Hi1a is a disulfide-rich spider-venom peptide inhibitor of acid-sensing ion channel 1a (ASIC1a). Its advancement toward therapeutic use required simultaneous attention to pharmacology, developability and scalable manufacture. We describe an integrated strategy that combined parallel CMC evaluation, chemical peptide synthesis and cyclic-peptide optimisation to progress the ASIC1a programme toward clinical candidate selection.
Five commercial recombinant-expression and pilot-scale production approaches were evaluated in parallel. The platforms were assessed for product quality, correct folding, functional activity, process reproducibility, downstream-processing requirements, scalability and anticipated manufacturability. These studies supported selection of a preferred production route for further development. Chemical synthesis generated sufficient Hi1a material to enable expanded dose-ranging and pharmacology studies, which refined the programme’s target product profile and highlighted requirements for additional candidate optimisation.
In parallel, 12 cyclic peptides licensed from The University of Queensland, originally identified through rapid screening at the University of Tokyo, were assessed as alternative starting points. Initial peptides demonstrated promising activity but required optimisation to address off-target pharmacology and improve their overall development profile. Iterative design and testing were used to balance ASIC1a potency and selectivity with biological stability, chemical stability and other key developability attributes.
IB409 was selected as the clinical candidate based on an integrated assessment of pharmacology, selectivity, stability and CMC suitability. The programme demonstrates the value of identifying manufacturing and dose-response risks early, and of maintaining multiple chemical and biological solution paths when translating complex venom-derived peptides into drug candidates