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.