First-in-Human Clinical Trial to Assess the Safety, Tolerability and Pharmacokinetics of Single Doses of NTM-1633, a Novel Mixture of Monoclonal Antibodies against Botulinum Toxin E
2022 Apr 19
Journal Article
Authors:
Raja, S.M.;
Guptill, J.T.;
Juel, V.C.;
Walter, E.B.;
Cohen-Wolkowiez, M.;
Hill, H.;
Sendra, E.;
Hauser, B.;
Jackson, P.;
Tomic, M.;
Espinoza, Y.;
Swamy, G.K.
Secondary:
Antimicrob Agents Chemother
Volume:
66
Pagination:
e0173221
Issue:
4
PMID:
35311524
URL:
https://pubmed.ncbi.nlm.nih.gov/35311524/
Keywords:
Animals; Antibodies, Monoclonal; Botulinum Toxins; Botulism; Double-Blind Method; Horses; Humans; Immunoglobulin G
Abstract:
Botulism is a rare, life-threatening paralytic disease caused by botulinum neurotoxin (BoNT). Available treatments including an equine antitoxin and human immune globulin are given postexposure and challenging to produce and administer. NTM-1633 is an equimolar mixture of 3 human IgG monoclonal antibodies, E1, E2, and E3, targeting BoNT serotype E (BoNT/E). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1633. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1633 (0.033, 0.165, or 0.330 mg/kg) or saline placebo. Safety monitoring included physical examinations, clinical laboratory studies, and vital signs. Blood sampling was performed at prespecified time points for PK and immunogenicity analyses. Twenty-four subjects received study product (18 NTM-1633; 6 placebo), and no deaths were reported. An unrelated serious adverse event was reported in a placebo subject. Adverse events in the NTM-1633 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1633 has a favorable PK profile with a half-life >10 days for the 0.330 mg/kg dose and an approximately linear relationship with respect to maximum concentration and area under the concentration-time curve (AUC). NTM-1633 also demonstrated low immunogenicity. NTM-1633 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile supports further development as a treatment for BoNT/E intoxication and postexposure prophylaxis.
