Antag Therapeutics: Developing Peptide-Based Treatments For Obesity Management

Antag Therapeutics, a Danish biotech company, has been exploring innovative approaches to obesity treatment for nearly a decade. With its scientific roots tracing back to the laboratory of Jens Holst, the father of GLP-1 receptor agonists, Antag is now focusing on a different mechanism: targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR).

This receptor plays a crucial role in metabolic regulation, influencing insulin secretion, nutrient absorption, and fat metabolism. Under the leadership of newly appointed CEO Joerg Moeller, Antag is challenging conventional wisdom in obesity research with its antagonist approach, aiming to deliver superior weight loss and metabolic benefits without the common side effects associated with current obesity drugs.

The GIPR is far more than a simple biological switch, Moeller explained to In Vivo: “GIP is an incretin hormone released by the small intestine in response to food intake. This hormone plays a very crucial role in the regulation of insulin secretion, glucose metabolism, and fat storage.”

The genetic foundation for inhibiting GIPR is well-established. People with genetic variants of GIPR that diminish its function tend to have lower body mass index (BMI) and reduced body fat, leading to a leaner physique compared to those with normal GIPR activity.

Moeller believes that this mechanism is different from GLP-1R agonists and offers a new approach that surpasses current obesity drugs in terms of tolerability, efficacy, and combinability with other mechanisms involved in obesity. “This new mechanism has the potential to go beyond what existing classes of obesity drugs are able to deliver these days,” he said.

There has been a wider clinical debate about whether GIPR agonism or antagonism is the best strategy to target the GIPR for managing obesity and diabetes. GIPR agonism, which activates the receptor, has shown potential in enhancing insulin secretion and improving glycemic control, but may lead to receptor desensitization over time.

Conversely, GIPR antagonism, which blocks the receptor, has demonstrated benefits in reducing weight gain and improving metabolic profiles, especially when combined with GLP-1 receptor activation, without causing gastrointestinal side effects. Researchers continue to explore both approaches to determine the most effective and sustainable treatment for patients.

What sets Antag apart in the biotech field is its antagonist approach, a strategy that challenges conventional wisdom in obesity research. “When we first began exploring GIPR antagonism, it wasn’t widely considered a viable approach,” said Moeller. “But the data we’ve generated since then has helped shift that perception.”

Setting Aside The Side Effects

That data comes from preclinical studies of Antag’s lead molecule AT-7687, a peptide intended to be used as monotherapy or alongside current or future obesity treatments, including GLP-1 medications, to enhance weight loss and metabolic benefits. This dosing flexibility offers several advantages over other treatment modalities used to treat obesity , such as antibodies directly linked to GLP-1, by allowing optimal targeting for maximum effectiveness and tolerability.

In studies with non-human primates, the combination of AT-7687 and a GLP-1 achieved among the strongest weight loss effects reported in preclinical models. Moreover, AT-7687 improved blood sugar control and lipid profiles independently of weight changes, achieving these benefits without causing gastrointestinal side effects.

“Our vision is for our lead compound to become a preferred option for people seeking to maintain their weight loss - particularly those who struggle with the tolerability of existing therapies, including GLP-1R agonists.”

Joerg Moeller

Side effects are one of the main challenges for patient adherence on GLP-1 drugs such as semaglutide and tirzepatide. A Journal of the American Medical Association (JAMA) paper showed that nearly 30% of individuals discontinued semaglutide in the SELECT trial, with real-world estimates for GLP-1 receptor agonists discontinuation in the range of 50% to 75% at 12 months.

Another JAMA study has found that, of 125, 474 patients initiating GLP-1s, 46.5% of patients with and 64.8% without type 2 diabetes discontinued within 1 year; 47.3% of patients with and 36.3% without type 2 diabetes subsequently reinitiated a GLP-1 within one year. Weight loss, income and adverse events were significantly associated with discontinuation, while weight regain was significantly associated with reinitiation.

“We all know that drugs don’t work when they are not administered and taken, and so tolerability is key,” said Moeller. “Our vision is for our lead compound to become a preferred option for people seeking to maintain their weight loss - particularly those who struggle with the tolerability of existing therapies, including GLP-1R agonists.”

Antag’s lead molecule was developed following the pioneering discovery of a natural GIPR antagonist by University of Copenhagen professors Jens Holst, known for discovering GLP-1, and Mette Rosenkilde. Both professors co-founded Antag and bring decades of expertise in incretin biology. Holst also leads Antag’s scientific advisory board.

A Fresh Season Of Leadership

Joerg Moeller brings more than just scientific expertise to Antag. With over three decades in the pharmaceutical industry and previous leadership roles at Leo Pharma, head of global R&D at Bayer’s Pharmaceutical Division, and most recently the CEO of BenevolentAI, he wants to bring a leadership approach that sets the company’s cultural tone.

“I try to lead a team by ensuring that people feel they are not only able to speak up, they’re actually mandated to speak up,” he explained. “I demand what I often describe as passionate, unfiltered debate. Creating an environment that allows for these unfiltered debates, for me, is very important. We take the decision, and then is the expectation that everyone stands behind that decision, unless we have new data, new information that warrants us to go back and revisit what we have decided before,” he explained.

Moeller replaces company co-founder Alexander Sparre-Ulrich, who played a pivotal role in establishing the company as a future player in GIPR antagonism, a new mechanism of action in the obesity field, and to reach clinical inflection points. Sparre-Ulrich now moves to the role of COO.

It was serendipitous timing that brought Moeller to Antag. He was at a point in his career, he told In Vivo, where he wanted to focus on science that really interested him, and Antag fitted the bill. “I spent most of my career in clinical development, so it felt like a natural match joining a company that is driven by top notch science and is entering a stage where they can use my experience and expertise to plan and execute the development stage of its assets,” he said.

The US Food and Drug Administration (FDA) accepted the IND application for Antag’s lead molecule in October 2024, enabling Antag to initiate plans for Phase I trials. The study will evaluate the safety, tolerability and pharmacokinetics in both healthy lean and people living with obesity. The company will also explore AT-7687 as a monotherapy and in combination with a GLP-1 receptor agonist in obese individuals.

Driving this trial forward is the €80m Series A financing that closed in December 2024. Led by a syndicate of global investors, the round was led by Versant Ventures, with participation from original investor Novo Holdings, SR One and Dawn Biopharma (a platform controlled by KKR).

What’s Next?

While Antag’s lead asset is anticipated to be a once weekly injectable, it is also working on a monthly injectable.

Moeller explained that AT-7687 in pre-clinical studies has demonstrated additional beneficial effects, such as significantly lowering LDL and increasing HDL levels. If confirmed clinically, the LDL-lowering effect is substantial enough to potentially qualify as a lipid lowering agent.

He also noted that a drug profile which lowers LDL and increases HDL is expected to provide significant benefits for the obesity-associated cardiometabolic risk profile, giving them additional optimism regarding the profile and differentiation of this mechanism compared to other classes of obesity drugs.

Antag now has a cash runway of three and a half years, which ensures the company can complete a Phase IIa program. Moeller expects data from the single and multiple dose escalation study by the end of 2025, and the team is planning further studies to explore combination with a GLP-1 receptor agonist. These studies will generate data inflection points and help guide the company’s next stages of development.

In the meantime, Moeller’s vision for Antag includes building a strong, dedicated team and planning for success in a rapidly evolving field. He stressed that Antag will continue to be frugal and lean, but the team wants to “plan for success” in a field where data is generated frequently.