When Danish scientist Jens Juul Holst identified in 1986 that gut hormone GLP-1 stimulates insulin and suppresses appetite, obesity was far from the health problem it is now and a drug harnessing the finding was a distant prospect.
But with a billion, or 1 in 8, people at present classed as obese worldwide, the work on GLP-1 by Holst and other scientists has proved crucial to the development of two blockbuster injectable weight-loss drugs: Wegovy and Zepbound. Developed respectively by Novo Nordisk and Eli Lilly, they are now being prescribed to millions of people.
Wegovy has been on sale since only 2021 and Zepbound was approved just five months ago, but Novo Nordisk and Eli Lilly are already leading the development of the next generation of weight-loss drugs. Hoping to catch up and win a share of a market that is predicted to be worth up to $150bn by 2030 are dozens of biotechs and other pharma groups.
“We are looking at a new era where it’s possible to treat obesity in the same way it’s been possible to treat high blood pressure,” said Holst from his University of Copenhagen office.
According to health data company Airfinity, there are 232 anti-obesity medications at various stages of development, from pre-clinical studies on animals to late-stage, phase 3 trials.
The most advanced prospects are all based on GLP-1, generally in combination with other hormones. Targets include boosting effectiveness, developing a pill to replace the weekly injections, tackling conditions linked to obesity such as kidney disease, reducing the frequency of injections, and reducing common side effects such as nausea and muscle wasting.
Louise Chen, analyst at Cantor Fitzgerald, said the key question was: “Can someone hopscotch ahead of Lilly and Novo? I think it will be hard.” But she said believed new entrants would be able to break into the market “if the product is sufficiently differentiated”.
Eli Lilly and Novo Nordisk first received approval for GLP-1-based treatments — for diabetes — in 2005 and 2010 respectively. Both are now aiming to cement their leadership in weight-loss drugs: between them they have five new, and potentially more effective. treatments in phase 3 trials.
Among the Novo Nordisk candidates at this stage is CagriSema, a combination of GLP-1 and other proteins that is targeting average weight loss of more than 20 per cent, higher than 15 per cent for Wegovy and challenging the 21 per cent average weight loss of Zepbound. In addition to the phase 3 study, Novo Nordisk has launched a head-to-head trial of Wegovy versus Zepbound.
Meanwhile, Eli Lilly’s retatrutide drug, also in phase 3 trials, is based on three separate gut hormones. It cut average body weight by 24 per cent in early stage trials, the best result to date.
Novo Nordisk also has a promising candidate at an earlier stage of development: it announced in March that results from a preliminary phase 1 trial suggested its amycretin pill, combining GLP-1 and a pancreatic hormone, amylin, could be more effective than Wegovy.
“We have a very nice palette across the range of efficacy, safety and scalability and that allows us to be in the driver’s seat,” said Martin Holst Lange, Novo Nordisk’s vice-president of development.
“These guys keep raising the bar as everyone else is trying to catch up,” said Emily Field, an analyst at Barclays.
One pharma M&A adviser said new entrants would need more than just bigger reductions in body weight to avoid “falling between the cracks of current and next-generation obesity treatments”.
Many biotechs hoping to enter the market will aim for partnerships with larger groups, a well-trodden path in the pharmaceutical industry. Roche and AstraZeneca have already struck deals to buy or license early stage weight-loss drugs.
One biotech with a promising drug is US-based Viking Therapeutics — its shares doubled after it published phase 2 trial results in February showing better weight loss than current drugs after 13 weeks.
Adam Steensberg, chief executive of Zealand Pharma, one of the smaller groups hoping to break into the market, believes consumers need to be offered something different.
“It’s not about more and more weight loss. It’s about similar degrees of weight loss but with the potential to better address specific [illnesses that occur with] obesity,” he said.
German pharma group Boehringer Ingelheim is commercialising a Zealand treatment for both obesity and liver disease that is set to launch by 2028. Zealand’s earlier drug candidates include a non-GLP-1 drug for obesity based on amylin that Steensberg said could reduce side effects such as nausea.
Investors are also excited about an experimental drug from US biotech Aardvark Therapeutics that combines GLP-1 and another digestive hormone, CCK, and could limit nausea and muscle wasting side effects.
Meanwhile Eli Lilly last year bought Versanis, a biotech developing an antibody treatment that aims to preserve muscle mass in patients taking weight-loss drugs.
Developing drugs that can also tackle illnesses associated with obesity is key to convincing more health systems to pay for them. So far 50mn Americans have insurance coverage for Wegovy and last month the FDA approved its use to cut cardiovascular risks in obese and overweight patients. It is also offered on the UK’s NHS, along with Mounjaro, the brand name for Zepbound in the country.
Offering “convenience” to patients was another way for new entrants to stand out, said Michael Yee, an analyst at Jefferies.
US biotech Amgen is working on a weight-loss injection that would be used monthly or even less frequently. According to preliminary data, it cut body weight by 14.5 per cent after 12 weeks, a similar result to the weekly injection being trialled by Viking Therapeutics.
But pills are the holy grail of convenience, making them a key development in the next generation of weight-loss drugs.
They tended to be cheaper and therefore preferable for health providers and patients, said Raymond Stevens, chief executive of Structure Therapeutics, which has a GLP-1 pill in mid-stage phase 2 trials. “The price is just too high today . . . so I think the oral pills will allow obesity drugs to be embraced at a large scale,” said Stevens.
Novo Nordisk’s main expertise is in “biological” medicines grown from living cells. In addition to the amycretin trial, it has oral semaglutide, a pill version of Wegovy, in late-stage trials.
But according to Holst, who has worked as a consultant for the company, it has struggled to develop small-molecule GLP-1 drugs, which are much easier and cheaper for manufacturers to produce at scale.
In the race to develop a small molecule pill, Eli Lilly’s phase 3 orforglipron was “a bit of a frontrunner”, Novo Nordisk’s Lange acknowledged, but he said it was not as effective as injectables.
Pills also generally require larger amounts of active ingredients because they are more easily broken down in the body. This is an added challenge when high demand for weight-loss drugs is already causing shortages in the US and Europe.
As more treatments come to market, some worry that societies will become too reliant on them, to the detriment of public health measures.
It is a view rejected by Holst. “More than half of the population wear glasses. There’s nothing immoral about improving your eyesight,” Holst said. “Here, you improve your lousy appetite regulation, which was made by the creator, by taking a pill. I don’t really see the problem.”
Visuals and graphics by Bob Haslett and Steve Bernard
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