Merck Advances Scalable Manufacturing for Oral PCSK9 Therapy

Merck & Co. has published new research in Science describing a scalable biocatalytic synthesis platform for enlicitide decanoate, the company’s investigational oral PCSK9 inhibitor for lowering low-density lipoprotein cholesterol (LDL-C). The work addresses longstanding manufacturing challenges associated with macrocyclic peptide therapeutics and may represent a broader advancement in scalable peptide drug development.³

According to the publication, Merck researchers used a tailored suite of enzymes to enable selective peptide fragment formation, coupling, and macrocyclization during synthesis of enlicitide. The process also incorporates crystallization-based purification techniques intended to support large-scale manufacturing while reducing reliance on more resource-intensive traditional synthetic chemistry methods.

Overcoming Challenges in Macrocyclic Peptide Development

Macrocyclic peptides have attracted increasing interest across the pharmaceutical industry because of their ability to target protein-protein interactions often inaccessible to conventional small molecules. However, manufacturing complexity and poor oral bioavailability have historically limited broader adoption of peptide-based therapeutics.⁵

Merck’s findings suggest advances in biocatalysis may help overcome some of these limitations by enabling more selective and sustainable synthesis pathways for complex peptide medicines.

“The scalable production process for enlicitide described in this publication showcases Merck’s scientific capabilities and underscores our sustained commitment to helping address the global cardiovascular epidemic,” Dean Y. Li, MD, president of Merck Research Laboratories, said in the company announcement.³

Potential Impact of Oral PCSK9 Inhibition

Enlicitide is being developed as a once-daily oral PCSK9 inhibitor designed to reduce LDL-C levels through the same biological pathway targeted by currently marketed injectable monoclonal antibody therapies. PCSK9 regulates LDL receptor degradation, and inhibition of the protein increases receptor availability for clearing LDL cholesterol from circulation.

Existing PCSK9-targeting biologics, including evolocumab and alirocumab, have demonstrated substantial LDL-C lowering and cardiovascular risk reduction in major clinical trials, but injectable administration has created adherence and accessibility challenges for some patients.⁴ An oral PCSK9 inhibitor could potentially broaden uptake among patients requiring intensive lipid management, particularly those with high-risk atherosclerotic cardiovascular disease.

Interest in oral PCSK9 therapies continues to grow as cardiovascular disease remains the leading cause of mortality globally. Despite widespread statin use, many patients remain above recommended LDL-C targets, sustaining demand for additional lipid-lowering therapies.²

Broader Implications for Biocatalysis

Merck’s announcement also reflects a broader industry shift toward biocatalysis as pharmaceutical manufacturers pursue greener and more efficient production methods. Biocatalytic approaches use engineered enzymes to facilitate chemical transformations under milder conditions, often reducing waste generation while improving stereoselectivity compared with conventional synthetic chemistry.

Over the past two decades, enzyme-enabled synthesis has become increasingly integrated into pharmaceutical manufacturing, particularly for complex molecules requiring precise stereochemical control.¹ Application of these methods to macrocyclic peptide assembly, however, remains relatively novel because of the structural complexity of cyclic peptide scaffolds.

The Science publication may have implications beyond enlicitide itself by offering a potential framework for future oral macrocyclic peptide programs targeting difficult intracellular or extracellular protein interactions.

If approved, enlicitide could become the first oral PCSK9 inhibitor available for clinical use, potentially reshaping lipid management and preventive cardiology.

References

1. Bornscheuer, U. T., Huisman, G. W., Kazlauskas, R. J., Lutz, S., Moore, J. C., & Robins, K. (2012 May 9). Engineering the third wave of biocatalysis. Nature. https://doi.org/10.1038/nature11117
   
2. Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., ... ESC Scientific Document Group. (2020 Jan 1). 2019 ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal. https://doi.org/10.1093/eurheartj/ehz455
   
3. Merck & Co., Inc. (2026, May 7). Merck scientists publish landmark paper on novel method for large-scale biocatalytic synthesis of investigational oral PCSK9 inhibitor, enlicitide decanoate. Merck. https://www.merck.com/news/merck-scientists-publish-landmark-paper-on-novel-method-for-large-scale-biocatalytic-synthesis-of-investigational-oral-pcsk9-inhibitor-enlicitide-decanoate/
   
4. Sabatine, M. S., Giugliano, R. P., Keech, A. C., et al. (2017 May 4). Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. https://doi.org/10.1056/NEJMoa1615664
   
5. Vinogradov, A. A., Yin, Y., & Suga, H. (2019 Feb 15). Macrocyclic peptides as drug candidates: Recent progress and remaining challenges. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.8b13178