Breaking the Stapled Peptide Bottleneck: WuXi AppTec's WuXi TIDES Delivers Kilogram-Scale GMP API in 8 Months

A Phase 2 triple stapled peptide project that stalled at another CDMO was transferred to WuXi AppTec. Through integrated WuXi TIDES execution — in-house UAA supply in 6 weeks, re-engineered RCM lifting crude purity 33%, and a metal-scavenging step cutting residual ruthenium ~75-fold — kilogram-scale GMP API was delivered in 8 months and Phase 2 CTM released in 11.

Peptide therapeutics have become an increasingly important modality, with over 100 peptide drugs now on the market globally. Stapled peptides improve drug-like properties by constraining conformation through macrocyclization such as ring-closing olefin metathesis (RCM), stabilizing the alpha-helical structures central to protein-protein interactions. Yet clinical-scale manufacturing faces CMC challenges — unnatural amino acid (UAA) sourcing, RCM conversion and metal residue control. One biotech's Phase 2 triple stapled peptide suffered low and unstable yield, high catalyst loading and difficult catalyst residue control, while also requiring an ultra-high concentration injectable formulation and timely clinical trial material (CTM) delivery.

After extensive challenges at another CDMO, the molecule was transferred to WuXi AppTec, where the WuXi TIDES team applied an integrated approach. The team developed in-house synthetic routes for two non-commercial UAAs, delivering 25 kg of >99% purity UAA within 6 weeks and removing external supply uncertainty. In parallel, it re-engineered the RCM process — optimizing the solvent system, substrate concentration and catalyst addition strategy — improving conversion under strong conformational constraints, reducing catalyst burden and lifting crude purity by 33%.

For residual-ruthenium control, a pre-column metal-scavenging step before prep-HPLC cut residual ruthenium in the final API by ~75-fold versus the crude, while extending column life and shortening the purification cycle by 30%. Final yield more than doubled and several kilograms of GMP API were delivered within 8 months — a material improvement in both process performance and clinical supply readiness for a complex triple-stapled peptide with sequential RCM and demanding metal-residue control.

Speed also came from parallel CMC execution: analytical method development and validation advanced alongside GMP API scale-up, and the drug product team screened 30+ formulation prototypes within ~5 weeks, achieving a stable injectable peptide solution above 100 mg/mL. With UAA supply, API process optimization, analytical work, formulation and CTM manufacturing advancing without idle time, CTM manufacturing, packaging and release were completed within 3 months, and the overall program — from onboarding to Phase 2 CTM release — took 11 months.