WHAT HAPPENED

Novo Nordisk has invested in EraCal Therapeutics, a Swiss biotech startup developing new treatments for metabolic syndrome.

Metabolic syndrome is a combination of at least three of five medical conditions such as abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL) cholesterol.

Metabolic syndrome is associated with an increased risk of many serious pathologies, including cardiovascular (heart failure, atherosclerosis, coronary heart disease, peripheral artery disease), type 2 diabetes mellitus, non-alcoholic steatohepatitis (NASH), asthma, Alzeimer’s disease, and others.

EraCal’s primary business focus is on the treatment of obesity.

The Danish pharmaceutical giant has pledged to give up to €235 million ($255 million) to the Swiss company as it develops the drug project, as well as pay royalties from sales of the finished drug.

This is an oral small-molecule compound characterized by a fundamentally new mechanism of action aimed at controlling appetite for weight loss. It is assumed that weight loss with the new drug will be completely safe and as effective as bariatric surgery.

If all goes well, the revolutionary weight loss drug will be on the market tentatively in 2028.

The partnership between EraCal and Novo Nordisk was originally formalized two years ago, in mid-January 2022, when the parties agreed to search for new drug targets relevant to food regulation and additional metabolic phenotypes.

In mid-February 2023, EraCal began collaborating with Nestlé to discover and develop new nutraceuticals that can control food intake.

EraCal, which emerged from the walls of the University of Zurich and Harvard University in September 2018, had previously raised a combined CHF 1.1 million ($1.27 million) in grants and seed investments.

EraCal Therapeutics

 

WHY IT MATTERS

Back in 1997, the World Health Organization (WHO) officially recognized obesity as a global epidemic [1].

As of 2016, over 1.9 billion adults were overweight (39% of the world’s population), of which more than 650 million were obese (13% of the world’s population). The global prevalence of obesity nearly tripled between 1975 and 2016 [2].

Overweight is a major risk factor for cardiovascular diseases, diabetes mellitus, osteoarthrosis, and some cancers [2]. Obesity kills at least 2.8 million people each year [3].

 

FIGHTING STIGMA

Obesity is stigmatized and discriminated against in most countries of the world: It is considered to be a lifestyle issue only — they say that being overweight is a consequence of lack of willpower, inability to control eating behavior [1] [2].

The American Medical Association (AMA) classified obesity as a chronic disease only in 2013 [3].

The suggestion that obesity is not a disease but rather a consequence of a chosen lifestyle exemplified by overeating and/or inactivity is equivalent to suggesting that lung cancer is not a disease because it was brought about by individual choice to smoke cigarettes [4].

AMA

According to the AMA, things are very complicated. Obesity should be viewed as a multi-metabolic and hormonal disease state including impaired functioning of appetite dysregulation, abnormal energy balanced, endocrine dysfunction including elevated leptin levels and insulin resistance, infertility, dysregulated adipokine signaling, abnormal endothelial function and blood pressure elevation, non-alcoholic fatty liver disease, dyslipidemia, and systemic and adipose tissue inflammation [4].

The UK, unlike many countries and organizations, including WHO and the European Parliament, still does not officially recognize obesity as a disease [5].

The Royal College of Physicians (RCP) is calling on the government and the wider health community to urgently recognize obesity as a complex progressive chronic multifactorial disease. Until this happens, its prevalence is unlikely to be reduced [6] [7].

It is important to the health of the nation that we remove the stigma associated with obesity. It is not a lifestyle choice caused by individual [food] greed but a disease caused by health inequalities, genetic influences and social factors. It is governments, not individuals, which can have an impact on the food environment through regulation and taxation, and by controlling availability and affordability. Governments can also promote physical activity by ensuring that facilities are available to local communities, and through legislation and public health initiatives [6].

RCP

 

CHALLENGING TREATMENT

Weight-loss medications have long had a bad reputation.

Since the introduction of 2,4-dinitrophenol (2,4-DNP), a thermogenic agent and the first modern pharmacologic treatment for obesity, in 1933, many therapeutic compounds have been tried. Most of them reduce body weight very little.

Between 1964 and 2009, twenty five anti-obesity drugs were withdrawn from the market. The main reason for terminating the marketing license was serious adverse events associated with administration, such as psychiatric disorders, cardiotoxicity, drug abuse, and drug dependence. Some medicines dramatically increased the risk of death [1].

 

SAFEST AND MOST EFFECTIVE DIET PILL FOR WEIGHT LOSS

Bariatric surgery is the single most effective and long term method of weight loss, although not always ideal and accessible to patients [1] [2]. To call bariatrics completely safe, however, is not possible [3].

With obesity remaining one of the most poorly treated chronic diseases worldwide for decades and its prevalence increasing at an alarming rate, there is a great unmet medical need for new weight loss drugs that are as effective as bariatric surgery and as safe as possible.

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Swiss biotech startup EraCal Therapeutics seems to have found a solution to the problem.

Josua Jordi
Josua Jordi, CEO of EraCal Therapeutics. Image: UZH Foundation.

Era-379, the main experimental asset of EraCal, is an oral small-molecule appetite suppressant [4].

Since the main cause of overweight and obesity is an energy imbalance, when the caloric content of the food intake exceeds the body’s energy needs [5], proper regulation of eating behavior in the form of reducing the amount of food consumed will definitely lead to the desired weight loss.

