Toll-like receptors 7 and 8 (TLR7/8) detect single-stranded viral RNA, initiating immune cell activation, differentiation, cytokine secretion, antibody production and NETosis. M5049, a highly potent and selective TLR7/8 inhibitor, is being investigated for autoimmune conditions such as SLE, in which aberrant TLR7/8 activation by endogenous RNA is implicated.
Compound potency was optimized in TLR7/8-stimulated cells. Pharmacokinetic and pharmacodynamic (PK/PD) activity and efficacy in lupus models were assessed in mice. Population PK/PD models were developed from first-in-human (FIH) data of M5049 in healthy participants receiving single or multiple daily doses from 1–200mg (NCT03676322). Dose simulations were performed to identify regimens achieving target PD inhibition with adequate safety margins.
In mice, M5049 demonstrated dose-dependent inhibition of cytokine release, long duration of action, and ≥1mg/kg suppressed disease development in BXSB-Yaa and interferon-α accelerated NZB/W lupus models. In humans, simulations suggested 25 and 100mg M5049 twice daily (BID) would maintain concentrations above 60% and 90% PD (cytokine) inhibition, respectively, throughout the dosing interval. Supported by non-clinical and FIH safety data, M5049 doses of 25mg and up to 150mg BID are investigated to assess safety, PK and PD in lupus patients.
M5049 effectively reduces lupus pathogenesis in mice. Based on PK, PD and safety data from a successfully completed FIH study, and model-informed dose selection guided by preclinical knowledge, a Phase Ib study was initiated investigating oral M5049 as a novel therapy for SLE and CLE patients (NCT04647708).
Acknowledgements: Merck KGaA, Darmstadt, Germany, fund M5049 development. Bioscript, Macclesfield, UK, provided medical editing support.