OBJECTIVE:Overweight or obesity is prevalent in 72% to 82% of individuals with psoriatic arthritis (PsA). We assessed the efficacy and safety of ixekizumab (IXE) concomitantly administered with tirzepatide (TZP) compared with IXE alone in adult participants with active PsA and overweight with at least one weight-related comorbidity or obesity. METHODS:TOGETHER-PsA (ClinicalTrials.gov identifier: NCT06588296) is a phase 3b, randomized, 52-week trial in adults with active PsA and overweight (body mass index [BMI] ≥27 to <30) with at least one weight-related comorbidity or obesity (BMI ≥30) using US-approved doses for IXE and TZP. The primary end point was simultaneous achievement of 50% improvement in American College of Rheumatology response criteria (ACR50) and ≥10% weight reduction at 36 weeks. Key secondary outcomes included ACR50. Additional secondary outcomes and patient-reported outcomes (PROs) were assessed. Safety was assessed as adverse events (AEs), treatment-emergent AEs, and serious AEs. RESULTS:A total of 271 participants were randomized (IXE + TZP, n = 138; IXE, n = 133). The primary end point was achieved with significant improvements in the IXE + TZP arm (31.7%) compared to IXE alone (0.8%) (P < 0.001). Greater improvements in ACR50 were demonstrated in IXE + TZP (33.5%) versus IXE alone (20.4%) (P = 0.02), with significant early separation at week 4 (nominal P < 0.05). IXE + TZP demonstrated nominally significant improvements in ACR20 (P < 0.001), minimal disease activity (P < 0.05), and absolute Psoriasis Area and Severity Index score (P < 0.01) compared to IXE alone. IXE + TZP demonstrated significant improvements in PROs, including Health Assessment Questionnaire-Disability Index (∆ -0.2; nominal P < 0.001) and Functional Assessment of Chronic Illness Therapy-Fatigue (improvement of 3.8; nominal P < 0.01) compared to IXE alone. Safety profiles were consistent with previous studies for each drug. CONCLUSION:Participants with active PsA and complex inflammatory-metabolic disease achieved clinically meaningful improvement of PsA, physical function, weight reduction, and quality of life when treated with IXE + TZP compared to IXE alone, with no new safety concerns.
OBJECTIVE:DISSOLVE I and II examined the efficacy and safety of nanoencapsulated sirolimus (NAS) plus pegadricase (NASP) in patients with uncontrolled gout (UG). METHODS:In these double-blind, placebo-controlled Phase 3 trials of NASP, patients were randomized 1:1:1 to infusions of high-dose (HD) or low-dose (LD) NAS plus pegadricase (HD NASP, LD NASP, respectively) or placebo, given every 4 weeks for 6 doses. The primary endpoint was proportion of patients with serum urate (SU) < 6 mg/dL for ≥ 80% of the time during Weeks 21-24. Secondary endpoints included health-related quality of life, tophus resolution, tender joints, and gout flares. Safety was also assessed. RESULTS:Overall, 265 patients received HD NASP, LD NASP, or placebo. SU response during weeks 21 to 24 was significantly higher with NASP than with placebo (HD NASP: 51%; LD NASP: 43%; placebo: 8%; P < 0.0001 for both doses vs placebo). Common adverse events included gout flares (HD NASP: 42.5%; LD NASP: 44.3%; placebo: 43.3%), infections (HD NASP: 23.0%; LD NASP: 18.2%; placebo: 16.7%), and stomatitis (HD NASP: 9.2%; LD NASP: 3.4%; placebo: 0%). Infusion reactions within 1 hour were infrequent (4%) in NASP-treated patients. During weeks 1 to 12, the proportion of patients with flares was similar between NASP- and placebo-treated patients; thereafter, it decreased in NASP-treated patients but remained unchanged with those receiving the placebo. CONCLUSION:NASP treatment resulted in a significantly higher proportion of patients with complete SU response during weeks 21 to 24 compared with placebo and was generally well tolerated. NASP, an every-4-week treatment, can markedly alleviate disease burden in patients with UG.
