Researchers created tricyclic peptide pills that lower LDL cholesterol in monkeys just as well as the injectable PCSK9 antibody drugs already on the market.
Equivalent LDL lowering to approved antibodiesAchieved via oral dosing in monkeys — a first for macrocyclic peptide PCSK9 inhibitors
What the researchers found
Starting from earlier lead compounds, the researchers optimized a series of bi- and tricyclic peptide structures to create compound 44, which demonstrated sufficient oral bioavailability in both rats and cynomolgus monkeys to maintain therapeutic blood levels using an enabled formulation.
When tested in monkeys, the optimized peptides achieved target engagement and LDL cholesterol lowering essentially identical to the clinically approved injectable PCSK9 antibodies (evolocumab and alirocumab). This represents the first demonstration that macrocyclic peptides can match antibody-level efficacy through oral delivery for this target.
Why it matters
Millions of people worldwide take injectable PCSK9 antibodies like Repatha (evolocumab) and Praluent (alirocumab) to manage high cholesterol and reduce heart disease risk. However, the need for regular injections limits who is willing to use them. A once-daily oral pill that works just as well could dramatically increase the number of patients who benefit from PCSK9-targeted therapy, similar to how statins became widely used because of their convenience.
The numbers in context
Oral bioavailability in 2 species; LDL lowering equivalent to approved antibodies; once-daily oral potential; compound 44 lead candidate
How the study worked
This was a medicinal chemistry optimization study. The team designed and synthesized a series of bi- and tricyclic peptide PCSK9 inhibitors, refining their chemical structures to improve potency and oral absorption. They used X-ray crystallography to understand how the peptides bind their target. The best candidates were tested in rats and cynomolgus monkeys for oral bioavailability, and the lead compound was evaluated in monkeys for its ability to engage PCSK9 and lower LDL cholesterol levels.
Who was studied
Rats and cynomolgus monkeys
What this study cannot tell us
All testing was done in animals (rats and monkeys), with no human data yet available. The oral formulation required special 'enabled' delivery technology, meaning a standard pill might not work. Long-term safety has not been established. Sample sizes for the animal studies were not specified in the abstract, and it remains to be seen whether the results will translate to humans.
How to read the evidence
This study has a 'strong' evidence rating for preclinical work because it demonstrated efficacy in two animal species with a clinically relevant endpoint (LDL cholesterol lowering) and benchmarked results against approved therapies. However, no human data exist yet.
When this study was published
Published in 2021 in the Journal of Medicinal Chemistry. The oral PCSK9 peptide inhibitor field has continued to advance, and these compounds may be progressing toward clinical development.
The bigger picture
This work sits at the cutting edge of peptide drug delivery — the long-standing challenge of making peptides survive the gut and reach the bloodstream. If successful in humans, oral PCSK9 peptide inhibitors could join the growing wave of oral peptide drugs (like oral semaglutide) that are replacing injectable treatments. It also validates macrocyclic peptide chemistry as a platform for targeting protein-protein interactions that were previously considered 'undruggable' by small molecules.
Questions still open
- Will these tricyclic peptides maintain their oral bioavailability and cholesterol-lowering efficacy in human clinical trials?
- Can the 'enabled formulation' be manufactured at scale and at a competitive cost compared to injectable antibodies?
- How will the long-term safety profile of daily oral PCSK9 peptide inhibitors compare to the established biweekly antibody injections?
Common questions
What is PCSK9 and why does blocking it lower cholesterol?
How is an oral peptide different from injectable PCSK9 antibodies like Repatha?
Read the original research
A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.
Journal of medicinal chemistry, 64(22), 16770-16800
Citation
Tucker, Thomas J; Embrey, Mark W; Alleyne, Candice; Amin, Rupesh P; Bass, Alan; Bhatt, Bhavana; Bianchi, Elisabetta; Branca, Danila; Bueters, Tjerk; Buist, Nicole; Ha, Sookhee N; Hafey, Mike; He, Huaibing; Higgins, John; Johns, Douglas G; Kerekes, Angela D; Koeplinger, Kenneth A; Kuethe, Jeffrey T; Li, Nianyu; Murphy, BethAnn; Orth, Peter; Salowe, Scott; Shahripour, Aurash; Tracy, Rodger; Wang, Weixun; Wu, Chengwei; Xiong, Yusheng; Zokian, Hratch J; Wood, Harold B; Walji, Abbas. (2021). A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.. Journal of medicinal chemistry, 64(22), 16770-16800. https://doi.org/10.1021/acs.jmedchem.1c01599