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词条 Heptavalent botulism antitoxin
释义

  1. History

      Development and domestic contracts    International contracts  

  2. Description

     Neutralizing efficacy  Side effects  HE-BAT 

  3. FDA clinical trials

  4. Use

     Indications  Administration 

  5. See also

  6. References

  7. External links

{{Use mdy dates|date=September 2016}}

The Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) (BAT) – BAT, made by Emergent BioSolutions Canada Inc. (formerly Cangene Corporation),[1] – is a licensed, commercially available botulism anti-toxin that effectively neutralizes all seven known botulinum nerve toxin serotypes (types A, B, C, D, E, F and G). It is indicated for sporadic cases of life-threatening botulism and is also stockpiled for the eventuality of botulinum nerve toxins being used in a future bioterrorist attack.[2]

BAT was approved in 2010 by the CDC for the indication of treating naturally occurring non-infant botulism on an investigational basis, replacing two earlier products. It was licensed for commercial marketing by the FDA in 2013.[3]

History

Development and domestic contracts

HBAT was developed from equine (horse) plasma at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The main funding stream was the Biomedical Advanced Research and Development Authority (within the US Department of Health and Human Services' Office of the Assistant Secretary for Preparedness and Response). It was then available for many years on an IND (investigational) basis from the US Centers for Disease Control and Prevention (CDC).[4]

On June 1, 2006, the DHHS awarded a $363 million contract to Emergent BioSolutions, (then Cangene Corporation) for 200,000 doses of HBAT over five years for delivery into the US Strategic National Stockpile (SNS).[5] The CDC began supplying doses to the SNS in 2007 under a now $427 million contract with the DHHS, according to a Cangene press release. In 2010, the CDC replaced the licensed bivalent botulinum antitoxin AB (BAT-AB) and the investigational monovalent botulinum antitoxin E (BAT-E) with HBAT when the former two products indications expired. This action left HBAT as the only botulinum antitoxin available in the US for naturally occurring non-infant botulism.[6]

On March 22, 2013, the US Food and Drug Administration (FDA) approved HBAT as the first product to treat all serotypes of botulism. This was considered a significant step in the US armamentarium for emergency use against a bioterrorist attack. The CDC continues to distribute the stockpiled antitoxin.[4]

The FDA approved HBAT for marketing based on its efficacy as established in animal studies (efficacy trials in humans not being considered feasible or ethical). The safety of the antitoxin, however, was established in a study of 40 healthy volunteers as well as in the experimental treatment of 228 patients in a CDC program.[7]

After the February 2014 acquisition of Cangene Corporation by Emergent BioSolutions, Emergent took control of Cangene's products and contracts, including BAT.[8] In March 2017, Emergent extended its contract with the Biomedical Advanced Research and Development Authority (BARDA), adding $53 million in value throughout 2022 for the production and bulk storage of BAT. Under the conditions of the extension, future transport of BAT to the SNS was approved. BAT remains the only recognized, licensed, and distributed botulism antitoxin within the Food and Drug Administration and the Centers for Disease Control and Prevention.[9]

International contracts

In 2012, Emergent signed a 10-year contract to provide BAT to the Canadian Department of National Defense and the Public Health Agency of Canada, as well as individual provincial health officials. In December 2016, Health Canada approved Emergent's New Drug Submission for BAT under the Extraordinary Use New Drug Regulations, which provide guidelines for consideration of drugs that do not have clinical information about impacts on humans due to the nature of the conditions that the drugs are used to treat. Pleased with Canada’s decision to prepare for botulinum toxin events, one of the "more likely biological threat agents", Adam Havey, executive vice president and president of the biodefense division at Emergent BioSolutions, said, "Emergent is committed to helping allied governments fulfill their preparedness needs. We expect to expand upon our longstanding relationship with the Canadian government and develop similar relations outside of North America..."[10]

Description

Neutralizing efficacy

HBAT is derived from "despeciated" equine IgG antibodies, which have had the Fc portion cleaved off, leaving the F(ab')2 portions. This process renders it less efficacious at neutralizing toxin than the other product{{snd}} trivalent botulinum antitoxin (TBAT){{snd}} available from local health departments (via the CDC) for treatment of wound and foodborne botulism. TBAT (effective against types A, B, and E) is derived from equine sources utilizing whole antibodies (Fab & Fc portions). But only HBAT is considered effective against all known strains of botulism (A, B, C, D, E, F, and G). These antitoxins neutralize only circulating toxin in patients with symptoms of botulism that are continuing to progress; they have no effect on toxin already bound to the nerve terminals. (This is not, however, considered a reason to withhold the product from any patient, even if treatment has been delayed.)[11]

