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Claire Daien, MD, discusses the safety and efficacy of ABX464, the primary and secondary endpoints, and what differentiates the medication from other rheumatoid arthritis therapies.
Rheumatology Network interviewed Claire Daien, MD, lead investigator of the ABX464 phase 2a study in the treatment of rheumatoid arthritis. Daien is a professor at the University of Montpellier. We discuss the safety and efficacy of ABX464, the primary and secondary endpoints, and what differentiates the medication from other rheumatoid arthritis therapies.
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Rheumatology Network: What was your initial interest in analyzing the efficacy for ABX464, a medication previously proven safe and efficacious in patients with ulcerative colitis (UC), in patients with rheumatoid arthritis (RA)?
Claire Daien, MD: When the decision to start a clinical phase 2a study in rheumatoid arthritis was taken, ABX464 had already shown a potent anti-inflammatory effect in a preclinical RA model (the collagen-induced arthritis model, which showed ABX464’s capacity to prevent joint swelling), as well as in a proof-of-concept clinical study in ulcerative colitis, another chronic inflammatory disease. With these encouraging results, we decided to test the beneficial effect of the molecule to dampen the inflammation in rheumatoid arthritis patients.
RN: What differentiates ABX464 from other RA medications?
CD: ABX464 is a highly differentiated oral drug candidate, with a novel mechanism of action based on the upregulation of a single microRNA, called miR-124, with potent anti-inflammatory properties. We could observe in the phase 2a proof-of-concept study that the efficacy of the molecule to treat rheumatoid arthritis is comparable to currently available drugs. In addition, in the RA induction study, a once daily oral administration of 50 mg ABX464 showed a very good safety and tolerability profile. This was also observed in phase 2a and phase 2b trials in ulcerative colitis, where safety data is available of up to 2 years for the phase 2a UC study. Therefore, ABX464 could potentially become a potent, long-term treatment alternative with a very good safety and tolerability profile.
RN: Do you think ABX464 could become part of the therapeutic arsenal to treat RA?
CD: There is still a substantial proportion of patients that do not respond or lose responsiveness to currently available drugs after a certain period of time. It is therefore critical to develop new therapeutic approaches based on completely different mechanisms of action. As I mentioned before, during the phase 2a trial, 50 mg of once daily oral administration of ABX464 showed a very favorable tolerability profile with mainly mild to moderate and transient side effects. We do not yet have long-term data in RA for the molecule, the 1-year open-label maintenance results are expected for Q1 2022. However, the 1- and 2-year safety and efficacy data published for the UC phase 2a study give us reason to believe that ABX464 could show a similar durable efficacy along with a very good tolerability profile.
RN: What were the study designs and methods that were used?
CD: The clinical phase 2a induction study was designed to evaluate the safety, tolerability and preliminary efficacy of two oral dose-levels of ABX464 administered once daily (50 mg and 100 mg), in combination with methotrexate (MTX). Sixty patients who had an inadequate response to MTX and/or to 1 or more anti-tumor necrosis factor alpha (TNFα) biological therapeutics participated in this randomized, double-blind, placebo-controlled trial. Patients received ABX464 (50 mg or 100 mg) or placebo during the 12-week induction treatment phase. The study was conducted in 21 study centers across 4 European countries (France, Belgium, Poland, and Hungary). The treatment groups were well balanced in terms of disease severity as well as patient demographics.
All patients who completed the induction study could roll over into a 2-year open-label maintenance study to evaluate the long-term safety and efficacy of 50 mg once daily oral ABX464 in RA.
RN: What were the primary and secondary endpoints in the ABX464 study for patients with RA?
CD: The primary endpoint of the study was safety and tolerability of 50 mg and 100 mg ABX464 with a once daily oral administration during the 12-week induction phase.
The key secondary efficacy endpoints included, among others, American College of Rheumatology 20 (ACR20), ACR50, ACR70, Disease Activity Score-28 C-Reactive Protein (DAS28-CRP), Clinical Disease Activity Index (CDAI) as well as biological markers, eg CRP, Erythrocyte Sedimentation Rate (ESR), miR-124, and interleukin 6 (IL-6).
RN: What were the phase 2a clinical safety and efficacy results from the trial of ABX464 for patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate and/or TNFa inhibitors?
CD: The primary endpoint of this study, safety and tolerability, was met with 50 mg ABX464 once daily demonstrating a good safety and tolerability profile in the overall patient population during the 12-week induction phase.
Although the sample size of this study was not powered to show efficacy, the 50 mg group already showed statistically significant differences for the key secondary endpoint, ACR20. Approximately 60% of the per protocol patient population, dosed with 50 mg ABX464, reached the ACR20 endpoint at week 12 compared to 22% in the placebo group, with a p-value of p < 0.03. ACR50 and ACR70 improvements were achieved in 34% and 27% of patients dosed with ABX464 50 mg, compared to 6% in the placebo group, respectively. This is important for us, as ACR20 is the key primary efficacy endpoint for FDA, as a benchmark for licensure of new drugs in rheumatoid arthritis in the US.
In addition, a DAS28-CRP remission (DAS-CRP < 2.6) has been reported in 19% of patients dosed with 50 mg ABX464 compared to 5% in the placebo group, within the intent-to-treat (ITT) patients population. For the per protocol population, a DAS28-CRP remission of 25% has been observed in the 50 mg group compared to 5% in the placebo group. Regarding the biomarkers, a significant upregulation of miR-124 expression was observed for every patient dosed with ABX464, and a decrease in IL-6 blood levels was observed in both active dose groups compared to placebo.
RN: What are you most excited about as your team prepares for the start of the phase 2b program in RA?
CD: With this encouraging phase 2a results, my team and I, together with the Abivax team, are very much looking forward to advancing ABX464 in phase 2b clinical testing in RA, with a planned start of recruitment beginning of next year. In the meantime, we are very curious to get additional information on the phase 2a induction data, including more details on the various secondary endpoints as well as on the different biomarkers including predictive biomarkers of response. Further, we are obviously very much interested in the first data after 6 and 12 months of treatment within the open-label maintenance study. We hope to confirm the positive observations regarding efficacy and safety during the long-term treatment.
RN: Is there anything else you’d like our audience to know?
CD: Based on the exciting data from its clinical trials in chronic inflammatory indications (UC and RA), Abivax is now working on a global phase 3 program in ulcerative colitis (to be initiated before the end of 2021), a phase 2b study in Crohn’s disease (also to be initiated in 2021) and a phase 2b study in RA (to be initiated in early 2022). The fact that ABX464 has now shown to be efficacious and safe in 2 different chronic inflammatory indications (UC and RA) is increasing the probability that the drug candidate may also work in other chronic inflammatory conditions.