Development of B8C1AD as an orphan drug for iatrogenic botulism
Ended Project Grant Awarded Last action
- Award ID
- R43NS130849
- Recipient
-
Cytodel, Inc. UEI C1AUXSRGH7W5
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $886,095
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Place of performance
- New York, USA
Award details come from USAspending.gov.
Description
- Abstract
- Botulinum neurotoxin serotype A1 (BONT/A1) has become an important therapeutic tool for multiple indications, despite being the most toxic protein known to science. Although serious adverse events (AES) are rare, their importance is recognized by the black box warning included in the labeling for all FDA-approved BONT/A1 products. During a recent 3-year period FDA received 13,087 AE reports specifically described as "overdose", primarily associated with therapeutic indications. Involving the treatment of large muscle groups (EG post-stroke spasticity, cerebral palsy and cervical dystonia). No treatment is available for BONT/A1-associated iatrogenic AES other than supportive care. The only available botulism therapeutic is an equine-derived antitoxin (BAT, emergent biosolutions) that cannot access the intraneuronal toxin protease responsible for iatrogenic symptoms, and is therefore of little use in treating AES associated with BONT/A1 overdose and off-target actions. We have developed a post-symptomatic antidote to BONT/A1 intoxication with an intraneuronal mechanism of action, designated B8C1AD. B8C1AD is produced by genetically fusing a single domain antibody (sdab, B8) to a recombinant atoxic derivative of BONT/C1 (C1AD for atoxic derivative) that acts as a molecular vehicle to deliver the B8 antibody to the neuronal cytoplasm where the BONT/A1 toxic protease resides. The B8 antibody was selected from a camelid VHH library for its potent inhibition of the BONT/A1 protease. B8C1AD has been demonstrated to effectively rescue animals with systemic BONT/A1 intoxication at times post-intoxication when conventional antibodies are ineffective, because they cannot access the intra-neuronal BONT/A1 LC protease. The safety and effectiveness of B8C1AD to reverse BONT/A1 intoxication symptoms and rescue animals has been published in three species, including non-human primates. We here propose establishing a model for BONT/A1 overdose via intramuscular administration of supratherapeutic doses, and developing B8C1AD as an orphan drug to treat off-target iatrogenic AES associated with the clinical use of BONT/A1 pharmaceutical products. Successful completion of the proposed studies will support assembly of a target product profile for B8C1AD, which will be shared with FDA to request a type C meeting for guidance on the regulatory pathway for B8C1AD approval as an orphan drug to treat iatrogenic overdose associated with BONT/A1 pharmaceuticals.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $295,365 | |
| Amendment | $295,365 | |
| Original award | $295,365 |
Quick answers
Who received award R43NS130849?
R43NS130849 was awarded to Cytodel, Inc. by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on January 1, 2023.
How much is award R43NS130849 worth?
$886,095 has been obligated on R43NS130849.
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