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Research ArticleDrug Discovery and Translational Medicine

CSF-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

Francois Pognan, Philippe Couttet, Ivan Demin, Birgit Jaitner, Yinuo Pang, Ronenn Roubenoff, Esther Sutter, Yoav Timsit, Marie Anne Valentin, Beate Vogel, Gaetane Woerly, Armin Wolf and Ursula Schramm
Journal of Pharmacology and Experimental Therapeutics March 20, 2019, jpet.118.254128; DOI: https://doi.org/10.1124/jpet.118.254128
Francois Pognan
1 Novartis Pharma AG;
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Philippe Couttet
1 Novartis Pharma AG;
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Ivan Demin
1 Novartis Pharma AG;
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Birgit Jaitner
1 Novartis Pharma AG;
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Yinuo Pang
2 Novartis Institutes for BioMedical Research
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Ronenn Roubenoff
1 Novartis Pharma AG;
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Esther Sutter
1 Novartis Pharma AG;
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Yoav Timsit
2 Novartis Institutes for BioMedical Research
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Marie Anne Valentin
1 Novartis Pharma AG;
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Beate Vogel
1 Novartis Pharma AG;
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Gaetane Woerly
1 Novartis Pharma AG;
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Armin Wolf
1 Novartis Pharma AG;
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Ursula Schramm
1 Novartis Pharma AG;
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Abstract

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1–dependent mechanisms are also involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 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. The majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free/unbound lacnotuzumab serum concentration–time profiles showed nonlinear PK across doses from 0.01 to 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, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.

  • drug discovery
  • monoclonal antibodies
  • pharmacodynamics
  • pharmacokinetics
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleDrug Discovery and Translational Medicine

CSF-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

Francois Pognan, Philippe Couttet, Ivan Demin, Birgit Jaitner, Yinuo Pang, Ronenn Roubenoff, Esther Sutter, Yoav Timsit, Marie Anne Valentin, Beate Vogel, Gaetane Woerly, Armin Wolf and Ursula Schramm
Journal of Pharmacology and Experimental Therapeutics March 20, 2019, jpet.118.254128; DOI: https://doi.org/10.1124/jpet.118.254128

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Research ArticleDrug Discovery and Translational Medicine

CSF-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

Francois Pognan, Philippe Couttet, Ivan Demin, Birgit Jaitner, Yinuo Pang, Ronenn Roubenoff, Esther Sutter, Yoav Timsit, Marie Anne Valentin, Beate Vogel, Gaetane Woerly, Armin Wolf and Ursula Schramm
Journal of Pharmacology and Experimental Therapeutics March 20, 2019, jpet.118.254128; DOI: https://doi.org/10.1124/jpet.118.254128
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