[JMC] Novo Nordisk’s Development of Long-Acting Peptide Drugs: Molecular Design of the Amylin Analog Cagrilintide

CagriSema is a fixed-dose combination of semaglutide and cagrilintide—an amylin analog—designed as a long-acting therapy. Cagrilintide promotes satiety and reduces food intake, requiring only once-weekly administration. Phase III clinical trial results are expected by the end of this year. Previously, Novo Nordisk reported Phase II results in patients with type 2 diabetes, showing that CagriSema achieved 15.6% weight loss over 32 weeks—significantly higher than the 5.1% and 8.1% weight loss observed with Wegovy (semaglutide) and cagrilintide monotherapy, respectively. Recently, Novo Nordisk stated that CagriSema’s adverse effects are similar to those of its marketed GLP-1 drugs. Moreover, CagriSema is projected to achieve at least 25% weight loss—making it the strongest competitor to Eli Lilly’s Zepbound. Novo Nordisk claims CagriSema effectively addresses the problem of ‘weight regain after discontinuation’, positioning it as the most effective anti-obesity drug to date. Here, we share an article on the molecular design of the cagrilintide peptide drug—a piece worth noting, as researchers detail numerous aspects of peptide drug development. 1. Background and Peptide Design Rationale Amylin is a 37-amino-acid peptide produced in pancreatic β-cells and co-secreted with insulin. It plays important roles in appetite regulation, glucose homeostasis, and gastric emptying—and thus holds therapeutic potential for diabetes and obesity. In the islets of type 2 diabetes patients, cytotoxic amyloid (protein aggregates) formation has been observed. Therefore, developing amylin analogs that avoid fibril (amyloid fiber) formation is critical. In 2005, pramlintide—a modified amylin analog discovered by Amylin Pharmaceuticals—was approved for use alongside insulin in diabetes treatment. Pramlintide (Table 1) contains three proline substitutions relative to human amylin. These same prolines are present in rat amylin, which is known not to form fibrils (Table 1). Pramlintide has a short half-life (20–45 minutes), necessitating three daily subcutaneous injections—indicating clear room for improvement in dosing frequency. In multiple trials, pramlintide consistently induced weight loss—either alone (<5 kg) or in combination with leptin. At treatment initiation, however, pramlintide commonly causes nausea and vomiting. A long-acting analog could therefore maintain therapeutic concentrations over extended periods, enhancing efficacy for weight loss without exacerbating side effects. Table 1. Structures of Selected Related Peptides Red font indicates mutations relative to h-amylin. Bold font denotes chemically modified residues. This work was conducted at a time when several established strategies for extending peptide half-lives were unavailable. Efforts to extend the half-life of peptide hormones have been undertaken previously—with GLP-1 being the most prominent example.

Novo Nordisk’s $2 Billion Bet on United Laboratories’ Pipeline Obesity Drug: What Are United Laboratories’ Core R&D Competencies?

Eli Lilly did not stand idle: in 2014, it launched dulaglutide—a longer-acting GLP-1 receptor agonist administered once weekly—and within a few years surpassed liraglutide in revenue, exacting sweet revenge. Truly, ‘when you beat the junior, the senior arrives.’ The commercial rivalry between these two pharmaceutical giants is, at its core, a story of evolution and surpassing one another. In 2017, Novo Nordisk launched semaglutide (also known as semaglutide)—a more potent agent—which outperformed dulaglutide head-to-head in both glycemic control and weight-loss trials. Semaglutide has since emerged as a leading candidate for the title of ‘world’s best-selling drug’ (achieving ~$29.3 billion in sales in 2024), reclaiming dominance. Yet Eli Lilly struck back hard: its tirzepatide—approved in 2022—has demonstrated explosive uptake. With superior efficacy shown head-to-head against semaglutide, tirzepatide reached $16.5 billion in sales just two years post-launch. Notably, Eli Lilly is deploying full force in the obesity space—not only with tirzepatide but also with its triple-agonist retatrutide (Phase III), the oral small-molecule GLP-1 agonist orforglipron (Phase III), and the multi-target peptide mazdutide (developed in collaboration with Innovent Biologics, already submitted for approval in China). Of particular interest, orforglipron is currently undergoing a Phase III head-to-head trial versus the oral formulation of semaglutide (Rybelsus). Phase II data show orforglipron achieving 12.6% weight loss at 26 weeks and 14.7% at 36 weeks. In contrast, the Rybelsus 50 mg arm in the Phase III OASIS-1 trial achieved approximately 14% weight loss at 36 weeks. With Eli Lilly pressing forward relentlessly, Novo Nordisk responded decisively—acquiring United Laboratories’ triple-agonist anti-diabetic/anti-obesity drug UBT251 for $2 billion—delivering a powerful counterstrike. 03 United Laboratories’ Endocrinology Strategic Roadmap Novo Nordisk has not been idle in response. It has previously built a robust pipeline of obesity therapeutics—including combination therapies like CagriSema, the CB1R inverse agonist monlunabant, and the GLP-1/amylin dual agonist amycretin. CagriSema—the fixed-dose combination of the long-acting amylin analog cagrilintide and semaglutide—is formulated for once-weekly subcutaneous injection and is currently undergoing Phase III trials for overweight/obese and type 2 diabetic adults. According to Phase III REDEFINE-1 trial results, patients in the CagriSema group achieved 22.7% weight loss after 68 weeks—comparable in magnitude to tirzepatide’s efficacy. Monlunabant was acquired by Novo Nordisk for nearly $1.1 billion from Inversago Pharma and is now in Phase IIb trials for obesity. Phase II data showed 6.5% weight loss after 16 weeks of treatment. Amycretin—a GLP-1/amylin dual agonist—is being developed in both subcutaneous (NN9490) and oral (NN9487) formulations. Phase Ib/IIb clinical data indicate 20% weight loss after 36 weeks of treatment. Thus, while UBT251—licensed from United Laboratories—is not Novo Nordisk’s sole trump card, it may well represent a particularly elegant and timely counterpunch against Eli Lilly.

Novo Says CagriSema Tops Eli Lilly Rival in Diabetes Patients for Weight Loss

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Novo Nordisk announced its experimental drug CagriSema achieved 12.4% average weight loss in late-stage diabetes trials, outperforming Eli Lilly's tirzepatide at 9.1%. The combination therapy positions CagriSema as a potential successor to Wegovy.

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Novo Says CagriSema Tops Eli Lilly Rival in Diabetes Patients for Weight Loss

Novo Says CagriSema Tops Eli Lilly Rival in Diabetes Patients for Weight Loss

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