist, a systematic review of nine RCTs with a total of 9818 patients found the overall safety profile similar to GLP-1RAs, except for hypoglycemia (tirzepatide 15mg, pooled RR=3.83, 95% CI [1.19- 12.30], P=0.02) and discontinuation (tirzepatide 10mg, pooled RR=1.75,95%CI[1.16-2.63], P=0.007 and 15mg, pooled RR=2.03, 95%CI [1.37-3.01], P=0.0004). Compared with 5mg, tirzepatide 10mg and 15mg were associated with more frequent nausea (P<0.001), discontinuation (P<0.05) and injection-site reaction (P<0.01), with rates of vomiting and diarrhea dose-dependence at the range of 5-15mg. A meta-analysis of six trials comprising 6,579 subjects (4,410 in the tirzepatide group and 2,054 in the control group) showed tirzepatide treatment resulted in reducing HbA1c (WMD: -1.07%; 95% CIs: -1.44, -0.56), FSG (WMD, -21.50 mg/dl; 95% CI: -34.44, -8.56), and body weight (WMD: -7.99 kg; 95% CI -11.36, -4.62), without increasing hypoglycemia, with increased risk of gastrointestinal adverse events mainly in add-on therapy but not in terms of pancreatitis or cholelithiasis. In a 12-week randomized, double-blind, placebo-controlled study, absolute HbA1c change from baseline was placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19], with incidence of nausea of placebo, 7.7%; 12 mg group, 24.1%; 15 mg-1 group, 39.3%; 15 mg-2 group, 35.7%. Real-world FAERS analysis of 65,974 reports from 2022 to Q1 2025 found incorrect dose administration as the top AE, increasing 8-fold from 1248 (2022) to 9800 (2024), with other common AEs including injection-site reactions (e.g., pain [5273 cases in 2024]), gastrointestinal issues (nausea [3602 in 2024]), and off-label use. A case report described a 73-year-old female patient without typical risk factors who developed appendicitis one week following initiation of Tirzepatide, with symptoms dramatically improved once Tirzepatide was stopped and improvement demonstrated on CT imaging, highlighting appendicitis as a potential adverse effect linked to delayed gastric emptying and changes in gastrointestinal motility.