Codexis

As siRNA therapeutics expand into larger patient populations and commercial-scale indications, manufacturers face increasing pressure to deliver high-quality drug substance at greater scale, improve efficiency, and with improved sustainability. This case study highlights how Codexis and Bachem collaborated to advance RNA manufacturing through a modular, enzymatic approach that combines short-fragment synthesis with engineered ligases to overcome the limitations of traditional oligonucleotide manufacturing. Using vutrisiran as a model siRNA, the study demonstrates how optimized fragment and enzyme design via Codexis’s FragLinkSM can drive high ligation efficiencies, reduce purification burden, and enable scalable multi-kilogram GMP production. The result is a flexible manufacturing strategy that helps developers accelerate scale-up, improve manufacturing economics, and prepare for future commercial demand.

Enereductases (EREDs) and ketoreductases (KREDs) are highly selective enzymes that offer greener alternatives to more traditional asymmetric hydrogenation reactions. Enzyme cascades are a powerful way to enable more environmentally friendly and cost-effective synthetic processes for the manufacture of APIs. Here we report the discovery and development of an ERED/KRED biocatalytic cascade to enable efficient installation of the two stereocenters on a cyclohexyl ring for the synthesis of BMS-986278, a potent small-molecule LPA1 antagonist. A combination of protein engineering and process development optimized the cascade, resulting in orders of magnitude improvement over the original cascade proof-of-concept, and an over four-fold reduction in PMI over the first generation non-biocatalytic campaign for synthesis of the fragment. The synthesis of BMS-986278 was honored as a co-winner of the 2023 Peter J. Dunn award for Green Chemistry & Engineering Impact in the Pharmaceutical Industry, in large part because of the sustainability improvements enabled by this enzymatic cascade.

Mandy Vink, VP of Business Development at Codexis, explains how the company leverages over 20 years of expertise in small molecule APIs to advance biocatalysis across pharma.

Britton Jimenez, SVP of Sales and Marketing at Codexis, explains how the ECO Synthesis® Manufacturing Platform overcomes the limitations in scalability and sustainability that currently challenge the RNA therapeutics industry.