ADA 2022 – Move over Mounjaro?
Lilly believes it has two promising new molecules for diabetes and obesity. But which to choose – and might toxicity yet scupper one or both?
The early data released this week on Lilly’s triple-G LY3437943 showed the GIP, GLP-1 and glucagon receptor agonist to best Trulicity on measures of blood sugar and weight loss. But last night the plot thickened: Lilly said on a call that early data on the molecule make it look almost twice as good as its newer, highly impressive drug Mounjaro.
And the company reckons it might have something even better than the triple-G up its sleeve. Mazdutide, a GLP-1 and glucagon receptor dual agonist at a slightly earlier stage of development, also showed strong data at ADA. Lilly will soon decide which of these candidates to take forward, though there are reasons to believe that safety could come to be an issue with one or both of these projects.
On a conference call yesterday, to discuss the various datasets Lilly presented at the American Diabetes Association’s meeting, the company said that weight reduction in type 1 diabetes patients treated with LY3437943 – of up to 8.7kg over 12 weeks – was “almost double what we observed with tirzeptide [Mounjaro] over a similar period of time, in a similar patient population”.
The company attributed the triple-G’s decent showing to both a decrease in food intake and “strong contribution of energy expenditure”.
Impressively, the data on mazdutide, which is also known as LY3305677 and oxyntomodulin, look markedly better than LY3437943 on weight loss, and similar on blood sugar reductions.
|Comparison of Lilly's new diabetes/obesity agents|
|Trial||Ph1 (NCT04143802) - data at 12wk||Ph1 (NCT03928379) - data at 16wk|
|Change from baseline in HbA1c (%)||-1.7||-1.9||-1.6||-0.3||-1.7||-0.7|
|Change from baseline in body weight (kg)||-4.39||-7.52||-8.65||+0.31||-11.24||-2.03|
|Source: company presentation.|
Unlike mazdutide, LY3437943 is already in phase 2, in both obesity and diabetes. Lilly intends to wait for these data before deciding, in 2023, which of its new agents to develop further.
One thing the company will be alert for in its ongoing clinical trials is any signs of toxicity. Novo Nordisk ditched both a double and a triple agonist on safety concerns a couple of years ago (Novo adds weight to its obesity goals, September 10, 2020).
A preprint of data from a phase 1 trial of the GLP-1/glucagon receptor co-agonist, NNC9204-1177, in obese or overweight patients, lays out the concerns. Signals included increased heart rate and decreased reticulocyte count, both of which were dose dependent. Increased markers of inflammation, increased levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase, impaired glucose tolerance in the higher dose groups and reduced blood levels of some amino acids were also seen.
Ruth Gimeno, vice-president of Lilly’s diabetes and metabolic research division, said yesterday that glucagon in particular has effects on food intake and energy expenditure, but also directly affects the liver and the kidney, and can lower blood pressure. She said that the ratio of the glucagon and GLP1 agonists is important, and added that none of the issues seen with Novo’s GLP-1/glucagon agonist had yet emerged in trials of either LY3437943 or mazdutide.