“The development of GLP-1 and incretin-based drugs has revolutionised the space. It has carved out the biggest class of drugs ever. And it has the power to truly revolutionise our health-span,” said Associate Professor Garron Dodd, head of the Metabolic Neuroscience Research Laboratory at the University of Melbourne and founder of Gallant Bio, which is developing its own obesity drugs. “It’s a glorious dawn, but it’s just the start.”
Garron Dodd, head of the Metabolic Neuroscience Research Laboratory at the University of Melbourne, is also founder of Gallant Bio.Credit: Chris Hopkins
Weight loss in a pill
Much as our eyes and ears sense the world and send data to our brains, our digestive tracts need ways of sending back data on what they are eating, and how much. They do this, in part, by secreting various chemical signals – hormones.
Glucagon-like peptide-1 is secreted by the intestines and triggers the pancreas to produce insulin. The first GLP-1 drugs took advantage of this to become powerful treatments for diabetes.
But GLP-1 has much wider effects beyond blood-sugar control. Receptors for the hormone spread throughout the body, even in the brain, where they trigger a feeling of fullness and decrease appetite. A once-weekly dose of semaglutide, plus lifestyle changes, led volunteers in a phase 3 trial to lose 14.9 per cent of their body weight over 15 months.
GLP-1 drugs like Wegovy essentially copy that human hormone. That makes them fragile. They need to be kept refrigerated, and injected subcutaneously rather than taken by mouth – as the stomach’s acid would quickly break them down. An oral version of semaglutide has been developed, but only 1 per cent of the drug actually makes its way to the target receptors, and it appears less effective than the injectable version for weight loss.
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Researchers at Japan’s Chugai Pharmaceutical Co figured out a way around this problem. They designed a small molecule that can bind to the same receptor as GLP-1 and trigger it. It mimics the effect without mimicking the structure. “It’s a development I never would have thought feasible,” said Professor Michael Horowitz, a University of Adelaide researcher who authored a commentary on the drug in the Lancet.
Chugai licensed the molecule to US-based Eli Lilly in 2018. Last week, the company reported participants on the highest dose in a clinical trial lost 7.9 per cent of their body weight over 40 weeks.
The full details of the trial have not yet been reported, and whether the weight loss is maintained over the longer term is unclear. More than a quarter of patients reported diarrhoea, 16 per cent nausea and 14 per cent vomiting.
The preliminary results are “close enough to broadly call it similar” to semaglutide, said Professor Jonathan Shaw, who led the Australian arm of Lilly’s trial at the Baker Heart and Diabetes Institute in Melbourne. “I don’t think we can confidently say it’s better or worse. It’s definitely in the same ballpark.”
It’s also not known if the drug will offer the range of other benefits that GLP-1 inhibitors provide in addition to weight loss, like reductions in cardiovascular disease and Alzheimer’s risk (and maybe even addictive behaviours).
Horowitz said the efficacy data was promising, but he wanted to see more information about adverse effects, which he said were understated generally across semaglutide trials because they relied on patients to report their own side effects. “It hasn’t served the interests of pharma to quantify how well this is tolerated.”
Pfizer was developing a similar once-daily GLP-1 pill but cancelled the program in April after a patient in a clinical trial suffered liver damage.
A pill should, theoretically, be cheaper and easier to make than an injector – Novo Nordisk, maker of Wegovy and its diabetes drug antecedent Ozempic, has struggled to keep up with demand for semaglutide – and dramatically easier to transport. At present, the drug must be kept refrigerated right from European factories to a patient’s home. “That all adds to the cost,” said Shaw.
There could also be cost benefits from increased competition as more drugs are approved – possibly pushing the price down far enough for governments to consider subsidising it. Lilly expects to apply for regulatory approval for the drug later this year.
While orforglipron has attracted the most excitement – Eli Lilly’s shares have surged since they announced the trial results – it is just one of several new drugs in late-stage development.
These drugs might be of particular value to 15 per cent or so of people whose bodies do not seem to respond to semaglutide. And people don’t seem to stay on the injectable drugs – less than half are still using them a year later, per a study 2024 study – despite the fact weight rebound is likely if you stop using them. “Is it the injection? Is it the cost? Or is it due to adverse effects? We don’t know,” said Horowitz.
The new drugs might also offer weight-loss benefits. Mounjaro, for example, mimics both GLP-1 and the gastric inhibitory polypeptide, which increases metabolism and appears to lead to better weight-loss results. The new drugs, like Lilly’s retatrutide, target even more receptors, with the hope of even greater effects.
It’s all good news for Rochelle McDonald. She does not mind taking a weekly injection – “the stabby-stab” – now she’s found ways of coping with the side effects. But paying $240 a month for her current dose of the medicine is “a commitment in itself”.
“I think a daily pill would be good,” she said. “If it comes in at a good price point.”
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