Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll‐like receptors 7 and 8

Abstract

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll‐like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), double‐blind, placebo‐controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single‐dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple‐dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo‐stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open‐label, one‐way crossover study in the 25 mg single‐dose cohort. Single‐ and multiple‐oral doses of enpatoran up to 200 mg were well tolerated and no significant dose‐limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose‐proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure‐dependent inhibition of ex vivo‐stimulated interleukin‐6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID‐19 pneumonia.

Applying Modeling and Simulations for Rational Dose Selection of Novel Toll‐Like Receptor 7/8 Inhibitor Enpatoran for Indications of High Medical Need

“…The population consisted of 72 White adults, 2 of whom were women, with a geometric mean age of 32 (range: 20–45) years and geometric mean body mass index of 25 (range: 20–29) kg/m 2 . The study was performed in accordance with international guidelines, including the Declaration of Helsinki and Council for International Organization of Medical Sciences International Ethical Guidelines, and was approved by the Ethics Committee of the Bavarian Chamber of Physicians, Munich, Germany 2 . All participants gave informed consent 2 …”

“…A phase I, randomized, double-blind, placebo-controlled, firstin-human, single and multiple ascending dose clinical study that assessed the safety, tolerability, PKs, and PDs of enpatoran in healthy participants was completed (NCT03676322). 2 During the study, preliminary population PK (PopPK) and PK/PD (PopPK/PD) models were developed from emerging enpatoran PK and PD data and updated in real-time to evaluate safety margins and guide dosing regimen adaptations during the study. Moreover, by integrating the PK and PD data across the investigated subjects and dose levels, the models captured and derived informative PK and PD characteristics of enpatoran in humans to support further clinical development.…”

Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019

“…A TLR7/8 antagonist, Enpatoran (M5049), is a potent dual TLR7/8 inhibitor that is expected to cease the hyperinflammatory milieu in symptomatic patients with COVID-19. Furthermore, Merck has already initiated a phase II randomized, controlled clinical study evaluating the efficacy and safety of M5049 in the COVID-19 patient population ( Khalifa and Ghoneim, 2021 ; Port et al, 2021 ). Similarly, famotidine, a specific histamine H2 receptor antagonist, can inhibit TLR3 expression in SARS-CoV-2 infected cells and reduce TLR3-dependent NF-κB and IRF3 signaling, subsequently controlling antiviral and inflammatory responses ( Mukherjee et al, 2021 ) and reducing the risk of intubation and death in hospitalized patients with COVID-19 ( Freedberg et al, 2020 ).…”

A glimpse into the future of systemic lupus erythematosus

“…When keeping the dose range of up to 5 mg/kg actual body weight and performing adequate regular ophthalmological safety examinations, including visual field testing and optical coherence tomography, hydroxychloroquine is a very safe drug with considerable long-term efficacy and benefits for cardiovascular risk as well. 110,111 Today’s standard 3 will likely remain the standard for hydroxychloroquine in 10 years, even though novel toll-like receptor (TLR) antagonists 112 may prove to be at least as effective and free of any retinopathy risks. Somewhat similarly, belimumab has gained an established position in keeping the disease controlled in patients who did not sufficiently respond to more basic measures, in reducing fatigue in a subset, and in doing so without relevantly increasing infections.…”