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Retatrutide is an investigational drug that is a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. It is being developed by Eli Lilly (LLY) for the treatment of obesity and is essentially a second-generation anti-obesity drug. This is a large and growing therapeutic area currently dominated by a number of approved GLP1 agonists (Ozempic [Novo Nordisk] and Mounjaro [Eli Lilly]). There are also a number of oral GLP1 in development as well, but Retatrutide is the leading triple agonist in development. Eli Lilly recently reported phase II data and they are quite impressive.

The biggest take-home point from the recently released data is the extraordinary weight loss with an average of 17.5% decline at week 24 that increases to a 24.2% decline at week 48. The weight loss curves also do not seem to have plateaued, so it remains likely that additional follow-up will lead to a larger peak decline in weight. The effects are even more impressive as retatrutide lowered LDL by 20% and increased liver function by 5 to 7 points on the eFGR. Finally, the treatment showed a decrease in liver fat by over 80%. So not only did it have the desired effect on weight but improved a significant number of additional secondary endpoints.

Eli Lilly reported that the most common adverse events were gastrointestinal in nature and relatively mild. I do think, however, that the most critical issue will be the potential cardiac safety signal. The abstract of the New England Journal of Medicine article did note “dose-dependent increases in heart rate [that] peaked at 24 weeks and declined thereafter.” What exactly does that mean and how important would it be considering the strong efficacy?

There is little question as to the efficacy and it speaks to a very large potential commercial market, which is exactly why any safety issue is vital to understand. The larger the potential treatment population the more important safety becomes, especially for indications that are not immediately life-threatening. Transient effects on the heart for a late-stage cancer drug matters less than those same effects in an obesity drug. This does not mean a cardiac safety signal would completely derail the drug, but it could limit its potential and will certainly be closely followed by regulators.

The cardiac adverse events were dose-dependent, which is good and bad. It is good in that it implies that the risks could potentially be managed with dose adjustments, and it is bad in that it implies that the signal is an on-target toxicity (which is consistent with earlier results and pre-clinical testing that showed a potential impact on the heart). In other words, if more drug leads to more events, then it looks like the drug is the cause of the adverse events. As such, I think the cardiac effects are likely real and likely related the drug but we need significantly more data to delineate the exact impact it will have on the commercial potential.

There is a large and robust set of phase III trials (four separate trials) that are going to answer a lot of these questions. The key is going to be both to confirm the stunning efficacy seen in the phase II trial and perhaps more importantly to further understand and delineate the potential cardiac side effects. All that being said, the early data are quite impressive.

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