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

• Published in: Antimicrobial agents and chemotherapy Vol. 66; no. 4; p. e0173221
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 19.04.2022
• Subjects: Animals; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antimicrobial Chemotherapy; Botulinum Toxins; Botulism; Double-Blind Method; Experimental Therapeutics; Horses; Humans; Immunoglobulin G; clinical trials; Clostridium botulinum; monoclonal antibodies
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.01732-21

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. 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 0→t ). 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.