Therapeutic advances in musculoskeletal disease · 2024
Correlation of changes in inflammatory and collagen biomarkers with durable guselkumab efficacy through 2 years in participants with active psoriatic arthritis: results from a phase III randomized controlled trial.
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Siebert Stefan, Schett Georg, Raychaudhuri Siba P, Guma Monica, Chen Warner, Gao Sheng, Chakravarty Soumya D, Lavie Frederic, Rahman Proton
Аннотация
BACKGROUND: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit.
OBJECTIVES: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA).
DESIGN: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory (N = 100) and collagen (N = 178) biomarker cohorts.
METHODS: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model.
RESULTS: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated (r = 0.26-0.30; p < 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated (r = 0.34-0.58; p < 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated (r = 0.27-0.31; p < 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly (p < 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100.
CONCLUSION: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2.
TRIAL REGISTRATION: NCT03158285 (clinicaltrials.gov identifier).
OBJECTIVES: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA).
DESIGN: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory (N = 100) and collagen (N = 178) biomarker cohorts.
METHODS: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model.
RESULTS: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated (r = 0.26-0.30; p < 0.05) with improved joint disease activity (Disease Activity in Psoriatic Arthritis); decreases in IL-17A, IL-17F, IL-22, and BD-2 levels correlated (r = 0.34-0.58; p < 0.05) with improved skin disease (Psoriasis Area and Severity Index); and decreases in C1M, C3M, C4M, and C6M correlated (r = 0.27-0.31; p < 0.05) with improved overall disease activity (Psoriatic Arthritis Disease Activity Score). Significantly (p < 0.05) greater reductions from baseline at Week 100 in CRP, IL-6, SAA, and C1M levels were observed in participants improving from Week 24 ACR50 nonresponse to Week 100 ACR50 response and were accompanied by a significant decrease in C1M from Week 24 to Week 100 versus nonresponders at both Weeks 24 and 100.
CONCLUSION: In biologic-naïve participants with active PsA, guselkumab elicited substantial and enduring reductions in biomarkers that were associated with durable improvements in joint, skin, and overall disease activity through 2 years of DISCOVER-2.
TRIAL REGISTRATION: NCT03158285 (clinicaltrials.gov identifier).