Cagrilintide, a lipidated amylin analogue engineered for once-weekly dosing, has shown significant weight loss in clinical trials alone and in combination with semaglutide.
Once-weekly dosing achievedUnlike pramlintide which requires three daily injections, cagrilintide's lipidation strategy enables convenient once-weekly administration
What the researchers found
Researchers developed cagrilintide, a stable, lipidated long-acting amylin analogue that overcomes two major challenges of native amylin: its tendency to form amyloid fibrils and its very short half-life. Unlike pramlintide (the only approved amylin analogue), which requires three daily injections, cagrilintide's lipidation strategy enables once-weekly dosing.
Cagrilintide has induced significant weight loss in clinical trials both when used alone and when combined with the GLP-1 analogue semaglutide. The paper details the structure-activity relationship studies that led to selecting cagrilintide (compound 23) from a series of candidates for clinical development with obesity as the primary indication.
Why it matters
The obesity treatment landscape was transformed by GLP-1 drugs like semaglutide, and cagrilintide adds a complementary mechanism through the amylin pathway. Combined as CagriSema, these two peptides may represent the most effective non-surgical weight loss approach developed to date. This paper reveals the medicinal chemistry behind how cagrilintide was engineered — knowledge that informs future peptide drug design.
The numbers in context
Compound 23 selected from series · Long-acting via lipidation · Once-weekly dosing potential · Significant weight loss alone + with semaglutide
How the study worked
This is a medicinal chemistry study describing the iterative design, synthesis, and optimization of amylin analogues. Researchers evaluated structure-activity relationships across a series of peptide modifications, focusing on fibril resistance, lipidation strategies for extended half-life, receptor activity, and pharmacokinetic properties. Clinical trial data on weight loss efficacy are referenced from separate studies.
Who was studied
Medicinal chemistry study; clinical references involve people with obesity
What this study cannot tell us
This paper focuses on the drug design process rather than comprehensive clinical data. Full efficacy and safety results come from separate clinical trials. The structure-activity relationships described are specific to amylin analogues and may not generalize to other peptide classes.
How to read the evidence
This is a medicinal chemistry paper describing the drug design process, with clinical trial data referenced from separate studies. The evidence for cagrilintide's efficacy comes from Phase I-III clinical trials, providing moderate-to-strong clinical evidence.
When this study was published
Published in 2021, this paper describes the foundational chemistry behind cagrilintide. Since publication, clinical trials have continued to advance, with CagriSema (cagrilintide + semaglutide) progressing through Phase III trials.
The bigger picture
The development of cagrilintide represents a masterclass in peptide drug design. By solving the amyloid fibril problem that has plagued amylin-based drugs, researchers opened a new therapeutic pathway for obesity that complements GLP-1 receptor agonists. The combination of cagrilintide with semaglutide (CagriSema) is now one of the most anticipated obesity treatments in development.
Questions still open
- How much additional weight loss does cagrilintide add when combined with semaglutide compared to semaglutide alone?
- Could the lipidation strategy used for cagrilintide be applied to other problematic peptide hormones?
- What are the long-term cardiovascular and metabolic benefits of dual amylin-GLP-1 receptor agonism?
Common questions
What is amylin and how does cagrilintide mimic it?
Why is cagrilintide being combined with semaglutide?
Read the original research
Development of Cagrilintide, a Long-Acting Amylin Analogue.
Journal of medicinal chemistry, 64(15), 11183-11194
Citation
Kruse, Thomas; Hansen, Jakob Lerche; Dahl, Kirsten; Schäffer, Lauge; Sensfuss, Ulrich; Poulsen, Christian; Schlein, Morten; Hansen, Ann Maria Kruse; Jeppesen, Claus Bekker; Dornonville de la Cour, Charlotta; Clausen, Trine Ryberg; Johansson, Eva; Fulle, Simone; Skyggebjerg, Rikke Bjerring; Raun, Kirsten. (2021). Development of Cagrilintide, a Long-Acting Amylin Analogue.. Journal of medicinal chemistry, 64(15), 11183-11194. https://doi.org/10.1021/acs.jmedchem.1c00565