WAYNE, PA — Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, announced positive preliminary topline results from a 12-week, Phase 2a, multicenter, randomized, investigator and patient-blind, sponsor-unblinded, parallel-group, placebo-controlled clinical trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of ATI-450, an investigational oral MK2 inhibitor, in subjects with moderate to severe rheumatoid arthritis (RA) (ATI-450-RA-201). ATI-450 was developed internally utilizing Aclaris’ proprietary KINect™ drug discovery platform.
In the trial, 19 subjects were randomized in a 3:1 ratio and received either ATI-450 at 50 mg twice daily or placebo, in combination with methotrexate, for 12 weeks. The primary endpoint was safety and tolerability. Key secondary and exploratory endpoints included the disease activity scores, DAS28-CRP and ACR20/50/70, and the change from baseline in high sensitivity C-reactive protein (hsCRP) and relevant endogenous cytokine levels. As this trial was designed to generate proof of concept, it was not powered to detect statistically significant outcomes on efficacy endpoints.
The mean DAS28-CRP score at baseline was 5.71 for the 16 subjects in the treatment arm and 5.77 for the three subjects in the placebo arm. Seventeen subjects (15 in the treatment arm and two in the placebo arm) completed 12 weeks of treatment.
In this trial, ATI-450 demonstrated durable clinical activity, as defined by a marked and sustained reduction in DAS28-CRP and evaluation of ACR20/50/70 responses over 12 weeks. The mean change from baseline in DAS28-CRP score at week 12 was a 2.0 reduction in the treatment arm compared to a 0.35 increase in the placebo arm. The proportion of subjects with a DAS28-CRP score at week 12 of ≤ 3.2 (low disease activity or remission) was 40% and 0% in the treatment and placebo arms, respectively, and the proportion of subjects with a DAS28-CRP score of < 2.6 (remission) was 20% and 0% in the treatment and placebo arms, respectively.
ACR20/50/70 was observed at week 12 in 60%, 33% and 20%, respectively, of the 15 subjects in the treatment arm, and in 0% of the two subjects in the placebo arm. The median reduction from baseline in hsCRP was >40% throughout the 12 weeks of the trial in the treatment arm. A sustained median reduction from baseline in hsCRP was not observed in the placebo arm. An interim analysis (11 treatment, two placebo) of ex vivo stimulated cytokines from blood samples taken from the treatment arm showed a marked and durable inhibition of TNFα, IL1β, IL6, and IL8 over the 12 week dosing period. Similarly, analysis of endogenous cytokines also demonstrated a marked and sustained inhibition of median concentrations of TNFα, IL6, IL8, and MIP1β in the treatment arm over the 12 week period.
ATI-450 was generally well tolerated. No serious adverse events were reported and all adverse events were mild to moderate. The most common adverse events (each reported in 2 subjects) were urinary tract infection (UTI), elevated lipids and ventricular extrasystoles, all of which were determined to be unrelated to treatment except for one UTI. Two subjects withdrew from the trial, one in the treatment arm and one in the placebo arm.
ATI-450 was also evaluated at higher doses in a separate Phase 1 clinical trial in healthy subjects (ATI-450-PKPD-102). In this placebo-controlled Phase 1 trial, one group of healthy subjects received 80 mg of ATI-450 twice daily and another group of healthy subjects received 120 mg of ATI-450 twice daily over 6.5 days. No dose-limiting toxicity was observed. Ex vivo analysis of blood samples from this Phase 1 trial showed that increased cytokine inhibition was achieved with these higher doses of ATI-450. A final analysis of this trial is underway.
Dr. David Gordon, Chief Medical Officer of Aclaris, said, “We’re very pleased with these data which demonstrate that ATI-450 was generally well tolerated and showed durable clinical activity in RA over 12 weeks. We believe these data support our hypothesis that MK2 inhibition is an important novel target for the treatment of immuno-inflammatory diseases, such as rheumatoid arthritis, and we look forward to progressing ATI-450 to Phase 2b. We want to thank everyone who participated in these informative trials.”
“Despite recent advances, rheumatoid arthritis continues to be a significant burden for large numbers of patients,” said Stanley Cohen, MD, Clinical Professor in the Department of Internal Medicine and a Clinical Faculty Member in the Division of Rheumatology at UT Southwestern Medical School, and a Co-Director of the Division of Rheumatology at Presbyterian Hospital, Dallas. “These results are very encouraging and support further development of ATI-450 to treat rheumatoid arthritis with a new mechanism of action.”
Aclaris expects to submit a full analysis of the Phase 2a data for publication in a peer-reviewed scientific journal. The full analysis will include data from other secondary and exploratory endpoints evaluated in the trial, including the four-week safety follow-up data and a full analysis of MRI, pharmacodynamic and pharmacokinetic data.
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