Background/Purpose: p38 inhibition has been a focus of research in RA but efficacy in clinical studies was underwhelming, possibly because a large number of pro and anti-inflammatory pathways as well as negative feedback loops were modulated by this target. ATI-450 specifically blocks the downstream MK2-mediated inflammatory drive on the p38 pathway and may therefore avoid the tachyphylaxis associated with p38 inhibitors. Inhibition of ex vivo-stimulated IL1, IL6, TNFa and IL8 was seen in phase 1. This study explored whether MK2 inhibition was well tolerated and could deliver sustained anti-inflammatory effect leading to durable clinical activity in patients with RA.

Methods: A phase 2a, randomized, investigator/patient-blind, sponsor-unblinded, placebo (PBO) controlled study was conducted to investigate safety, tolerability, PK, and PD of ATI-450 versus PBO (both + MTX) in MTX inadequate responders with moderate to severe RA. Patients were randomized in a 3:1 ratio to receive oral ATI-450 (50 mg) or PBO, both BID. A 12-week treatment period was followed by a 4-week follow-up period. The primary endpoint was safety and tolerability. Secondary and exploratory endpoints included DAS28-CRP, ACR20/50/70, change from baseline in hsCRP and relevant endogenous cytokine levels in blood. MRI imaging will be reported elsewhere. The study was not powered to detect statistical significance on efficacy endpoints.

Results: Nineteen subjects were randomized (16:ATI-450, 3:PBO). Mean DAS28-CRP at baseline was 5.71 in the treatment arm and 5.77 in the PBO arm. Seventeen subjects (15 ATI-450, and 2 PBO) completed 12 weeks of treatment. One subject from each arm withdrew during the treatment period: the ATI-450 subject withdrew for an AE of elevated CPK.

ATI-450 was generally well tolerated. No serious adverse events were reported during the treatment period (1 unrelated SAE of COVID-19 pneumonia was reported off-treatment in the follow-up period in the ATI-450 arm). The most common adverse events (each reported in 2 subjects) were urinary tract infection and ventricular extrasystoles. All adverse events were mild to moderate.

In the per-protocol analysis (includes 15 ATI-450, 2 PBO who completed 12 weeks), the mean change from baseline in DAS28-CRP score at week 12 was -2.0 in the ATI-450 arm versus +0.35 in the PBO arm. 40% and 20% of ATI-450 subjects had a DAS28-CRP score ≤ 3.2 and < 2.6 at week 12, respectively, versus 0 PBO patients. ACR20/50/70 was observed at week 12 in 60%, 33% and 20% of 15 ATI-450 subjects versus 0% of 2 PBO subjects. The median reduction from baseline in hsCRP was >40% throughout the 12-week treatment period in the treatment arm; a sustained median reduction was not observed in the placebo arm. A marked and sustained inhibition of median endogenous plasma concentrations of TNFα, IL6, IL8, and MIP1β was observed in the treatment arm over the 12-week period.

Conclusion: ATI-450 was generally well tolerated and demonstrated durable clinical activity over 12 weeks in RA. This study is the first to demonstrate that MK2 inhibition can overcome key deficiencies associated with p38 inhibition. ATI-450 has potential to be an important new drug in RA and progression to phase 2b is supported.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ati-450-an-investigational-mk2-inhibitor-is-well-tolerated-and-demonstrated-clinical-activity-in-patients-with-mod-severe-ra-a-12-week-phase-2a-randomized-investigator-patient-blind-study-investi/