Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study

Abstract

Purpose

ATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics.

Patients and Methods

Healthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27).

Results

The most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC₈₀ for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. Mean C_max was 3.5, 5.4, 5.6, and 6.0 times greater than the IC₈₀ for TNF-α, IL-1β, IL-8, and p-HSP27, respectively. IL-6 inhibition >50% was noted for part of the dosing interval.

Conclusion

ATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.

Keywords:

• immunologic diseases
• rheumatoid arthritis
• serine-threonine kinases
• protein kinase inhibitors
• pharmacokinetics/pharmacodynamics

Acknowledgments

Writing and editorial assistance was provided to the authors by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by Aclaris Therapeutics, Inc. The authors would like to thank the volunteers; clinical personnel; Aclaris CMC, Laboratory and Operational Team; and Data Management and Biostatistical staff. Also, the authors thank Daniel Dickerson, MD, the principal study investigator, and Marco Cardillo, CCRA, Madison Bangs, BA, Emma Huff, BS, Aparna Kaul, PhD, Anne Hildebrand, PhD, and Barry Burnette, PhD for their contributions to the conduct of the study and analysis.

Data Sharing Statement

All data requests should be submitted to the corresponding author for consideration. Access to de-identified data may be granted following review.

Disclosure

David Gordon, Joseph B Monahan, Edward T Hellriegel, Heidi Rath Hope and David Burt are employees and shareholders of Aclaris Therapeutics. Dr David Gordon has patents 63076689, 63126173, 63136080, 63136967, 63138672, 63128523, and 63140116 pending. Mr Edward T Hellriegel has patents 62986954, 62986955, 63076689, 63126173, 63136080, 63136967, 63138672, and 63140116 pending to Aclaris Therapeutics. Dr Joseph B Monahan has patents 8563558, 8507499, 9359300, 9365546, 9365547, 9056110, 9115089, 9636333, and 63136967 pending to Aclaris Therapeutics; patents 63138672, 63140116, 63136080, 63126173, 63076689, 62980955, 62986954, 63128523, and 63024160 issued to Aclaris Therapeutics.

Additional information

Funding

This study was sponsored by Aclaris Therapeutics, Inc., Wayne, Pennsylvania, USA. Neither honoraria nor other form of payment was made for authorship. Writing and editorial assistance was provided to the authors by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by Aclaris Therapeutics, Inc.