They sound like names of creatures that Harry Potter could have encountered in the Forbidden Forest. But no, these are the names of two new drugs that may force the current golden boy of the weight control world, Ozempic, onto the back burner. Given the widespread incidence of obesity and its serious health consequences, it is easy to understand why scientists have a large appetite for drugs that control appetite and why they get excited when studies emerge with impressive results. And that is exactly the case for orforglipron and retatrutide.
Appetite is controlled by many factors, with a number of hormones playing a part. Recent research has focused on three of these that are released when food enters the intestines. “Glucagon-like peptide-1 (GLP-1)” has received the most attention since it is known to slow the emptying of the stomach and increase the feeling of fullness. Unfortunately, GLP-1 cannot be introduced either orally, or by injection, because it is quickly broken down by enzymes in the body. That finding stimulated a search for analogues, chemically similar substances, that would have a longer-half-life in the bloodstream. Semaglutide (Ozempic), originally developed for the treatment of type-2 diabetes, is one such analogue, and is already available as a weekly injection, at a somewhat higher dose than Ozempic, for weight control under the name Wegovy.
A common practice in the development of pharmaceuticals is to search for “improved versions” of existing drugs usually by altering their molecular structure to produce a novel entity. One obvious improvement here would be an oral version of semaglutide, but the problem is that semaglutide is very poorly absorbed from the digestive tract. An “absorption enhancer” can promote oral bioavailability, and one such compound has been paired up with semaglutide to produce Rybelsus, a pill form of semaglutide. (For the chemically curious, that would be sodium N-[8-(2-Hydroxybenzoyl)amino]-caprylate.) Currently Rybelsus is only approved for type-2 diabetes and has to be taken after an overnight fast with patients being advised not to eat or drink anything for thirty minutes after taking the drug. Even with the enhancement, Rybelsus cannot achieve blood levels comparable to the injected form of semaglutide and therefore its effect on body weight is limited.
Another improvement would be a drug that mimics not only the action of GLP-1, but also two other hormones that also affect the appetite, namely “glucagon” and “glucose-dependent insulinotropic polypeptide (GIP).” These hormones are all “polypeptides,” meaning they are composed of a string of amino acids. Producing analogues is based on manipulating the amino acid composition of the polypeptide.
One such manipulation by chemists at the Eli Lilly Company resulted in retatrutide, a drug that mimics not only GLP-1, but glucagon and GIP as well. That was certainly motivation for designing a clinical trial! Adults with a body mass index (BMI) of over 27 were divided into an experimental and a placebo group with the experimental group receiving weekly injections of different doses of retatrutide over 48 weeks. The results proved to be, well, spectacular! At the highest dose (12 mg), participants lost 25% of their body weight! A second study in diabetic subjects with a BMI over 25 corroborated the results, with a 17% weight loss at a weekly dose of 12 mg. As had already been noted with GLP-1 mimics, a significant percentage of subjects experienced gastrointestinal side effects, meaning nausea, diarrhea, vomiting and constipation. Such side effects of course have to be weighed against the benefits of increased fat metabolism, increased energy expenditure and reductions in blood glucose, food intake and body weight.
Orforglipron, also developed by Eli Lilly, makes for an even more remarkable tale. The weight loss is not quite as dramatic, although at 15% it is still nothing to sneeze at. But what makes orforglipron appealing is that it is a pill to be taken once a day with no dietary restrictions. No scary injections! Unlike semaglutide, its effect on body weight was not a chance finding, but rather the result of very sophisticated research that involved mapping the receptor for GLP-1. This hormone functions by fitting into a receptor on the surface of cells, much like a key fits a keyhole. When the fit is just right, the cell swings into action releasing chemicals that curb the appetite.
The key to mapping the GLP-1 receptor was the use of “cryogenic electron microscopy (Cryo-EM),” a technique for which Jacques Dubochet, Joachim Frank and Richard Henderson were awarded the 2017 Nobel Prize in Chemistry. Cryo-EM involves cooling a sample to slow down molecular motion allowing for the high-resolution determination of the structure of biomolecules in solution. The GLP-1 receptor is one such biomolecule.
Obviously GLP-1 itself fits the receptor, but as previously mentioned, this molecule is not viable as a drug because it quickly breaks down in the bloodstream. The question raised by researchers was whether some smaller molecule, not as susceptible to breakdown as a polypeptide by the body’s enzymes, could still trigger activity even if it only fits into a part of the receptor. Based on identifying “pockets” in the GLP-1 receptor, as determined by Cryo-EM, chemists synthesized a number of molecules, one of which, orforglipron, did trigger activity. And the molecule was stable enough to be administered orally! Furthermore, it also lowered blood pressure, cholesterol and triglycerides, all of which are risk factors for cardiovascular disease when elevated. Another benefit is that potentially orforglipron, a relatively simple molecule, can be produced more economically than polypeptides, making it available to segments of the population that cannot afford semaglutide and its analogues. One significant drawback for all these medications is that treatment has to be continuous. If the drugs are stopped, the weight returns.
What’s next for orforglipron and retatrutide? So far, the studies have been what are known as “Phase-2,” meaning that they are relatively short term and involve just a few hundred subjects. Next will be “Phase-3” trials that enroll thousands of overweight subjects who will be treated for several years. If no serious side effects are noted, and efficacy is demonstrated, applications for approval to market the drug will follow. At that point, a trade name will have to be chosen, hopefully one that rolls off the tongue more easily than orforglipron or retatrutide.
