Phase IIa Proof-of-Concept Study Success: ADC ABBV-3373 Offers New Therapeutic Approach for Rheumatoid Arthritis

On June 10, AbbVie announced positive data from a Phase IIa proof-of-concept study evaluating the antibody-drug conjugate (ADC) ABBV-3373 in adult patients with moderate-to-severe rheumatoid arthritis (RA).This is the first clinical data disclosed for ADC drugs in the indication of rheumatoid arthritis.

ABBV-3373 is an antibody-drug conjugate (ADC) composed of adalimumab and a novel glucocorticoid receptor modulator (GRM). It delivers the glucocorticoid payload directly to activated immune cells expressing membrane-bound TNF, thereby modulating TNF-mediated inflammatory signaling pathways. This design enables precise targeting and regulation of activated immune cells, significantly reducing systemic side effects associated with glucocorticoids. ABBV-3373 is being developed for the treatment of rheumatoid arthritis and other immune-mediated diseases.

This Phase IIa, multicenter, randomized, double-blind, active-controlled study, coded M16-560, enrolled a total of 48 patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to methotrexate. The primary objective was to evaluate the safety, tolerability, pharmacokinetics, and efficacy of ABBV-3373 compared with the control drug Humira (adalimumab). Patients were randomized in a 2:1 ratio to receive either ABBV-3373 100 mg (n=31) or adalimumab 80 mg (n=17) once every two weeks for 12 consecutive weeks.

The study employed a Bayesian statistical approach incorporating historical data to achieve sufficient statistical power for the primary endpoint. This was accomplished by supplementing the adalimumab trial data from the current study with pre-specified historical adalimumab data, followed by comparative analysis against ABBV-3373. The primary endpoint was the change from baseline in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12, with two pre-specified statistical comparisons: one comparing ABBV-3373 with the mean results of historical adalimumab data, and the other comparing ABBV-3373 with adalimumab data combining both historical and current study data.

The results of the first comparative analysis showed that the change from baseline in DAS28-CRP score at Week 12 in the ABBV-3373 group was -2.65, compared to a prespecified mean change of -2.13 derived from historical adalimumab data, with a statistically significant difference between the two groups (P=0.022). The second comparative analysis, using a Bayesian approach, demonstrated a 90% probability that ABBV-3373 provides a greater improvement in DAS28-CRP score at Week 12 compared to adalimumab.

Regarding safety, the ABBV-3373 treatment group and the adalimumab treatment group were similar, with a lower overall incidence of adverse events (35% vs. 71%). Adverse events with an incidence rate exceeding 5% in both groups included urinary tract infection (2 cases in each group) and headache (2 cases and 1 case, respectively). The proportions of patients discontinuing treatment due to drug-related adverse events were 3% (1 case) and 6% (1 case), respectively. At Week 12, 4 patients (13%) in the ABBV-3373 group experienced serious adverse reactions, including one case of non-cardiac chest pain and one case of anaphylactic shock (the patient fully recovered and did not experience allergic reactions after the completion of dosing). The serious adverse reactions in the other two patients (pneumonia and upper respiratory tract disease) were considered unrelated to the study drug. The incidence rate of serious adverse reactions in the adalimumab group was 0%.

Furthermore, the assessment of serum cortisol levels at Week 12 demonstrated that ABBV-3373 has no systemic glucocorticoid effects. Detailed study results are planned for presentation at upcoming scientific conferences and/or publication in peer-reviewed journals.

Michael Severino, Vice President of AbbVie, stated, “This proof-of-concept study demonstrates the clinical utility of the TNF-ADC program and its potential to improve the standard of care for patients with rheumatoid arthritis. Based on these results, we will continue to advance the development of our TNF-ADC program for the treatment of rheumatoid arthritis and initiate clinical studies in other immune-mediated diseases.”

AbbVie has become the leading player in the rheumatoid arthritis (RA) field with Humira. Biosimilars of adalimumab are already widely available in Europe, and market exclusivity in the United States is set to expire in 2023. To bolster its RA portfolio, AbbVie has introduced new small-molecule oral agents: upadacitinib (a JAK1 inhibitor, already marketed) and filgotinib (a JAK1 inhibitor, under New Drug Application review). Additionally, ABV-599 (a BTK inhibitor), currently in Phase II clinical trials, serves as a pipeline reserve. In the biologics segment, AbbVie’s strategic assets include BI 655064 (an anti-CD40 monoclonal antibody) and ABBV-3373 (a TNF-targeting antibody-drug conjugate), both in Phase II development.