Retatrutide

The weaker-than-hoped weight loss seen with Novo Nordisk’s CagriSema knocked the company’s shares badly on Friday. The Danish group spearheaded the GLP-1 revolution, but is now in danger of being eclipsed by newer products — or even worse, by existing ones. In last week’s readout, Novo’s amylin-GLP-1 combo allowed obese patients to lose 22.7% of their weight when using the per-protocol analysis, which excludes patients who didn’t receive the test medicine as planned. In the more conservative intent-to-treat analysis, which counts those patients as non-responders and is what would end up on the drug’s label, weight loss was 20.4%. These are respectable figures, but Novo needed more. Its stated goal was weight loss of 25%, and falling short cost it dearly, its stock closing down 17% on Friday. The data leave Novo, and all companies active in the obesity space, with several questions to answer. The placebo-adjusted weight loss seen with CagriSema (using the intent-to-treat analysis) was almost the same as that with Eli Lilly’s rival first-generation product Zepbound in its pivotal trial, though it took Lilly’s drug longer to get there. And as a combination of two molecules, CagriSema is more complicated and expensive to produce than Zepbound, and potentially less profitable. It may also turn out to have a worse safety profile. Novo has stayed largely silent on this aspect so far. A head-to-head Phase 3 trial of CagriSema and Zepbound in around 800 non-diabetic obese patients is ongoing, and could yield data towards the end of 2025. If Novo’s product lags behind Zepbound here, Novo could be in for a further fall. Again, the side-effect profile will be key. The CagriSema flop raises the possibility that there might be a maximum to the weight loss that can be achieved with incretin-based drugs. A handful of second-generation products in development could be particularly helpful in answering that question. Even drugs with the same mechanism have shown broadly varying efficacy. Novo’s older GLP-1 Saxenda has been on the market for obesity for a decade, but has never been anywhere near as effective as Wegovy and its followers. Newer products in development could be more efficacious yet, despite their shared mechanisms. For example, Lilly’s triple agonist retatrutide achieved startling results — better than both Zepbound and CagriSema — at 42 weeks in its Phase 2 trial. Roche’s CT-388, a GLP-1/GIP agonist it acquired via its $2.7 billion acquisition of Carmot, achieved steeper weight loss still, at around 19% on a placebo-adjusted basis at the six-month mark. However, these data came from a small Phase 1b trial and will need to be backed up by larger, later studies. There’s also anticipation for Viking Therapeutics’ GLP-1/GIP agonist VK2735, which allowed obese patients to lose nearly 15% after just three months’ treatment. That’s roughly on par with what Novo’s first-gen product Wegovy achieved at around a year and four months. Weight loss tends to plateau with these products at around 60 months, with patients seeing minimal effect after that point. It is possible that any of these three experimental injected products might show a step-change in the weight loss that can be achieved after many months’ treatment, breaking through the ceiling seen so far. The vast increases in manufacturing capacity Novo and Lilly have been making mean injected incretins are finally starting to reach all the new patients who need them. But what happens once patients have been taking the shots for months or years? The next battleground will be maintenance therapy, and that means oral options. Oral drugs require higher doses than subcutaneous formulations to achieve the same effect, and new manufacturing, so production capacity will be an issue all over again when the market shifts to pills. But before that, these assets will have to prove themselves in the clinic. An oral version of Novo’s Wegovy showed itself to be roughly as good as injected Wegovy when its Phase 3 trial reported last spring. However, there has been little movement on the regulatory front — Novo has not publicly said whether it has submitted the product for approval. Lilly is not trialing an oral version of Zepbound and is instead backing a different GLP-1/GIP agonist, orforglipron. That pill showed weight loss of nearly 15% after 36 weeks in a Phase 2 trial, a steeper trajectory than Novo’s pill. Phase 3 trials are ongoing. Some other big names are trying to jump straight into the oral market, though not all with success. In December 2023, Pfizer shelved the twice-weekly version of its oral GLP-1 agonist danuglipron, and is working to optimize the dose of a daily version for Phase 3. Data could come soon in 2025 , and a decision on Phase 3 will be made then. Roche has its own effort, as well. Its CT-996, also a Carmot product, managed weight loss of 7.3% after only one month, at the time the best of any pill at such an early point. This was pipped in November by Viking’s oral from of VK2735, which, dosed at 100mg, allowed weight loss of 8.2% at 28 days. However, these data come from very small Phase I trials, so they aren’t the most robust. Editor’s note: This article was corrected to include data on Viking’s oral from of VK2735. A previous version said Roche’s CT-996 was the most effective pill at one month.

