a new drug candidate for obesity

Individual zebrafish larvae in a well of a 96-well plate.

EraCal Therapeutics used zebrafish to identify drug compounds that could alter food consumption.Credit: EraCal Therapeutics

EraCal Therapeutics is a spin-off from the University of Zurich, Switzerland, and Harvard University in Cambridge, Massachusetts.

Josua Jordi joined Harvard University in Cambridge, Massachusetts, to study the basic neurophysiological drivers of feeding behaviour in zebrafish, a popular animal model in biomedical research. He didn’t intend for the project to lead him down a path to starting a company.

He managed to identify dozens of drug compounds that could alter food consumption in zebrafish larvae without affecting spontaneous activity levels, responses to stimuli or other behaviours1. But Jordi worried that the promising results of his high-throughput drug screen would go nowhere unless he was committed to their therapeutic advancement. “If I didn’t believe in it,” Jordi says, “nobody was going to do it.” So he decided to step away from academia and focus instead on bringing his appetite-modulating drug candidates to market.

So in 2017, after a stint in Florian Engert’s neuroscience laboratory at Harvard, Jordi returned to the University of Zurich in Switzerland, where he had completed his PhD in human physiology several years earlier. After validating the initial zebrafish findings in mice with his Zurich colleague Thomas Lutz, who studies eating behaviours, Jordi started taking business courses and participating in start-up accelerator programmes.

Jordi secured modest seed funding from investors, licensed the requisite intellectual property from Harvard and Zurich and launched EraCal Therapeutics in Zollikon, Switzerland. The name is a portmanteau of the words “erase calories”.

Although EraCal has plans to develop appetite-stimulating drugs for people with chronic weight-loss conditions, the company is currently focusing on a pipeline of appetite suppressants for tackling obesity and its many metabolic complications. In unpublished studies in mice, the lead therapeutic candidate, Era-107, led to a 14% average reduction in body weight after just two weeks of therapy. By comparison, mice treated with approved anti-obesity drugs shed less than half as much weight.

What’s more, daily dosing with Era-107 produced none of the side effects that are typical of other therapies, which lack the behavioural selectivity of the EraCal compound. There was no cognitive impairment, gastrointestinal issues, nausea or conditioned taste aversion. “These are drugs that, in a very targeted and specific way, interfere with appetite,” says Engert, a scientific adviser to the company.

EraCal is now gearing up to carry out further toxicology studies ahead of first-in-human trials planned for late next year.

An example for the field

The, so far, clean safety profile of Era-107, speaks to the power of the high-throughput technique that Jordi and Engert developed for tracking food intake, and other behaviours, in zebrafish larvae, says chemical biologist Randall Peterson of the University of Utah College of Pharmacy in Salt Lake City. “It’s a beautiful assay,” says Peterson, who provided advice on the experimental design and analysis of the drug-screening data. “They looked at a whole host of different behaviours that gave them some confidence that these drug-induced changes were specific to appetite and not just generally messing up the physiology or neuronal function of the fish.”

Will Norton, a behavioural neuroscientist at the University of Leicester, UK, says that the method should serve as an exemplar for the field. “This approach sets out a new road map to identify psychoactive drugs, with the potential to both characterize the neural circuits that control behaviour, and improve treatment of human diseases such as anorexia or obesity,” says Norton.

As is typical of drugs discovered through behavioural studies, the precise mechanism of action of EraCal’s lead therapeutic candidate is something of a mystery (see ‘Appetite, interrupted’). Jordi and his colleagues have ruled out some molecular targets — it doesn’t bind to any of the receptors or enzymes targeted by other anti-obesity agents, nor does it act against any of the main neurotransmitter systems. The researchers are now running more experiments to pin down exactly how Era-107 works. “This is one of the challenges ahead,” Jordi says.

At the same time, the company is moving ahead with development of Era-309, a chemically distinct molecule that, like Era-107, selectively quashes appetite, but seems to act through a different neural circuit in the brain. Whereas Era-107 promotes satiety by enhancing feelings of fullness and therefore limiting the amount of food consumed at any one time, Era-309 diminishes the urge to eat.

The two drug strategies could prove helpful for people with different causes of obesity — some people are more responsive to food cues and tend to eat more often, others are less sensitive to fullness and consume more calories at each meal or snack.

“This is a two-armed approach,” Jordi says, emphasizing the need to personalize treatment for the almost 2 billion people worldwide who are overweight or obese. And at EraCal, that means taking a science-driven approach that still relies on the types of zebrafish experiment first devised by Jordi in Engert’s Harvard lab.

“The zebrafish,” says Jordi, “is core to everything we do.”

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