Pognan, Francois, Couttet, Philippe, Demin, Ivan, Jaitner, Birgit, Pang, Yinuo, Roubenoff, Ronenn, Sutter, Esther, Timsit, Yoav, Valentin, Marie-Anne, Vogel, Beate Elisabeth, Woerly, Gaetane, Wolf, Armin and Schramm-Franz, Ursula (2019) CSF-1 antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes. Journal of Pharmacology and Experimental Therapeutics. ISSN 118.254128

Abstract

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1–dependent mechanisms are involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti–CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. The presentedThis phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetic (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01 to 20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5x the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. At all doses, theThe majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Serum-fFree/unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK s across doses from 0.01–20 mg/kg, with faster apparent elimination at lower doses or concentrations; this was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, non-pathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.

Item Type:	Article
Date Deposited:	16 Apr 2019 00:45
Last Modified:	16 Apr 2019 00:45
URI:	https://oak.novartis.com/id/eprint/36785