ATX-304: The Other Side of the Diet & Exercise Equation in Metabolic Disease

6 mins to read

October 18, 2023


James Peyer, PhD; CEO, Cambrian Bio

The leading cause of death worldwide is cardiometabolic dysfunction, and one of the biggest risk factors for cardiometabolic dysfunction is obesity. Two drugs approved to reduce blood glucose in adults with type 2 diabetes (semaglutide and tirzepatide), have recently shown in clinical trials that they can induce weight loss in obese people. While only semaglutide is approved for weight management so far under the brand name Wegovy®, with more than 50% of the adult population in the US now considered obese1 some analysts predict that these medicines, which belong to a class called incretins, will become the best-selling drugs of all time and transform the way we treat metabolic dysfunction2.

With the promise of these drugs, Mounjaro® (tirzepatide) manufacturer Eli Lilly has become the most valuable pharma company in the world3 and the 10th most valuable company globally, more than doubling its stock price and adding $300B to its market cap since the start of 20224. Meanwhile, Wegovy® manufacturer Novo Nordisk’s market cap has surpassed the GDP of its home country of Denmark5.

A potential drawback of these drugs in their path to treating diabetes, obesity, and potentially other cardio-renal metabolic diseases is their effects on muscle6. Incretins work, in essence, by preventing people from becoming hungry, and so the effects that are observed are consistent with long-term fasting. During treatment, obese people lost about 1kg of muscle for every 2kg of lost fat7. The exact degree to which skeletal muscle loss occurs and ways to mitigate these effects through exercise and resistance training has not yet been investigated, but it’s certainly worth paying attention to (e.g., Eli Lilly acquired Versanis Bio for its drug to increase muscle mass in August)8.

Muscle loss is particularly important in older adults, who progressively lose skeletal muscle with age, becoming more vulnerable to falls and fractures, leading to a loss of independence, mobility, a reduction in quality of life, and premature death. This leaves older patients and their doctors with a dilemma: should they jeopardize their muscle health to manage other health issues?

However, there’s another side to this equation – reducing calorie intake can induce weight loss, but so can increasing the rate at which calories are burned. ATX-304, being developed by Cambrian pipeline company Amplifier Therapeutics, is an activator of a metabolic sensor called AMPK that is being studied in clinical trials to determine its safety and assess its potential to correct metabolic dysfunction by increasing energy expenditure. ATX-304 has been shown to induce weight loss in mouse models of obesity and diabetes, and MRI scans of body composition in mice show a parallel drop in fat mass. Mice given ATX-304 tended to eat more than control mice, even while losing weight. As we look at these results, the amount of fat loss measured by MRI is almost the same as the total weight loss observed in the animals. If these results hold in human trials, this could be a game-changer.

ATX-304 promotes weight loss in diabetes-prone hIAPP transgenic mice fed a high fat diet, with similarities observed between total weight loss and fat mass reduction9

ATX-304 has already been tested for safety in about 150 healthy subjects and patients with Type 2 diabetes, and this week we announced the dosing of the first participants in a new Phase 1B clinical trial to test whether the drug can correct metabolic dysfunction in prediabetic obese and overweight individuals.

Getting philosophical for a moment – mammals including humans evolved in a world where every calorie was precious. Our ancestors didn’t know where tomorrow’s meal would come from, and so our minds and bodies have been intricately programmed to eat when we could and use as little unnecessary energy as possible to avoid starvation. Happily, for more people today than ever in history, food is in abundance. So now these evolved behaviors are hurting us more than they’re helping - and health problems are coming from consuming more calories than we burn. What if instead of blaming people for these hard-wired behaviors, we used science to give ourselves the ability to burn more of the calories we take in instead of storing it in the form of fat?

It’s early innings, but between the impact we’re already seeing from the incretins and the potential of novel mechanisms like ATX-304, we may finally have the tools to reverse the trend of ever increasing cardiometabolic diseases.

Until next time.










9 Adapted from Steneberg, P., et. al. JCI Insight. 2018, 3 (12), e99114. DOI: jci.insight.99114. Mice fed ATX-304 formulated in 2mg/g food