Novo Nordisk said its highly anticipated Phase 3 readout showed that CagriSema only managed 22.7% weight loss at 68 weeks, failing to hit the 25% benchmark the company, investors and analysts were seeking. The result was still a statistically significant benefit over the placebo group, in which the weight loss was 2.3%. These figures were based on a per-protocol analysis, evaluating the effects of CagriSema if all people adhered to treatment. Using an intent-to-treat analysis, which is generally regarded as more rigorous and is designed to measure the treatment effect regardless of discontinuation or use of rescue medication, CagriSema recipients lost just 20.4% of their weight, versus a loss of 3% on placebo. Just over 40% of CagriSema recipients lost at least a quarter of their body weight. The data likely mean that sales of CagriSema will not hit the hefty sales estimates bankers had made. Before the readout, Jefferies analysts said consensus forecasts for CagriSema’s peak sales were around $20 billion in diabetes and obesity combined. As soon as the data dropped, Novo’s stock $NVO crashed by as much as 26% pre-market Friday. By market open the share drop was 20%, representing a loss of around $100 billion in Novo’s market value. A Novo spokesperson told Endpoints News that the company plans to conduct a new trial of CagriSema in the first half of next year, using optimized dose titration. Novo gave few details on the product’s safety, saying only that it “appeared to have a safe and well-tolerated profile.” The most common side effects were gastrointestinal, the “vast majority” being mild to moderate and diminishing over time. There had been worries about gastrointestinal side effects ahead of the readout. CagriSema combines the amylin analog cagrilintide and Ozempic and Wegovy’s active ingredient semaglutide. According to Barclays analysts, the allure behind combining the two is that semaglutide increases insulin secretion and that amylin works alongside that to manage postprandial glucose levels. By targeting multiple energy balance-regulating pathways concurrently, the combo could enhance the magnitude and duration of weight loss. Similar thinking underlies Lilly’s development of tirzepatide, a co-agonist of GLP-1 and gastric inhibitory polypeptide (GIP). This was more effective than Wegovy, which acts on the GLP-1 receptor alone, in a recent head-to-head trial. The new CagriSema data are roughly on par with tirzepatide’s in its pivotal obesity trial. Lilly’s retatrutide, which acts on the GLP-1, GIP and glucagon receptors and is also subcutaneous, is in Phase 3. In a mid-stage test, this candidate allowed obese patients to lose nearly a quarter of their body weight after just under a year’s treatment. The pivotal trial of retatrutide in non-diabetic obese patients will assess weight loss at 80 weeks, and data are expected in 2026. Retatrutide’s safety will be watched closely. Among all the patients in the Phase 2 study, 8% discontinued treatment because of adverse events, higher than was seen with Wegovy or Zepbound in their trials. The late-stage CagriSema trial enrolled 3,417 patients and studied the shot at weekly flexible doses of up to 2.4 mg of each component. Separate arms assessed the same doses of cagrilintide and semaglutide alone, as well as placebo. By the end of the study, 57.3% of patients treated with CagriSema were on the highest dose. Novo did not say whether patients stopped increasing their doses because they were happy with their weight loss at a lower dose or because they could not tolerate higher doses. CagriSema did not undergo Phase 2 trials in obesity, though both its individual parts have separately been trialed in that indication. Novo put the combo straight into Phase 3 in 2022. But CagriSema did go through a Phase 2 test in patients with diabetes who were overweight and offered weight loss of 15.6% at 32 weeks. The components were tested individually in this trial too; semaglutide delivered 5.1% weight loss and cagrilintide 8.1%. The frequency of gastrointestinal adverse events almost doubled with CagriSema compared with each component alone, at 58% with the combo versus 32% with the GLP-1 and 33% with cagrilintide. Data from CagriSema’s second pivotal trial, in patients with both type 2 diabetes and obesity or overweight, should come in the next six months. Editor’s note: This article was updated throughout to add more detail to the story and chart, as well as to include a company comment on an additional trial.