A phase 1 study in healthy participants to characterize the safety and pharmacology of inclacumab, a fully human anti-P-selectin antibody, in development for treatment of sickle cell disease.

Abstract

PURPOSE:

We evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody in development for the treatment of sickle cell disease, at doses up to and exceeding those previously tested in healthy individuals.

METHODS:

In this phase 1, open-label, single-ascending-dose study, 15 healthy participants were enrolled into cohorts receiving 20 mg/kg (n = 6) or 40 mg/kg (n = 9) IV inclacumab and observed for up to 29 weeks post-dose. Safety, PK parameters, thrombin receptor-activating peptide (TRAP)-activated platelet-leukocyte aggregate (PLA) formation, P-selectin inhibition, plasma soluble P-selectin, and anti-drug antibodies were characterized.

RESULTS:

Two inclacumab-related treatment-emergent adverse events were reported in 1 participant; no dose-limiting toxicities were observed. Plasma PK parameters were generally dose-proportional, with a terminal half-life of 13 to 17 days. Mean TRAP-activated PLA formation decreased within 3 h from the start of infusion, and inhibition was sustained for ~ 23 weeks. Mean P-selectin inhibition > 90% was observed up to 12 weeks post-dose. The mean ratio of free to total soluble P-selectin decreased rapidly from pre-dose to end of infusion, then increased gradually to 78% of the baseline ratio by week 29. Treatment-emergent anti-drug antibodies were observed in 2 of 15 participants (13%), without apparent impact on safety, PK, or PD.

CONCLUSIONS:

Inclacumab was well tolerated, with PK as expected for a monoclonal antibody against a membrane-bound target and a long duration of PD effects after both single IV doses, supporting a prolonged dosing interval.

TRIAL REGISTRATION:

ACTRN12620001156976; registered November 4, 2020.

• Authors: Christina Lourdes Mayer, Kathleen Koeck, Margot Hottmann, Andrew Redfern, Mark Davis, Aline Barth, Xin Geng, Carolyn Hoppe, Patrick Yue
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 79 Issue 9 Pg. 1219-1228 (Sep 2023) ISSN: 1432-1041 [Electronic] Germany
• PMID: 37436495 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• inclacumab
• Antibodies, Monoclonal
• Selectins
• Polyesters

Topics

• Humans
• Healthy Volunteers
• Antibodies, Monoclonal (adverse effects)
• Anemia, Sickle Cell (drug therapy, chemically induced)
• Selectins
• Polyesters
• Double-Blind Method
• Dose-Response Relationship, Drug