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Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase 1 dose escalation study in healthy volunteers receiving LPS.

Abstract: Toll-like receptor-4 (TLR4) pathways are major contributors to pathological inflammatory responses induced by tissue damage. NI-0101 is the first monoclonal antibody (mAb) blocking TLR4 signaling. This activity is independent of the ligand type and concentration, therefore, potentially blocking any TLR4 ligands. A phase I single ascending dose study was conducted in 73 healthy volunteers to evaluate NI-0101 tolerability, preliminary safety, pharmacokinetics (PKs), and pharmacodynamics (PDs), in absence and in presence of a systemic challenge with lipopolysaccharide (LPS), a TLR4 ligand. NI-0101 was well tolerated without safety concern. The PK profile was characterized by a half-life of ∼10 days at high concentrations and by a rapid elimination at low concentrations due to expected target-mediated drug disposition. NI-0101 prevented cytokine release following ex vivo and in vivo LPS administration and prevented the C-reactive protein (CRP) increase and the occurrence of flu-like symptoms expected following the in vivo administration of LPS.

Full Reference: Monnet, E., Lapeyre, G., Poelgeest, E. v., Jacqmin, P., Graaf, K. d., Reijers, J., Moerland, M., Burggraaf, J. and Min, C. d. (2017), Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin. Pharmacol. Ther., 101: 200–208. doi:10.1002/cpt.522

Link to full text: http://onlinelibrary.wiley.com/doi/10.1002/cpt.522/abstract

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