The next generation of major obesity drugs is not intended to replace the GLP-1 drugs.
On the contrary, pharmaceutical companies are developing therapies that can complement existing drugs to further promote weight loss, or to provide new options for millions of people who may not benefit sufficiently from GLP-1 drugs.
This represents the early potential of a new batch of injectables, oral medications, and combined treatment regimens targeting the amylin pathway. Amylin is a hormone released by the pancreas along with insulin, which helps to regulate feelings of hunger and fullness. For Eli Lilly and Novo Nordisk, amylin provides another biological approach that can be used to treat obesity and type 2 diabetes, either as a standalone therapy or in combination with existing medications.
Eli Lilly provided a promising initial signal of this strategy this week.
The company's experimental amylin targeted drug, when used in combination with the active ingredient tirzepatide of its blockbuster drugs Zepbound and Mounjaro injections in a phase 2 trial for patients with obesity and type 2 diabetes, resulted in significantly greater weight loss effects.
At 48 weeks, the group that received the highest dose of combined treatment experienced an average weight loss of 23.3%, while the group that used only the high dose of tirzepatide had an average weight loss of 14.8%. These data are based on efficacy analysis, assuming that the trial participants consistently followed the medication regimen.
"These results are encouraging," said Professor Brigham Young University, an expert in metabolic health and insulin resistance. "Adults with type 2 diabetes typically experience a smaller weight loss with these therapies than those without diabetes."
Eli Lilly is developing eloralintide as both a monotherapy and part of a combination therapy. Analysts believe these two components could form an important part of the company's future product pipeline.
Analysts Leerink Partners and David Risinger predict that by the end of 2035, the annual sales of eloralintide related products will reach $23.2 billion. He stated that it is expected that the monotherapy version will be launched first in 2029, followed by the combination therapy in 2030.
“Millions of people, potentially over 10 million, have tried the GLP-1 drug, but have not benefited from it due to issues with efficacy, tolerance, or genetic factors,” Risinger told CNBC. “We believe that this new mechanism, this amylin analog… will provide patients with an important new treatment option, whether as a monotherapy or in combination therapy.”
Risinger says that he is more optimistic about the potential of eloralintide, as there is still a "large independent patient population" that has not seen success with the existing GLP-1 drugs. Eli Lilly, on the other hand, still believes that combination therapy has clear opportunities.
"Patients may not be able to achieve the desired effects from medications like tirzepatide," said Ken Custer, President of Eli Lilly's Cardio-Metabolic Health Division, in an interview. "They may also not be able to obtain the desired effects from medications like eloralintide alone."
Bikman also indicates that he believes combined therapy is suitable for those patients who first use tirzepatide, but then enter a plateau in weight loss after that.
However, Eli Lilly still has a lot to prove. The current data comes from a relatively small Phase 2 study, and the company still needs to verify it in a Phase 3 trial that will be launched later this year.
Eli Lilly also hopes to improve patients' tolerance to the combination regimen in subsequent studies. In the trial, the proportion of patients who discontinued the medication due to side effects while using both drugs simultaneously ranged from 10.8% to 27%, depending on the dosage; whereas in the tirzepatide monotherapy group, the discontinuation rate was 2.9%.
"A therapy is only considered effective if patients can use it consistently, so tolerance during phase 3 trials will be just as important as its efficacy," said Bikman.
Co-Director of the Weight Management and Health Center, Dr. Caroline Apovian added, "27% is not a good number."
Nevertheless, these results further add evidence to support the possibility that amylin could become an important tool in the fight against obesity and diabetes.
It's not just Eli Lilly that bets on amylin becoming the cornerstone of the next generation of obesity drugs. Novo Nordisk has also been pursuing a similar strategy for many years.
Novo Nordisk's experimental amylin class drug cagrilintide demonstrated significant weight loss effects in a late-stage trial when used as a monotherapy. When combined with semaglutide, the combined regimen CagriSema resulted in even greater weight loss in clinical studies. CagriSema is expected to be launched at the beginning of next year, followed by the monotherapy cagrilintide and higher dose versions of CagriSema in 2028.
Novo Nordisk is also developing another therapy known as amycretin, also referred to as zenagamtide. This is a monomolecular drug that will target both GLP-1 and amylin simultaneously, for the treatment of obesity and type 2 diabetes. The Danish pharmaceutical company is testing both a weekly injectable version and a daily oral tablet version of this drug, which earlier this year announced promising phase 2 trial results.
Amylin and GLP-1
The first and, to date, only approved amylin therapy is an adjunctive injection administered during meals that was approved in the United States over 20 years ago for use by diabetic patients who require insulin. However, due to the need for multiple injections per day, its scope of use has been limited.
Bikman says that the new therapy being developed is a long-acting formulation, which means it is designed to mimic this hormone in a sustained manner and can be administered once a week.
Amylin helps to transmit satiety signals, suppress appetite, and slow down the movement of food in the stomach, which is similar to the effect of GLP-1. However, amylin acts through a completely different biological pathway.
“The results are the same, but the methods are different,” Bikman told CNBC.
The idea is that targeting multiple pathways may bring more benefits in terms of weight loss or other metabolic improvements than acting on a single pathway alone, and there is no need to rely entirely on higher doses of a single drug.
New data released this week by Novo Nordisk indicates that these benefits may not be limited to physical changes alone.
In a one-year functional magnetic resonance imaging (fMRI) study, CagriSema reduced “food noise” – that is, persistent thoughts about food – and showed improvements in organ and bone health. Functional MRI is a non-invasive method of measuring brain activity during specific tasks. Novo Nordisk stated that CagriSema altered the brain’s response to tempting high-calorie foods in people who are obese or overweight, involving areas related to craving, pleasure, and self-control.
"The signals in the brain change, and these changes are actually associated with an improvement in quality of life," said Martin Holst Lange, Chief Scientific Officer of Novo Nordisk, in an interview.
Developing therapies that target multiple hormone pathways rather than a single one is part of a broader shift in the competition for obesity drugs, and this is not even limited to amylin.
tirzepatide has combined GLP-1 with GIP, and Eli Lilly's experimental drug retatrutide also includes glucagon. Retatrutide has so far yielded one of the largest weight loss results announced in obesity drug trials. Bikman states that published data indicate that the drug can significantly reduce liver fat, triglycerides, and fasting insulin levels.
It is still too early to definitively assert whether the combined amylin drugs will be superior to tirzepatide or other next-generation therapies. They must first pass through more clinical trials and regulatory reviews.
But all the drugs in development are moving towards a broader goal that pharmaceutical companies jointly pursue: to provide patients with a variety of treatment options for obesity and diabetes to meet individualized needs.
