Amycretin

Novo Nordisk’s late-stage weight loss data showed CagriSema performed below analysts’ expectations. It’s the second late-stage clinical letdown for the candidate, and the findings mean it is more vital than ever that CagriSema succeeds in a major head-to-head readout later this year. On Monday , Novo reported weight loss of 15.7% in patients with both obesity and type 2 diabetes who took CagriSema for more than a year. Adjusting for placebo, CagriSema’s weight loss benefit was 12.6 percentage points. This finding is markedly stronger than the 6.2-point benefit over placebo shown by Novo’s existing blockbuster Wegovy in a similar patient population. But it is barely better than the 11.6% placebo-adjusted weight loss seen with the high dose of Eli Lilly’s rival product Zepbound in a Phase 3 obesity/diabetes trial. That could be a problem for Novo. The Danish pharma is currently running a head-to-head trial of CagriSema and Zepbound in patients with obesity but without diabetes, and data should emerge in the second half of this year. Novo needs CagriSema to meaningfully outperform Zepbound to give the drug a decent chance of competing with Lilly’s shot, which had sales just shy of $5 billion in 2024. Last month, Novo amended the primary endpoint of the head-to-head trial. It now plans to measure weight loss at 84 weeks rather than 72 weeks. This could put CagriSema in a good light, with the company betting that weight loss from Zepbound will plateau more quickly. Following Monday’s data, and the disappointing results of CagriSema’s other pivotal study in non-diabetic obese patients in December , Novo’s chances of CagriSema beating Zepbound by a notable margin are looking less and less likely. So, why does CagriSema keep disappointing? The drug is a once-weekly subcutaneous combination of the amylin analog cagrilintide at 2.4 mg and the GLP-1 agonist semaglutide at the same dose. Novo’s theory is that adding amylin could enhance weight loss while limiting the side effects associated with GLP-1s. One possible explanation is that the dose of cagrilinitide is too low. Zealand Pharma’s amylin product petrelintide, for example, is being dosed up to 9 mg in its ongoing Phase 2b trial . Another factor could simply be poor expectation management by Novo itself. The company has repeatedly stated its belief that CagriSema could hit 25% weight loss in non-diabetic obese patients. When the experimental drug missed that bar last year, investors made their displeasure known, wiping $100 billion off Novo’s market value. Amylin analogs are not necessarily an intrinsically bad idea. Another Novo molecule that activates both GLP-1 and amylin, dubbed amycretin, performed well in a mid-stage trial in January .

Kallyope has removed one of its weight loss candidates from its online pipeline and shuffled metabolic diseases lower on its priority list, below its efforts on neurological disorders.The changes on the company's website were spotted this week after the results of a Phase II obesity study were quietly posted to ClinicalTrials.gov — the same day a Phase IIb trial testing Kallyope's elismetrep (K-304) in patients with migraine was listed on the site.The obesity study's outcome could, in part, explain the lack of fanfare. While the combination of Kallyope's two oral "nutrient receptor agonists" K-757 and K-833 may have demonstrated a more tolerable gastrointestinal (GI) profile than other oral contenders, the rate of weight loss seen in the study falls well short of the levels achieved by the pack leaders (see – Vital Signs: A safety snapshot of oral GLP-1s).Kallyope had raised a $236-million series D in 2022 on the strength of its metabolic and GI programmes.Less than 3% weight lossKallyope was evaluating K-757 alone, and in combination with K-833, against placebo in 155 participants with obesity and without diabetes. The company has previously described the two compounds as agonists that "stimulate the secretion of multiple appetite-suppressing satiety hormones, including GLP-1, and several other well validated satiety hormones, such as PYY and CCK" (see – Vital Signs: Mapping the next generation of obesity targets after GLP).After 13 weeks, K-757 led to a 1.57% reduction in weight from baseline, while patients who received the duo saw a 2.94% decline; those in the placebo arm had a 0.15% reduction.Of the 52 patients who received K-757 plus K-833, 14 discontinued treatment due to an adverse event (AE). The overall AE rate in the cohort was 80.8%, with the most common side effects being nausea (51.9%), constipation (36.5%), vomiting (23.1%), dyspepsia (19.2%) and diarrhoea (11.5%).K-833 is no longer listed on Kallyope's pipeline, leaving K-757 as the sole disclosed metabolic candidate. The company lists three undisclosed assets in the discovery stage for the disease area, while three neurology programmes are named on its website. Outshined by competitors Keeping in mind the caveats with cross-trial comparisons, the rate of weight loss seen with Kallyope's combo appears to be less than a quarter than that of Novo Nordisk's oral obesity hopeful in a similar timeframe. At the European Association for the Study of Diabetes (EASD) meeting last year, the Danish drugmaker reported that patients given oral amycretin achieved mean weight loss of 13.1% after 12 weeks.Two other oral candidates have achieved a greater degree of weight loss in less time — albeit in far fewer participants. Roche's CT-996 showed placebo-adjusted mean weight loss of 6.1% in six patients at week four in a Phase I study; and earlier this month, China-based Ascletis reported up to a 6.2% weight reduction at week four in eight patients given its homegrown oral GLP-1 agonist ASC30. Phase III data for Eli Lilly's oral GLP-1, orforglipron, are due next quarter — and it's one of the most highly anticipated readouts of the year. At the American Diabetes Association (ADA) scientific sessions in 2023, the pharma reported weight loss of up to 12.6% after 26 weeks (see – Spotlight On: Viking, Structure prep for Eli Lilly's oral GLP-1 reckoning).