Side effects

In CDC studies of HBAT, headache, fever, chills, rash, itching, and nausea were the most observed adverse events. It can trigger allergic reactions and delayed hypersensitivity reactions in people sensitive to horse proteins.[11]

HE-BAT

A related product{{snd}} Botulism AntiToxin, Heptavalent, Equine, Types A, B, C, D, E, F and G (HE-BAT){{snd}} is also available to the U.S. military under IND (experimental) protocols. This "equine" antitoxin requires skin testing with escalating dose challenges before full dose administration to obviate serious sensitivity to horse serum.[12]

FDA clinical trials

BAT has undergone extensive testing for effectiveness and safety. Emergent BioSolutions, in a 2017 document published to describe prescription information for BAT, said that the effectiveness of the antitoxin is based on efficacy studies that demonstrably prove increased chances of survival. In two clinical studies cited by the company, the safety profile of BAT was proven acceptable when one or two vials of the antitoxin were intravenously delivered to healthy subjects.[13]

Another clinical trial, the BT-011 study, known also as Pharmacokinetics of Botulism Antitoxin Heptavalent in Pediatric Patients, was initiated to test the success of BAT in children who had contracted botulism (or had been suspected of contracting botulism). In the study, one serum sample was collected from pediatric patients to analyze the pharmacokinetics of BAT to better adjust pediatric dosing recommendations. The details of the study from ClinicalTrials.gov, are as follows:[14]

- Masking: Open Label- Primary Purpose: Basic Science
ItemValue
First receivedJanuary 29, 2014
Last updatedAugust 19, 2016
Last verifiedAugust 2016
Study TypeInterventional
Study Design
Official TitlePharmacokinetics of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine)

(BAT™) in Pediatric Patients With a Confirmed or Suspected Exposure to

Botulinum Toxin

ConditionBotulism
InterventionBiological: collection of one 5 mL of blood
Purpose“The purpose of this study is to verify the pediatric dosing recommendations for BAT® in

pediatric patients that are treated with BAT® due to a confirmed or suspected case of

botulism. One 5 mL blood sample will be obtained within 24 hours post BAT®

administration. Study BT-011 will be run concurrently with the BAT patient registry (BT-010).”

Estimated Enrollment10
Study Start DateOctober 2014
Estimated Study Completion DateApril 2018
Estimated Primary Completion DateOctober 2017 (Final data collection date for primary outcome measure)
Ages Eligible for StudyUp to 16 years (child)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria - Informed consent/assent- Pediatric patients (preterm and term newborn infants, infants and toddlers, children, and adolescents up to age 16)- Confirmed or suspected exposure to botulinum toxin- Treatment with BAT® from the Strategic National Stockpile or from state stockpiles
Exclusion Criteria - Exclusion if blood sample cannot be collected within 24 hours of administration of the antitoxin- 5 mL blood sample volume may be considered unsafe based on the weight of the patient, calling for removal of the subject from study
ClinicalTrials.gov identifierNCT02051062

Use

Indications

HBAT is the only product available for treating botulism in adults, and for botulism in infants caused by botulinum toxins other than types A and B. HBAT has been used to treat a case of type F infant botulism and, on a case-by-case basis, may be used for future cases of non-type A and non-type B infant botulism.[15]

Administration

Early administration of HBAT is considered critical as the antitoxin can neutralize only circulating toxin, not toxin that has become bound to nerve terminals.

One vial (20 mL) of HBAT is administered to a patient as an intravenous infusion. It must be diluted with 0.9% sodium chloride in a 1:10 ratio before use. A volumetric infusion pump is used for slow administration (0.5 mL/min for the initial 30 minutes) to minimize the possibility of allergic reactions. If no reactions are noted, the rate is increased to 1 mL/min for another 30 minutes, and then if still no reaction is evident, to 2 mL/min for the remainder of the procedure.[16]

