Background/Purpose: Rheumatoid arthritis (RA) patients (pts) with inadequate response or intolerance to current biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have limited options. Abiprubart, a humanized IgG4 monoclonal antibody with a stabilized/functionally-silent Fc, binds CD40 and inhibits CD40/CD154 costimulation without lymphocyte depletion. Abiprubart was well-tolerated and showed sustained target engagement and T-cell dependent antibody response suppression in phase 1. These data and abiprubart’s high-concentration liquid formulation support investigation of chronic subcutaneous (SC) administration in autoimmune diseases.  

Methods: This phase 2, randomized, double-blind, placebo (PBO)-controlled study enrolled [adult] pts with moderate-to-severe active RA with inadequate response or intolerance to ≥1 bDMARD or Janus kinase inhibitor. Participants were randomized in sequential cohorts to 12-week (wk) treatment [Fig 1]. Cohorts 1 & 2 measured safety and PK. Primary efficacy endpoint in Cohorts 3 & 4 was change from baseline (BL) in Disease Activity Score of 28 Joints using C-Reactive Protein (DAS28-CRP) at Wk 12. Change from BL at Wk 12 in Rheumatoid Factor (RF) was assessed. Efficacy comparisons used an analysis of covariance model comparing abiprubart groups vs PBO; BL value and randomization stratification as covariates. 

Results: In Cohorts 1 & 2 (n=16) and Cohorts 3 & 4 (n=129) demographics and BL disease activity were balanced. Abiprubart was well tolerated in Cohorts 1 & 2, enabling Cohort 3. In Cohort 3, the least-squares (LS) mean change [95% confidence interval] from BL in DAS28-CRP at Wk 12 in the 5 mg/kg SC qwk group (‑2.17 [‑2.60, ‑1.74], n=27) compared to PBO (‑1.61 [‑2.04, ‑1.17], n=26) was statistically significant (‑0.57, p=0.0470).  In the 5 mg/kg SC q2wk group, the improvement in LS mean change from BL in DAS28-CRP at Wk 12 (‑1.96 [‑2.40, ‑1.52], n=25) vs PBO (‑1.61 [‑2.04, ‑1.17], n=26) did not reach statistical significance (‑0.36, p=0.2124) [Fig 2A]. In Cohort 4, LS mean change from BL in DAS28-CRP at Wk 12 was ‑1.87 [‑2.54, ‑1.21] for abiprubart (400 mg SC q4wk; n=31) vs ‑1.30 [‑1.98, ‑0.62] in PBO (n=20) (‑0.58, p=0.109). Efficacy curves continued to separate until Wk 16 despite treatment cessation at Wk 12. Abiprubart significantly reduced RF (pharmacodynamic marker of CD40 target engagement) by >40% [Fig 2B]. During follow-up, RF levels returned to BL inversely to dose frequency. In a pooled (Cohorts 3 & 4) post-hoc analysis, LS mean change from BL in DAS28-CRP at Wk 12 for abiprubart (‑2.04 [‑2.34, ‑1.74], n=83) vs combined PBO (‑1.52 [‑1.88, ‑1.16], n=46) recipients was statistically significant (-0.52, nominal p=0.010). TEAEs were similar across groups, without dose relatedness; all mild or moderate in severity.

Conclusion: Abiprubart was well-tolerated in pts with b/tsDMARD-refractory RA, and reductions in DAS28-CRP at Wk 12 for all abiprubart groups were greater than PBO, with statistical significance in the 5mg/kg SC qwk dose group and pooled analysis. Abiprubart may provide benefit in autoimmune diseases involving CD40/CD154 costimulation. A phase 2B study [Fig 3] in Sjögren’s Disease is planned.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-safety-pharmacokinetics-of-anti-cd40-antibody-abiprubart-in-patients-with-rheumatoid-arthritis-a-phase-2-randomized-placebo-controlled-12-week-treatment-proof-of-concept-study/