Amylin analogs present a strong alternative or complement to GLP-1 receptor agonists, potentially eliciting higher-quality weight loss with a cleaner tolerability profile.
In the coming weeks, Novo Nordisk is expected to release fresh Phase III data for its next-generation weight loss treatment CagriSema, which analysts say could be the next big thing in the obesity space.
CagriSema has been developed as an improvement on Novo’s weight loss powerhouse semaglutide, a GLP-1 receptor agonist marketed as Ozempic for type 2 diabetes and Wegovy for obesity. The next-generation therapy combines semaglutide with cagrilintide, a long-acting analog of amylin, which is a pancreatic peptide that lowers blood glucose levels and slows down gastric emptying.
“We are highlighting amylin as the hottest new mechanism for obesity,” Leerink Partners analysts wrote in a Tuesday note to investors, explaining that amylin “mostly works as a satiety signal and affects hedonic aspects of eating.” The molecule acts on several regions of the brain to lower the feeling of being rewarded after eating.
Compared with GLP-1 therapies, amylin mimetics could lead improve the quality of weight reduction, resulting in lower loss of lean mass relative to fat, according to the Leerink analysts. Amylin analogs could also be particularly effective in type 2 diabetes patients due to its insulin sensitization effects. Additionally, the amylin pathway might prove to be more tolerable than GLP-1, the analysts wrote.
Novo is banking on these advantages with CagriSema, a move that has so far proven fruitful. In a Phase II readout released in August 2022, the pharma touted a 15.6% drop in body weight in patients taking CagriSema, versus 5.1% in comparators on semaglutide alone and 8.1% in patients treated with only cagrilintide. The combo injection also resulted in a greater reduction in HbA1c versus the individual drugs.
Novo has since launched a broad late-stage program for CagriSema, including the Phase III trials REDEFINE 1, which is assessing its efficacy as a weight loss therapy, and REDEFINE 2, designed to include type 2 diabetes patients with excess body weight. The pharma has previously announced that REDEFINE 1 is expected to read out by the end of the year, while data from REDEFINE 2 are expected in the first half of 2025.
CagriSema is also being tested in a Phase III head-to-head study versus Eli Lilly’s tirzepatide—the chief competitor of semaglutide, sold as Mounjaro in type 2 diabetes and Zepbound for weight loss.
The Leerink analysts expect CagriSema to “demonstrate best-ever weight loss … any day now,” adding that “we expect at least high-20% weight loss.” Still, CagriSema could pose practical challenges for Novo, particularly in terms of commercialization. “Cagrilintide can’t be codissolved with semaglutide so NVO will commercialize CagriSema in a dual-chamber injection device and thus sales potential is TBD,” according to the Leerink note.
Other Players in the Amylin Arena
Aside from Novo, Lilly is also advancing its own suite of amylin hopefuls, the most mature of which is eloralintide, a weekly therapy being tested in combination with tirzepatide in nondiabetic obese people. The Phase II study is expected to read out in mid-2025.
Lilly is also running two other trials with eloralintide plus tirzepatide, including another mid-stage study in obese and overweight type 2 diabetes patients, with an initial completion date in June 2026, and a Phase I trial in nondiabetic individuals, scheduled to complete in October 2025.
As per the Leerink analysts, Lilly has indicated that it could potentially co-formulate eloralintide with tirzepatide or its other experimental obesity drug retatrutide, though the pharma is administering the drugs separately in current trials.
Meanwhile, Zealand Pharma is advancing petrelintide, a long-acting analog that in a Phase Ib study showed a promising efficacy and safety profile. Data for the weekly subcutaneous injection, revealed in June 2024, showed that petrelintide could elicit an average weight reduction of 8.6% at 16 weeks, compared with 1.7% in placebo counterparts.
Aside from its clinical benefits, Zealand has also touted the chemical and physical stability of petrelintide, according to the Leerink analysts, which in turn could make the investigational drug a good candidate for other therapeutic peptides in a single solution. Following the Phase Ib readout, Zealand expects to initiate a mid-stage study for petrelintide “imminently,” with data expected by the end of 2025 or early 2026, as per the Leerink note.
Also advancing an amylin candidate is AstraZeneca, which is positioning its AZD6234 as a potential alternative or complement to GLP-1 therapies. The pharma last month presented early-stage data for AZD6234 at the 2024 ObesityWeek of The Obesity Society, touting an encouraging safety profile and promising weight loss—though data around the candidate remain scant.