OBJECTIVES:The objective of this study is to investigate the safety, biodistribution, and exploratory clinical outcomes of enekinragene inzadenovec (PCRX-201), a high-capacity, nonintegrating, nonreplicating adenovirus serotype 5 vector expressing interleukin-1 receptor antagonist under the control of an inflammation-inducible promoter, in patients with moderate-to-severe knee osteoarthritis. METHODS:This open-label phase 1 trial (NCT04119687) enrolled participants aged 30 to 80 years with symptomatic (Western Ontario and McMaster Universities Osteoarthritis [WOMAC] pain score ≥ 5 and ≤ 9 [0-10-point scale]) and radiographic (Kellgren-Lawrence grade 2-4) knee osteoarthritis. In part 1, participants received a single intra-articular injection of PCRX-201 at 1 of 3 doses (n = 36). In part 2, participants received intra-articular methylprednisolone acetate immediately before PCRX-201 at the same dose (n = 36). Outcomes at week 104 included safety (primary endpoint), biodistribution (secondary endpoint), clinical outcomes (exploratory patient-reported endpoint), and immunogenicity. Data were analysed as observed. RESULTS:Transient treatment-related knee effusion was the most common adverse event and occurred less frequently in participants receiving glucocorticoid pretreatment (13/36 [36.1%]) than in those who did not (22/36 [61.1%]). Very limited biodistribution was detected outside the knee; only 2 participants had detectable PCRX-201 in plasma on days 1 and 4 postinjection. By week 104, 33/72 (45.8%) of participants had discontinued the study; however, those remaining showed sustained improvements with PCRX-201 for the exploratory outcomes of pain, stiffness, and function across doses and groups, regardless of preexisting neutralising antibody levels, with greater improvements observed in the glucocorticoid-pretreated group. CONCLUSIONS:A single intra-articular injection of PCRX-201 demonstrated safety and localised distribution within the knee. Exploratory patient-reported clinical outcomes suggest promise and support further investigation of PCRX-201.
OBJECTIVE:To assess the efficacy and safety of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with psoriatic arthritis (PsA) who were naive to biologic disease-modifying antirheumatic drugs or received tumor necrosis factor inhibitors. METHODS:In the 52-week (W), double-blind, placebo-controlled, phase 3 POETYK PsA-2 study (NCT04908189), patients were randomized 3:3:1 to deucravacitinib 6 mg daily, placebo, or apremilast 30 mg twice daily (safety reference arm) through W16. From W16 to W52, patients continued receiving deucravacitinib or apremilast or switched from placebo to deucravacitinib. The primary endpoint was American College of Rheumatology 20% improvement in response (ACR20) at W16. Secondary endpoints were analyzed per prespecified order to control for multiplicity. RESULTS:Overall, 729 patients were randomized (312 deucravacitinib, 312 placebo, 105 apremilast). Significantly more patients achieved ACR20 at W16 with deucravacitinib versus placebo (54.2% vs 39.4%; P=0.0002); responses improved beyond W16 and were maintained through W52 (deucravacitinib-deucravacitinib, 62.2%; placebo-deucravacitinib, 67.3%). At W16, significant differences with deucravacitinib versus placebo were observed in hierarchal secondary endpoints of HAQ-DI, PASI-75, SF-36 PCS, and achievement of MDA. At W16, serious adverse events occurred in 1.0%, 1.9%, and 3.8% of patients with placebo, deucravacitinib, and apremilast, respectively. No new safety signals, deaths, or imbalances in cardiovascular events, malignancies, or opportunistic infections occurred through W52. CONCLUSION:Deucravacitinib was well-tolerated in patients with PsA and demonstrated superior efficacy versus placebo across multiple clinical endpoints and patient-reported outcomes, including functional ability and quality of life. Clinical responses and patient-reported outcomes were maintained through week 52.
Spondyloarthritis (SpA), including axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), comprises a diverse but interrelated family of inflammatory diseases characterized by inflammation of the joints and spine. Signs and symptoms of SpA vary widely, as patients experience a diverse spectrum of musculoskeletal and extra-musculoskeletal disease manifestations. Interleukin (IL)-17 is an inflammatory cytokine common to the pathogenesis of SpA disease development and progression. The IL-17A inhibitor secukinumab has been well established in clinical trials and real-world practice as an effective therapeutic tool to efficiently manage SpA indications axSpA and PsA in adults, as well as juvenile PsA (jPsA) and enthesitis-related arthritis (ERA), which are two subtypes of juvenile idiopathic arthritis. This review highlights the comprehensive response to IL-17 inhibition with secukinumab across SpA indications of PsA, axSpA, and ERA/jPsA and within each indication according to established disease domains. We provide context through expert commentary on the effect of inhibiting IL-17 with secukinumab on the full spectrum of SpA disease manifestations, as well as areas in need of further investigation.
