Lilly ends ADA on a high as obesity triple data pops

The first reveal of clinical data with Eli Lilly’s injectable triple receptor agonist for obesity suggests that the company could have a big winner on its hands if the drug makes it through to market.

Retatrutide targets GIP and GLP-1 – the same as Lilly’s fast-growing diabetes therapy Mounjaro (tirzepatide) – but adds in activity against glucagon. That three-pronged attack helped patients lose an average of about 24% of their body weight at 48 weeks in a phase 2 trial presented at the American Diabetes Association (ADA) congress.

At 24 weeks, the average reduction was 17.5%, and lead investigator Ania Jastreboff of Yale School of Medicine told the ADA that trial participants had not reached a plateau in their weight by the study’s cut-off, suggesting “full weight reduction efficacy was not yet attained.”

The results have also been published in the New England Journal of Medicine. The biggest weight reduction was seen with the highest dose on test (12 mg once weekly), with participants in that arm losing an average of 58 pounds or around 26 kg.

The results also suggested that retatrutide has an overall safety and tolerability profile similar to GLP-1 receptor agonists used for obesity treatment.

While still early, the data suggests a stronger weight-reducing effect than Novo Nordisk’s GLP-1 agonist Wegovy (semaglutide), which is already approved to treat obesity on the back of data showing it could reduce weight by around 16% over 68 weeks. Meanwhile, Mounjaro – which is approved for diabetes and under regulatory review for obesity – achieved a weight loss of up to 22.5% at 72 weeks in its pivotal trial.

The results also compare favourably with results seen with Boehringer Ingelheim and Zealand Pharma’s dual GLP-1 and glucagon agonist survodutide, which showed weight loss of around 19% at 46 weeks in a study reported earlier at the ADA, but had also not reached a plateau.

Lilly is losing no time in advancing retatrutide into phase 3 testing, announcing a large and wide-ranging programme called TRIUMPH across four studies to investigate the drug across diabetic and non-diabetic patients with obesity and who are overweight, including those with cardiovascular disease, obstructive sleep apnoea, and knee osteoarthritis.

“We believe that combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed this level of weight reduction,” said Dan Skovronsky, Lilly’s chief scientific and medical officer.

“[This phase 2 data has] given us confidence to further explore the potential of retatrutide in phase 3 trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively.”

The increase in weight-loss efficacy raises the possibility that some of these new pharmacological approaches to obesity could give patients an alternative to bariatric surgery, which is effective, but comes with safety risks.

Earlier at ADA, Lilly reported phase 2 results with its once-daily oral GLP-1 agonist orforglipron, which achieved a weight reduction of almost 15% at 24 weeks, potentially giving Lilly the option of a battery of different therapies for obesity that can address the differing needs of individual patients.

Pfizer chooses its oral GLP-1 candidate

Also at ADA, Pfizer revealed that it had decided to end the development of one of its once-daily oral GLP-1 agonist drugs called lotiglipron, on concerns about liver safety, and focus on twice-daily candidate danuglipron.

A phase 2b study of danuglipron is already fully enrolled, according to the drugmaker, and a phase 3 programme across obesity and type 2 diabetes will be finalised by the end of 2023.

Twice-daily dosing would put danuglipron at a disadvantage to Lilly’s oral GLP-1 candidate, but Pfizer said it is already working on a modified-release formulation that it hopes will allow a single daily dose.