Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2018 Oct;104(4):655-663.
doi: 10.1002/cpt.1111. Epub 2018 Jul 13.

A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway

Johann Bartko  1   2 , Christian Schoergenhofer  1 , Michael Schwameis  1 , Christa Firbas  1 , Martin Beliveau  3 , Colin Chang  3 , Jean-Francois Marier  3 , Darrell Nix  4 , James C Gilbert  5 , Sandip Panicker  6 , Bernd Jilma  1
Affiliations
Clinical Trial

A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway

Johann Bartko et al. Clin Pharmacol Ther. 2018 Oct.

Abstract

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibody-mediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complement-mediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase I, first-in-human, double-blind, randomized, placebo-controlled, dose-escalation trial of single and multiple doses of sutimlimab or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of sutimlimab were well tolerated without any safety concerns. sutimlimab exhibited a steep concentration-effect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 μg/mL. This study establishes the foundation for using sutimlimab as a highly selective inhibitor of the classical complement pathway in different diseases.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Flow diagram. [Color figure can be viewed at http://cpt-journal.com]
Figure 2
Figure 2
(a) Mean (+SE) serum concentrations of sutimlimab vs. time following a single 60‐minute i.v. infusion of sutimlimab in healthy volunteers (part A). (b) Mean (+SE) serum trough concentrations of sutimlimab vs. time following weekly 60‐minute i.v. infusions of sutimlimab (part B).
Figure 3
Figure 3
Individual body weight vs. PK parameters (parts A and B). AUC, area under the concentration–time curve; MAD, multiple ascending doses; Cmax, maximum serum concentration; HL, half‐life.
Figure 4
Figure 4
(a) Mean (+SE) serum classical complement pathway (CP) activity vs. time following a single 60‐minute i.v. infusion of sutimlimab in healthy volunteers (part A). (b) Mean (+SE) serum trough CP activity vs. time following single or weekly 60‐minute i.v. infusions of sutimlimab (part B).
Figure 5
Figure 5
Relationship between concentrations of sutimlimab and CP activity: parts A and B.
See this image and copyright information in PMC

References

    1. Shi, J. et al TNT009, a classical complement pathway specific inhibitor, prevents complement dependent hemolysis induced by cold agglutinin disease patient autoantibodies. Blood 122, 42 (2013).
    1. Colonna, L. , Parry, G.C. , Panicker, S. & Elkon, K.B. Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. Clin. Immunol. 163, 84–90 (2016). - PMC - PubMed
    1. Derhaschnig, U. , Gilbert, J. , Jager, U. , Bohmig, G. , Stingl, G. & Jilma, B. Combined integrated protocol/basket trial design for a first‐in‐human trial. Orphanet J. Rare Dis. 11, 134 (2016). - PMC - PubMed
    1. Meulenbroek, E.M. , Wouters, D. & Zeerleder, S.S. Lyse or not to lyse: clinical significance of red blood cell autoantibodies. Blood Rev. 29, 369–376 (2015). - PubMed
    1. Reynaud, Q. et al Efficacy and safety of rituximab in auto‐immune hemolytic anemia: a meta‐analysis of 21 studies. Autoimmun. Rev. 14, 304–313 (2015). - PubMed

Publication types

MeSH terms