Lilly unveils its triple threat
Retatrutide looks like the most powerful obesity agent yet, though side effects will need careful monitoring.
June 27, 2023
Watch out, Novo Nordisk. Lilly’s retatrutide, a so-called triple G, has bettered not only Novo’s Wegovy but Lilly’s own Mounjaro when data from three different obesity trials are compared. The project allowed obese patients to lose nearly a quarter of their bodyweight after around a year’s treatment.
The downside was, as so often with incretins, side-effects, with 16% of patients in the high-dose group suffering so badly they withdrew from treatment. While this is not as large a proportion as seen in trials of experimental obesity therapies from Boehringer and Altimmune, it raises the question of how much toxicity regulators and patients will tolerate.
Retatrutide (LY3437943) is an agonist of GIP, GLP-1 and glucagon, adding another mechanism to the highly effective GIP/GLP-1 agonist Mounjaro.
Data from a phase 2 obesity trial of retatrutide were presented yesterday by Dr Ania Jastreboff of Yale University Medical School at the American Diabetes Association’s annual meeting. It showed that patients on the highest dose lost 22% of their bodyweight on a placebo-adjusted basis at the 48-week point. Impressively, this beats Mounjaro’s figure after 72 weeks’ therapy.
Novo Nordisk
Lilly
Ph3 Step 1
Ph3 Surmount-1
Ph2
Wegovy 2.4mg
Mounjaro 15mg (high dose)
Retatrutide 8mg (fast escalation*)
Retatrutide 12mg**
GLP-1 agonist
GIP/GLP-1 agonist
GIP/GLP-1/glucagon agonist
Approx 9
Approx 12
16.3
15.8
Approx 18
21.8
22.1
27
22
49
34
16
9
4
18
11
25
14
6
8
13
How much toxicity will regulators and patients tolerate?
As always, this cross-trial comparison is not strictly fair; the data are from different trials, the retatrutide study being smaller and earlier than Mounjaro’s or indeed Wegovy’s. The primary endpoint of the triple G’s phase 2 study was weight loss at 24 weeks, at which point retatrutide already looked better than the better-known projects. It was the 48-week data, however, that elicited applause at the ADA presentation.
It also prompted one delegate to ask whether future obesity trials might look at getting patients out of the obese or even overweight categories altogether, bringing their body mass index down to 25 or less. The average weight loss of 58lb (26kg) seen in the trial could take a patient from a BMI of 35 to “a skinny 28”, Dr Julio Rosenstock of Velocity Clinical Research, another presenter at the symposium, said.
Dr Jastreboff had earlier pointed out that the weight reduction curve was still continuing at 48 weeks, suggesting that even greater weight loss could be produced after longer treatment. Maybe obesity resolution is not such a crazy thing to aim for.
That will only be a possibility, however, if patients can tolerate retatrutide. Nausea and vomiting were more of a problem with the triple G than with Wegovy and Mounjaro, and SVB analysts singled out the 7% rate of cutaneous hyperesthesia – hypersensitivity of the skin – as something requiring further investigation and management.
They also highlighted a patient in retatrutide’s highest dose group who had prolonged QT interval, albeit a subject who was also on ondansetron for nausea, a drug that is associated with this irregular heart rhythm. Still, prolonged QT interval also occurred in the phase 2 diabetes trial of Pfizer’s oral GLP-1 danuglipron, and this is a signal that will be watched for as the incretin class outcome trials report.
For now, the discontinuations seen with the high dose of retatrutide, all of which were due to gastrointestinal issues, are most worrisome. Dr Jastreboff said that dose escalation was still being optimised, suggesting that phase 3 trials might use a slower titration schedule. The dose for phase 3 has yet to be determined, she added.
Lilly is planning four phase 3 obesity trials, and has somewhat bumptiously named the programme Triumph. Triumph 3 is the only study to have begun recruitment so far.
The discontinuations seen with the high dose of retatrutide… are most worrisome.
The only other company pursuing the GIP/GLP-1/glucagon combination appears to be Hanmi, which is trialling efocipegtrutide (HM15211) in Nash rather than obesity. Lilly sees potential in this arena too: data from a subgroup analysis in non-alcoholic fatty liver disease were also presented at ADA.
Patients in the phase 2 obesity trial who had liver fat of greater than 10% were enrolled into this prespecified Nafld subgroup. After 24 weeks the 8mg and 12mg weekly doses produced complete resolution of excess liver fat in around 80% of those eligible for the analysis. At 48 weeks these responses had deepened slightly.
The last thing to consider from the ADA’s retatrutide-fest is the results of a separate phase 2 trial in obese and overweight patients with type 2 diabetes. Here the project cut bodyweight by 17% at 36 weeks. In the phase 3 Surmount-2 trial in a similar population, the high 15mg dose of Mounjaro managed bodyweight cuts of 12% at 72 weeks. In its obesity-plus-diabetes trial, Step-2, Wegovy managed 6% at 68 weeks. The retatrutide results are pretty spectacular as they stand; if the efficacy can be maintained and the tolerability improved in phase 3 Lilly will almost certainly have a major metabolic blockbuster on its hands.
As for the competition, Hanmi might be wise to begin obesity and diabetes trials with efocipegtrutide. It would not be entirely surprising to see other biopharmas rush triple Gs into human trials, either.