Beyond GLP-1: Better Weight Loss Drugs Are Coming

Wegovy (semaglutide) and Mounjaro (tirzepatide) have emerged as impressive weight loss drugs, both initially designed for diabetes treatment. Wegovy works by mimicking glucagon-like peptide 1 (GLP-1), a hormone that controls appetite and lowers blood glucose levels. Mounjaro also activates GLP-1 receptors but additionally stimulates glucose-dependent insulinotropic polypeptide (GIP) receptors. The market predicts Mounjaro’s annual sales could reach over $10 billion, with Wegovy close to $8 billion.

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However, GLP-1 agonists such as Wegovy are not suitable for all patients. Some may experience side effects like nausea, diarrhea, or vomiting, although these usually diminish over time. Moreover, Wegovy has to be injected, which could be a barrier for some patients. Another downside is the cost, which exceeds $1,300 per month, and its effects are not long-lasting; after ceasing the medication, patients regained most of the lost weight within a year.

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The pharmaceutical industry is tirelessly working on improving these drugs and developing new ones. One approach involves oral forms of the medications; for instance, Novo Nordisk is testing higher doses of oral semaglutide, which showed promising results. Another approach is combining GLP-1 agonism with GIP-modulating effects, as GIP is also involved in insulin secretion. However, the interaction between GLP-1 and GIP is complex, and careful balancing is necessary. Viking Therapeutics is among companies working on dual GLP-1/GIP agonists.

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Amgen's AMG 133 combines GLP-1 agonism with GIP antagonism, a combination that led to a weight loss of 14.5% in a phase 1 trial with 110 people. Other companies are exploring combinations of GLP-1 with glucagon, aiming for more potent metabolic outcomes. Moreover, different hormones and signaling molecules that regulate appetite are under investigation. For example, Novo Nordisk is testing semaglutide with cagrilintide, an amylin analog, in phase 3 trials.

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Aardvark Therapeutics is exploring the stimulation of natural gut hormones disrupted in obesity by using compounds that target specific receptors in the mouth and gut, triggering appetite-suppressing hormones like GLP-1, GIP, PYY, and cholecystokinin.

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Versanis Bio focuses on lean muscle mass, as it is associated with various metabolic benefits. Their monoclonal antibody bimagrumab targets receptors involved in muscle degradation and fat reduction. Other approaches aim at boosting energy expenditure, suppressing fat absorption, or using gut bacteria to induce weight loss.

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However, the field is fraught with challenges, as drug development for obesity has faced numerous failures due to the complexity of human metabolism and its regulatory mechanisms. The diversity of obesity as a condition necessitates a multi-faceted approach in treatment.

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With an estimated 650 million people affected worldwide, there is an urgent need for effective treatments. The development of GLP-1 agonists is just the beginning, and the industry is open to exploring diverse approaches, including intermittent treatments, in combating obesity.