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Home / Equine Research Bank / Antimicrob Agents Chemother / Safety, Tolerability, and Pharmacokinetics of NTM-1632, a No...
Antimicrobial agents and chemotherapy2021; 65(7); e0232920; doi: 10.1128/AAC.02329-20

Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B.

Abstract: Botulism is a rare, life-threatening paralytic disease caused by Clostridium botulinum neurotoxin (BoNT). Available treatments, including an equine antitoxin and human immune globulin, are given postexposure and challenging to produce and administer. NTM-1632 is an equimolar mixture of 3 human IgG monoclonal antibodies, B1, B2, and B3, targeting BoNT serotype B (BoNT/B). This first-in-human study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of NTM-1632. This double-blind, single-center, placebo-controlled dose escalation study randomized 3 cohorts of healthy volunteers to receive a single intravenous dose of NTM-1632 (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-1632; 6 placebo), and no deaths or serious adverse events were reported. Adverse events in the NTM-1632 groups were generally mild and similar in frequency and severity to the placebo group, and no safety signal was identified. NTM-1632 has a favorable PK profile with a half-life of >20 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-1632 demonstrated low immunogenicity with only a few treatment-emergent antidrug antibody responses in the low and middle dosing groups and none at the highest dose. NTM-1632 is well tolerated at the administered doses. The favorable safety, PK, and immunogenicity profile of NTM-1632 supports further clinical development as a treatment for BoNT/B intoxication and postexposure prophylaxis. (This study has been registered at ClinicalTrials.gov under identifier NCT02779140.).
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Publication Date: 2021-06-17 PubMed ID: 33875433PubMed Central: PMC8218613DOI: 10.1128/AAC.02329-20Google Scholar: Lookup
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  • Journal Article
  • Randomized Controlled Trial
  • Research Support
  • N.I.H.
  • Extramural

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study primarily investigated the safety, tolerance, and pharmacokinetics of NTM-1632, a mixture of three human antibodies, proposed as a treatment for botulism. The findings reveal high tolerance and low immunogenicity among healthy volunteers, encouraging further research and development of NTM-1632 as a potential treatment.

Research Context and Rationale

  • Botulism is a severe disease caused by the neurotoxin of Clostridium botulinum (BoNT), a bacteria that interrupts neural signal transmission, resulting in paralytic symptoms. Current treatments consist of equine antitoxin and human immune globulin, but these have limitations, including challenging production and administration processes.
  • NTM-1632 is a novel treatment. It consists of an equimolar mixture of three human IgG antibodies, B1, B2, and B3, targeting the BoNT of serotype B (BoNT/B).
  • This study aimed to understand the safety, tolerability, pharmacokinetics (the body’s process of drug absorption, distribution, metabolism, and excretion), and immunogenicity (ability to induce an immune response) of NTM-1632 in humans.

Study Design and Methodology

  • A single-center, double-blind, placebo-controlled dose escalation study was conducted with 24 healthy volunteers. The study setup allowed for concealed subject and observer identities, reducing bias and ensuring placebo control.
  • The volunteers were divided into three cohorts, each receiving different doses of NTM-1632 (0.033, 0.165, or 0.330 mg/kg) or a saline placebo via intravenous injection.
  • Various safety parameters, like physical examinations, vital signs, and clinical laboratory studies, were evaluated. The pharmacokinetics and immunogenicity of NTM-1632 were studied via blood sampling at predefined time points.

Findings

  • Across the 24 participants, no severe adverse events, including deaths, were reported. Adverse events recorded were deemed mild and were similar between the NTM-1632 and placebo groups, suggesting good tolerance of the drug.
  • Pharmacokinetics showed that NTM-1632 had a half-life of over 20 days at the highest dosage (0.330 mg/kg). This information indicates the time the drug concentration takes to reduce by half in the body, providing insights into the drug’s duration and intensity of effect.
  • The study also confirmed the proportionality between dosage and drug concentration in the body, suggesting a linear relationship.
  • Immunogenicity assessment revealed that the drug induced minimal immune response. Few treatment-emergent antidrug immune responses were seen in low and middle dosing groups and none in the highest dose group.

Significance and Implications

  • This study shows that NTM-1632 is well-tolerated, with a favorable safety profile and advantageous pharmacokinetics — key factors contributing to a drug’s effectiveness and viability.
  • Due to its low immunogenicity, there’s a lower risk of potentially harmful immune responses being produced against NTM-1632.
  • These findings support the further clinical development of NTM-1632 as a potential treatment for BoNT/B intoxication and postexposure prophylaxis in botulism. However, comprehensive efficacy studies are needed to solidify these initial results.

Cite This Article

APA
Guptill JT, Raja SM, Juel VC, Walter EB, Cohen-Wolkowiez M, Hill H, Sendra E, Hauser B, Jackson P, Swamy GK. (2021). Safety, Tolerability, and Pharmacokinetics of NTM-1632, a Novel Mixture of Three Monoclonal Antibodies against Botulinum Toxin B. Antimicrob Agents Chemother, 65(7), e0232920. https://doi.org/10.1128/AAC.02329-20

Publication

Antimicrobial agents and chemotherapy
ISSN: 1098-6596
NlmUniqueID: 0315061
Country: United States
Language: English
Volume: 65
Issue: 7
Pages: e0232920
PII: e02329-20

Researcher Affiliations

Guptill, J T
  • Department of Neurology, Duke University, Durham, North Carolina, USA.
  • Duke Clinical Research Institute, Durham, North Carolina, USA.
  • Duke Early Phase Clinical Research Unit, Durham, North Carolina, USA.
Raja, S M
  • Department of Neurology, Duke University, Durham, North Carolina, USA.
  • Duke Early Phase Clinical Research Unit, Durham, North Carolina, USA.
Juel, V C
  • Department of Neurology, Duke University, Durham, North Carolina, USA.
Walter, E B
  • Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
  • Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Cohen-Wolkowiez, M
  • Duke Clinical Research Institute, Durham, North Carolina, USA.
  • Duke Early Phase Clinical Research Unit, Durham, North Carolina, USA.
  • Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
Hill, H
  • The EMMES Corporation, Rockville, Maryland, USA.
Sendra, E
  • The EMMES Corporation, Rockville, Maryland, USA.
Hauser, B
  • Duke Early Phase Clinical Research Unit, Durham, North Carolina, USA.
Jackson, P
  • Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
Swamy, G K
  • Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
  • Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, North Carolina, USA.

MeSH Terms

  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / therapeutic use
  • Botulism / drug therapy
  • Double-Blind Method
  • Healthy Volunteers
  • Humans
  • Immunoglobulin G

Grant Funding

  • K23 NS085049 / NINDS NIH HHS
  • UL1TR002553 / HHS | NIH | National Center for Advancing Translational Sciences (NCATS)
  • UL1 TR002553 / NCATS NIH HHS
  • HHSN272201500002C / NIAID NIH HHS
  • K23NS085049 / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
  • HHSN272201300017C / NIAID NIH HHS
  • HHSN272201300017I / NIAID NIH HHS

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Citations

This article has been cited 7 times.
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