Efficacy and Safety of ABBV-3373, a Novel Anti-Tumor Necrosis Factor Glucocorticoid Receptor Modulator Antibody-Drug Conjugate, in Adults with Moderate-to-Severe Rheumatoid Arthritis Despite Methotrexate Therapy: A Randomized, Double-Blind, Active-Controlled Proof-of-Concept Phase IIa Trial.

ABSTRACT

OBJECTIVE: To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria. RESULTS: Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported. CONCLUSION: Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.