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A1056 - Extended Pharmacodynamic and Immunomodulatory Activity of the MAPKAP Kinase II (MK2) Inhibitor MMI-0100 Demonstrated in a Phase 1 Lipopolysaccharide (LPS) Challenge Study Conducted in Subjects Who Smoke
Author Block: C. Lander1, C. Peterson1, A. Panitch2, A. Luber1, R. Gerwien1, G. Nicholson3, B. Leaker4; 1Moerae Matrix, Morristown, NJ, United States, 2University of California, Davis, Davis, CA, United States, 3Respiratory Clinical Trials, London, United Kingdom, 4Heart Lungs Center, London, United Kingdom.
Objectives: MMI-0100 is a rationally-designed cell-penetrating peptide inhibitor of MK2, a terminal kinase in the TGFβ/p38 MAPK pathway implicated in inflammation and fibrosis. In multiple animal models conducted in diverse species, MMI-0100 consistently inhibits inflammation and fibrosis, in both prevention and treatment settings. LPS challenge is commonly used to assess drug anti-inflammatory activity. LPS responsiveness can be blunted in smokers, with suppressive effects of smoking (resembling endotoxin tolerance) restricted to lung. Pre-treatment with p38MAPK or NFκB translocation inhibitors and treatment with indomethacin restores LPS responsivity. Safety and efficacy of inhaled (IH) MMI-0100 was investigated in an LPS challenge study in smokers, with safety, group-level and responder analyses of primary sputum biomarker endpoints previously reported. Here, we present the extended pharmacodynamic (PD) effects and immunomodulatory activity of MMI-0100 revealed by the cross-over design, in both sputum and blood compartments.
Methods: An exploratory, double-blind, randomized, placebo-controlled LPS challenge study was conducted in smokers with normal lung function to assess effects of a single dosage (2.25mg) of IH MMI-0100 on anti-inflammatory and PD biomarkers of drug activity. A two-way cross-over design (21-42 day washout) allowed between- and within-subject comparisons, with period and sequence analyses conducted. Subjects received IH MMI-0100 or placebo daily for 5 days and then, post-washout, the opposite treatment; IH LPS (30µg) was given Day 5 each period. Biomarkers were evaluated in induced sputum (screening, Day 3, Day 5 post-LPS) and blood (Day 1 pre-treatment, Day 3 pre-/post-treatment, Day 5 pre-treatment/post-LPS).
Results: 20 subjects completed the study. On several biomarkers, MMI-0100 showed prolonged PD effect, despite the 21-42 day extended washout, and order of study treatment administration appeared to impact response to LPS challenge, in both analyte compartments. As one example, in period 1, blood IL-6 Day 5 post-LPS was significantly (p=0.006) lower in drug vs. placebo; blood IL-6 Day 5 post-LPS in period 1 placebo was significantly (p=0.01) different than period 2 placebo.
Conclusions: This first multi-day dosing study with IH MMI-0100 builds-upon the favorable safety and tolerability profile observed in preclinical pharmacology and safety studies and the single ascending dose clinical trial. The cross-over design reveals extended MMI-0100 PD activity, with immunomodulatory properties impacting LPS response on sputum and blood biomarkers. Consistent with p38 inhibitor literature, 5 days’ pretreatment with downstream MK2i MMI-0100 also restored sensitivity to LPS in lung, while inhibiting the systemic inflammatory response. When MMI-0100 was administered in period 1, effects persisted into period 2.