AbbVie, a research-based global biopharmaceutical company, announced new data from a phase 2a study of ABBV-3373, an investigational anti-tumor necrosis factor (TNF) Glucocorticoid Receptor Modulator (GRM) steroid antibody drug conjugate (ADC), in adult patients with moderate to severe rheumatoid arthritis. The primary endpoint was the change in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) from baseline to week 12 and two statistical comparisons were pre-specified. The first compared ABBV-3373 and mean outcome from historical adalimumab data.
The second compared ABBV-3373 and combined in-trial and historical adalimumab data. Results of the first comparison show a greater difference in the primary endpoint change in DAS28-CRP from baseline to week 12 for ABBV-3373 (-2.65) as compared to a pre-specified historical adalimumab mean (-2.13) (p=0.022). Results of the second comparison, based on a Bayesian analysis, predicted with a 90 percent probability that ABBV-3373 was associated with a greater improvement on DAS28-CRP from baseline to week 12 than adalimumab based on in-trial data combined with historical data. Additionally, evaluations of serum cortisol levels over 12 weeks indicate that ABBV-3373 showed no systemic glucocorticoid effects.
“This proof of concept study demonstrates clinical activity of the TNF-ADC platform and its potential to advance the standard of care for patients with rheumatoid arthritis,” said Michael Severino, M.D., vice chairman and president, AbbVie. “Based on these results we will advance the development of the TNF-ADC platform in rheumatoid arthritis and begin clinical studies in other immune-mediated diseases.”
These are the first results to be reported for the novel ADC in rheumatoid arthritis. ABBV-3373 is an investigational medicine that is not approved by regulatory authorities and is being studied for the treatment of rheumatoid arthritis and other immune-mediated diseases.
In the 31 rheumatoid arthritis patients on ABBV-3373 and 17 rheumatoid arthritis patients on adalimumab, in the trial, the safety profile of ABBV-3373 was generally similar to adalimumab. The overall adverse events (AE) rate of ABBV-3373 was lower than adalimumab (35 percent [n=11] vs. 71 percent [n=12], respectively). The AEs occurring in =5 percent of patients were urinary tract infections, with two events in each treatment group, and headache, with two events in the ABBV-3373 group and one event in the adalimumab group. Six percent (n=1) of subjects treated with adalimumab and three percent (n=1) of subjects treated with ABBV-3373 discontinued treatment due to an AE. Through week 12, serious adverse events (SAEs) occurred in four patients in the ABBV-3373 group (13 percent, [n=4]), compared to none in the adalimumab group (0 percent, [n=0]). In the ABBV-3373 group, two SAEs were deemed unrelated to study drug (pneumonia and upper respiratory tract disease). One SAE was non-cardiac chest pain and one SAE was reported as anaphylactic shock; this subject fully recovered and no further events of hypersensitivity were reported after drug administration time was extended for subsequently dosed subjects.
Being developed by AbbVie, ABBV-3373 is an investigational ADC comprised of a novel glucocorticoid receptor modulator (GRM) linked to adalimumab, and aims at modulating TNF-mediated inflammatory pathways by delivering a glucocorticoid payload directly into activated immune cells expressing membrane bound TNF. This ADC was designed to potentially allow precise targeting of activated immune cells while significantly dampening inflammation and minimizing the systemic side-effects associated with glucocorticoids. ABBV-3373 is an investigational medicine that is not approved by regulatory authorities and is being studied for the treatment of rheumatoid arthritis and other immune-mediated diseases.
The M16-560 study is a phase 2a, multicenter, randomized, double-blind, double-dummy, active-controlled study designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of ABBV-3373 in adult patients with moderate to severe rheumatoid arthritis with an inadequate response to MTX. Patients were randomized in a 2:1 ratio to ABBV-3373 (n=31) at 100 mg, every other week (EOW) or adalimumab (n=17) at 80 mg, EOW for 12 weeks.
Bayesian statistical methods incorporating historical data were used to achieve adequate statistical power in this proof of concept study, which was accomplished through pre-specified supplementation of adalimumab in-trial data with historical adalimumab data for comparison with ABBV-3373 for the primary endpoint analyses. The historical data were obtained from three historical adalimumab trials of similar settings. The primary endpoint was the change in DAS28-CRP from baseline to week 12 and two statistical comparisons were pre-specified. The first compared ABBV-3373 and mean outcome from historical adalimumab data with the success criteria of two-sided p-value =0.1. The second compared ABBV-3373 and combined in-trial and historical adalimumab data (success criterion: probability of >95 percent).