Efficacy, Safety, Pharmacokinetics, and Immunogenicity of ABBV-154 in Adults With Glucocorticoid-Dependent Polymyalgia Rheumatica: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Objective: An unmet need exists for glucocorticoid-sparing treatments for patients with polymyalgia rheumatica (PMR). The antibody-drug conjugate ABBV-154 comprises adalimumab conjugated to a glucocorticoid receptor modulator. We evaluated ABBV-154 versus placebo in patients with glucocorticoid-dependent PMR.

Methods: In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, eligible patients had confirmed PMR, glucocorticoid response and two or more unequivocal PMR flares while tapering glucocorticoids and still on ≥5 mg daily prednisone equivalent. Randomized patients received subcutaneous placebo or ABBV-154 40, 150, or 340 mg once every other week. The primary efficacy endpoint was time to flare. The sponsor voluntarily terminated the study early.

Results: Overall, 181 patients were randomized (placebo, n = 50; ABBV-154: 40 mg, n = 42; 150 mg, n = 45; 340 mg, n = 44), and 67.4% completed study drug at week 24. Time to flare was longer for patients receiving ABBV-154 than those receiving placebo, with Kaplan-Meier estimate of 24-week flare-free rate being lower for placebo. The hazard ratios of ABBV-154 versus placebo were 0.49 (95% confidence interval [CI], 0.27-0.88), P = 0.017 for 40 mg; 0.44 (95% CI, 0.25-0.79), P = 0.006 for 150 mg; 0.20 (95% CI, 0.09-0.42), P < 0.001 for 340 mg. Incidences of treatment-emergent adverse events were similar between groups, and the most common across ABBV-154 cohorts was COVID-19 (16.0%).

Conclusion: Treatment effects were observed for ABBV-154 cohorts compared with placebo for time to flare. ABBV-154 was generally well tolerated. Due to early study termination, results should be interpreted with caution.

Figure 1

Patient disposition during the double‐blind treatment period (full analysis set).

Figure 2

Kaplan‐Meier curves for time to flare (ITT population). (A) Time to flare overall, (B) time to flare in patients whose most recent flare occurred ≤12 weeks before baseline, and (C) time to flare in patients whose most recent flare occurred >12 weeks before baseline. EOW, every other week; ITT, intent‐to‐treat; Q2W, every two weeks.

Figure 3

Proportion of patients achieving flare‐free state at week 24 (ITT population). The 95% CI for the response rate is based on the normal approximation to the binomial distribution. The P value for the difference between each ABBV‐154 group and the placebo group is from Cochran‐Mantel‐Haenszel test adjusting for baseline randomization stratification factors (glucocorticoid use at baseline [≥10 mg/day; <10 mg/day prednisone equivalent]) and length of prior glucocorticoid treatment for PMR (≤1 year; >1 year). Patients with missing assessments who were flare free at the previous visit were imputed as flare free for the missing assessment. Missing assessments for patients who had a flare or had intercurrent events were imputed as flare. *** P < 0.001. CI, confidence interval; ITT, intent‐to‐treat; PMR, polymyalgia rheumatica; Q2W, every two weeks.

Figure 4

Dose of glucocorticoid (ITT population). (A) Mean cumulative dose (mg) at week 24 and (B) mean (95% CI) change from baseline to week 24 (mg/day). Data shown as observed for number of patients with measurements at baseline and week 24. The P values are based on an ANCOVA model adjusting for baseline randomization stratification factors (glucocorticoid use at baseline [≥10 mg/day; <10 mg/day prednisone equivalent]), length of prior glucocorticoid treatment for PMR (≤1 year; >1 year), and baseline glucocorticoid dose to compare ABBV‐154 with placebo. For change from baseline, patients with one or more available change from baseline value and no missing data for the factors and covariates in the model. * P ≤ 0.05; ** P ≤ 0.01; *** P ≤ 0.001. ANCOVA, analysis of covariance; CI, confidence interval; ITT, intent‐to‐treat; PMR, polymyalgia rheumatica; Q2W, every 2 weeks. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.43129/abstract.