According to studies on obese mice, a daily single dose of Era-379 provided weight loss of more than 20% over two weeks, and without any serious adverse events (AEs).

The target of Era-379 is a specific protein in the liver, the name of which EraCal has not yet disclosed, that controls the peripheral liver–brain signaling pathway. The molecule alters the peripheral perception of nutrients [6].

Importantly, Era-379 does not target popular obesity drug targets such as serotonin subtype 2C receptor (5-HT2C) or glucagon-like peptide-1 receptor (GLP1R). Era-379 does not interfere with neurotransmitters such as dopamine or the cannabinoid system. In other words, Era-379, which avoids targeting high-risk safety targets, promises to be devoid of serious AEs.

Era-379, unlike the incretins, is independent of the vagus nerve connecting the gut to the brain and therefore may act synergistically with GLP1R agonists.

Era-107, EraCal’s second experimental asset for the treatment of obesity, is an oral appetite suppressant targeting two different targets than Era-379. The molecule passes through the blood–brain barrier (BBB) and activates hypothalamic cells that send satiety signals. As a result, the feeling of satiety increases — the amount of food consumed in one meal decreases [7].

Testing Era-107 administered once a day to obese mice caused them to lose 14% weight in two weeks. No cognitive impairment, gastrointestinal difficulties, nausea or conditioned taste aversion was noted.

The development of another molecule, Era-309, which acts through a different neural circuit in the brain to suppress appetite by reducing the desire to eat, is underway.

Different therapeutic strategies are in demand for treating people with different causes of obesity. Some are more sensitive to food stimuli and tend to eat more often, while others are less sensitive to satiety and consume more calories at each meal.

EraCal’s development pipeline includes other small-molecule drug projects aimed at controlling energy expenditure, appetite induction, and circadian rhythms.

 

THE PLATFORM

At the heart of all EraCal Therapeutics’s drug development is a proprietary phenotypic screening platform based on the aquarium tropical fish Danio rerio (zebrafish, zebra danio), a vertebrate animal model popular in biomedical research.

Danio rerio. Image: Dan Olsen / Shutterstock.

In the last decade, phenotype drug discovery (PDD) has experienced a resurgence as an integral part of the drug discovery along with target-based approaches. The use of whole organisms can significantly accelerate the identification of “hits” and the selection of promising “leads” for the treatment of complex diseases for which a comprehensive mechanistic picture is lacking.

High-throughput screening (HTS) is a key tool for PDD, but developing disease-relevant and scalable biologics for phenotypic HTS platforms remains a challenge.

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In the hands of EraCal is a unique platform for evaluating drug compounds in a whole-organism context that exploits the multi-organ complexities of zebrafish physiology and behavior and is easily translatable to humans.

By identifying drug-induced changes at the whole-organism level, the EraCal authoring platform enables the collection of comprehensive and unbiased information on the action of a therapeutic molecule across the entire mechanistic target space, as well as an initial assessment of absorption, distribution, metabolism, and excretion (ADME) and safety. Such functional metrics are key to selecting “hits” with the highest a priori probability of becoming promising drug “leads”.

The high predictive validity of zebrafish with respect to human physiology significantly shortens the chain of translatability, paving a direct path to human studies for proof-of-concept.

 

FROM HISTORY

Josua Jordi entered Harvard University in Cambridge to study the basic neurophysiological factors that determine the feeding behavior of zebrafish [1] [2] [3] [4].

The young biochemist, who has been researching appetite modulators since 2014, developed a new strategy for finding neuroactive drug compounds while working as a postdoc in Florian Engert’s neuroscience lab at Harvard. While testing the effects of 10,000 molecules on zebrafish larvae, two dozen were selected that changed the pattern of food intake by regulating appetite. Most importantly, orexigenic and anorexigenic molecules acted exclusively selectively, that is, without any outside influence on the level of spontaneous activity of larvae, response to stimuli, habituation, sleepiness, and other behaviors [5].

Josua was worried that the promising results that had led to the discovery of “perfect drugs”, super-selective and completely safe, would come to nothing unless there was a way to put them into practice. This is why he decided to step back from his scientific endeavors to bring new appetite modulators to the market [6] [7].

In 2017, Josua returned to the University of Zurich in Switzerland, where he had earned a degree in human physiology a few years earlier. Following the validation in mice of the initial findings on zebrafish, supported by Thomas Lutz’s research on eating behavior, Josua started taking business courses and participating in startup accelerator programs.

In September 2018, with investors having already made a modest seed financing and the necessary intellectual property licensed from Harvard and Zurich, Joshua launched EraCal Therapeutics, headquartered in Zollikon, Switzerland. The business partner is Simon Breitler, who specializes in synthetic organic chemistry and was formerly a team leader in the preclinical Chemistry, Manufacturing, and Controls (CMC) department at Roche.

The company’s name is a portmanteau for erase + calories.

Although EraCal originally planned to develop appetite-stimulating drugs for patients with chronic diseases associated with weight loss, its priorities shifted to the opposite of appetite-suppressing drugs. However, appetite enhancers to help with the same anorexia nervosa have not been forgotten.

Simon Breitler and Josua Jordi, co-founders of EraCal Therapeutics. Image: Venture Kick.
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Julia Mardi

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