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P135 A phase I, first-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of M5049, a dual antagonist of TLR7/8, in healthy subjects
  1. Andreas Port1,
  2. Lena Klopp-Schulze1,
  3. Jamie Shaw2,
  4. Elizabeth Hussey2,
  5. Nadra Mammasse3,
  6. Ying Zhang4,
  7. Angelika Bachmann1,
  8. Christian Reh5 and
  9. Kosalaram Goteti2
  1. 1Translational Medicine, Merck KGaA, Darmstadt, Germany
  2. 2Translational Medicine
  3. 3Biostatistics, Cytel, Paris, France
  4. 4Global Patient Safety, EMD Serono Research and Development Institute*, Billerica, USA
  5. 5Nuvisan GmbH, Neu-Ulm, Germany
  6. *A business of Merck KGA, Darmstadt, Germany


Background Toll-like receptors 7 and 8 (TLR7/8) are widely expressed in a variety of immune cells and detect single-stranded RNAs, activating signalling cascades which trigger an immune response. Aberrant TLR7/8 activation by RNA-containing autoantibodies can result in autoimmunity. M5049 is an oral small molecule TLR7/8 antagonist which inhibits TLR7/8 activity in vitro and ex vivo and has demonstrated efficacy in mouse SLE models, suggesting potential to inhibit pathological immune complex activities in SLE patients.

Methods This was a phase I, randomized, double-blind, placebo-controlled (3:1), single and multiple ascending dose (SAD and MAD) study of oral M5049 conducted in healthy participants. SAD cohorts received a single dose of M5049 (1, 3, 9, 25, 50, 100 and 200 mg) or placebo, and MAD cohorts received M5049 (9, 25, 200 mg once daily, 25 and 50 mg twice daily) or placebo for 14 days. A sentinel dosing strategy was used in SAD cohorts. The study assessed safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (ex vivo-stimulated cytokine secretion). Food effect was assessed in the 25 mg SAD cohort.

Results Preliminary results showed that M5049 was well-tolerated over the dosing interval, with no significant or dose-limiting adverse events observed to date. PK parameters were linear and dose-proportional from 1 to 200 mg, with higher clearance and shorter half-life than predicted based on preclinical studies. Exposure-dependent inhibition of ex vivo-stimulated IL-6 secretion was observed, with maximum inhibition achieved at 200 mg. PK results indicate a slight food effect.

Conclusions M5049 was well-tolerated with no safety signals in healthy participants, warranting further investigation as a potential treatment for autoimmune diseases, such as SLE.

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