See also

  • Passive immunity
  • Antitoxin

References

1. ^{{Cite web|url=https://emergentbiosolutions.com/products#biologicalthreats|title=Biological Threats|last=|first=|date=|website=Emergent BioSolutions|archive-url=|archive-date=|dead-url=|access-date=2017-09-12}}
2. ^{{Cite web|url=http://www.centerforhealthsecurity.org/our-work/publications/botulinum-toxin-botulism-fact-sheet|title=Botulinum Toxin (Botulism)|last=|first=|date=|website=Center for Health Security|language=en|archive-url=|archive-date=|dead-url=|access-date=2017-09-12}}
3. ^https://pdfs.semanticscholar.org/c0ad/398c5a9d04fb5d0ba142cc1e601f3deb45e5.pdf
4. ^1 {{Cite web|url=https://webwiser.nlm.nih.gov/getSubstanceData.do?substanceId=437&displaySubstanceName=Clostridium%20botulinum%20toxin&STCCID=&UNNAID=&selectedDataMenuItemID=8&catId=85|title=WebWISER - Substance Data|website=webwiser.nlm.nih.gov|language=en|access-date=2017-09-12}}
5. ^{{Cite news|url=https://globenewswire.com/news-release/2017/03/31/947549/0/en/Emergent-BioSolutions-Signs-53-Million-Modification-to-BARDA-Contract-for-the-Manufacture-of-Botulism-Antitoxin.html|title=Emergent BioSolutions Signs $53 Million Modification to BARDA Contract for the Manufacture of Botulism Antitoxin|last=|first=|date=|work=GlobeNewswire News Room|access-date=2017-09-12|archive-url=|archive-date=|dead-url=|language=en-US}}
6. ^{{Cite news|url=https://globenewswire.com/news-release/2017/03/31/947549/0/en/Emergent-BioSolutions-Signs-53-Million-Modification-to-BARDA-Contract-for-the-Manufacture-of-Botulism-Antitoxin.html|title=Emergent BioSolutions Signs $53 Million Modification to BARDA Contract for the Manufacture of Botulism Antitoxin|last=|first=|date=|work=GlobeNewswire News Room|access-date=2017-09-12|archive-url=|archive-date=|dead-url=|language=en-US}}
7. ^https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm358200.pdf
8. ^{{Cite web|url=http://investors.emergentbiosolutions.com/phoenix.zhtml?c=202582&p=irol-newsArticle&ID=1902315|title=Emergent BioSolutions Completes Acquisition of Cangene Corporation|last=|first=|date=2014-02-21|website=investors.emergentbiosolutions.com|archive-url=|archive-date=|dead-url=|access-date=2017-09-12}}
9. ^{{Cite news|url=https://globenewswire.com/news-release/2017/03/31/947549/0/en/Emergent-BioSolutions-Signs-53-Million-Modification-to-BARDA-Contract-for-the-Manufacture-of-Botulism-Antitoxin.html|title=Emergent BioSolutions Signs $53 Million Modification to BARDA Contract for the Manufacture of Botulism Antitoxin|last=|first=|date=|work=GlobeNewswire News Room|access-date=2017-09-12|archive-url=|archive-date=|dead-url=|language=en-US}}
10. ^https://globenewswire.com/news-release/2016/12/12/896764/0/en/Emergent-BioSolutions-Receives-Health-Canada-Approval-for-Botulism-Antitoxin.html
11. ^1 https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM358262.pdf
12. ^USAMRIID (2011), >USAMRIID's Medical Management of Biological Casualties Handbook, 7th ed., U.S. Government Printing Office, pg. 126. {{ISBN|978-0-16-090015-0}}.
13. ^{{Cite web|url=https://emergentbiosolutions.com/sites/default/files/inline-files/2017-03-21_BAT%20USPI%20approved.pdf|title=Prescribing Information: BAT® [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine)] Sterile Solution for Injection|last=|first=|date=|website=Emergent BioSolutions|archive-url=|archive-date=|dead-url=|access-date=2017-09-12}}
14. ^{{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT02051062|title=BT-011 Pharmacokinetics of Botulism Antitoxin Heptavalent in Pediatric Patients - Full Text View - ClinicalTrials.gov|website=clinicaltrials.gov|language=en|access-date=2017-09-12}}
15. ^{{Cite web|url=http://www.biospace.com/News/fda-approves-cangene-corporations-treatment-for/291417|title=FDA Approves Cangene Corporations Treatment for Botulism|website=www.biospace.com|access-date=2017-09-12}}
16. ^{{Cite web|url=http://reference.medscape.com/drug/hbat-botulinum-antitoxin-heptavalent-999488|title=HBAT (botulinum antitoxin, heptavalent) dosing, indications, interactions, adverse effects, and more.|website=reference.medscape.com|language=en|access-date=2017-09-12}}

External links

  • CDC/MMWR (March 19, 2010): [https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5910a4.htm “Investigational Heptavalent Botulinum Antitoxin (HBAT) to Replace Licensed Botulinum Antitoxin AB and Investigational Botulinum Antitoxin E”].
  • FDA News Release (March 22, 2013): “FDA approves first Botulism Antitoxin for use in neutralizing all seven known botulinum nerve toxin serotypes”.

6 : Antitoxins|Immune system|Immunology|Medical treatments|Biological warfare|Botulism
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