Addressing the bigger picture in obesity and liver health issue

Human Health

Over 1 billion people around the world live with obesity—a disease that raises the risk for cardiovascular, renal and metabolic complications like MASH, chronic kidney disease, type 2 diabetes and cardiovascular diseases. Boehringer Ingelheim is committed to addressing these hidden connections, focusing on integrative approaches that benefit patients holistically.

Heike Neubauer, director of external innovation in eye health & research beyond borders, spends her days collaborating with colleagues and external stakeholders to identify and drive strategic opportunities that strengthen our pipeline. “It’s a dream for researchers of any disease to discover a gamechanger for patients,” says Heike. 14 years ago, Heike was herself hoping to improve the lives of those living with obesity and metabolic dysfunction-associated steatohepatitis (MASH). Over a decade later, and in a new role, the project she initiated might be close to finding success.

It’s a dream for researchers of any disease to discover a gamechanger for patients
Heike Neubauer, director of external innovation in eye health & research beyond borders

In 2011, Heike, a lab director at the time, and her team began to explore an approach to treating obesity and MASH. Inspired by human physiology, the idea was to combine the benefits of two naturally occurring hormones into a single therapy: glucagon and glucagon-like peptide-1, more commonly known now as GLP-1. That’s what the team hopes to achieve with survodutide, a dual agonist that activates both the glucagon and GLP-1 receptor.

Inspired by our natural physiology

For many trying to lose weight, their goals are often based on a simplistic fundamental: eat less, move more. The body, Heike says, is more complex than that. For example, hormonal imbalances or insulin resistance could present barriers for someone with obesity or overweight. Treatments should therefore account for these complexities while overcoming the cause of obesity: a chronic imbalance of energy intake and expenditure.

Global obesity prevalence

The GLP-1 hormone acts through the GLP-1 receptor and plays several important roles in the body. That includes stimulating insulin secretion, slowing digestion, and decreasing food intake and appetite. But there are natural limitations. “The body goes into energy saving mode, for example,” explains Heike. “When you eat less, the body tries to save energy and hence, energy expenditure decreases.”

Counteracting that is where the glucagon receptor agonist comes in. Produced in the pancreas, glucagon increases the liver’s metabolic rate and energy expenditure. This could help patients to use more energy and augment weight loss.

Obesity definition & relevant factors

Obesity is a disease caused by a chronic imbalance of energy intake and expenditure. This can lead to a build-up of excessive fat in organs and may mean they stop working well.

Energy balance

Energy expenditure

• Physical activity

• Resting metabolic rate

(with factors for that being age, gender, genetics, hormones, body & organ size)

Energy intake

Appetite & hunger

Decreased satiety

Food preference & craving

Oxyntomodulin, the blueprint for the survodutide peptide, activates both the glucagon and GLP-1 receptors. However, all three endogenous hormones, meaning they’re naturally produced by the body, have a short half-life. For example, once secreted, GLP-1 takes just two minutes to reach half its initial concentration.

Addressing interconnections in metabolic health with a dual agonist

Another crucial component is that the mobilization of hepatic fat, or fat stored in the liver, could help another patient group: those living with MASH.

MASH is a progressive liver disease characterized by the inflammation of the liver due to a buildup of excessive fat in the liver cells, often leading to chronic inflammation and fibrosis. It’s connected with other cardiovascular-renal-metabolic (CRM) conditions, such as chronic kidney disease, heart failure and diabetes. These diseases are interconnected—living with one condition increases the chance of developing another.

While Heike is quick to point out that having obesity doesn’t directly cause MASH, she notes the strong connection. Obesity can lead to a build-up of excessive fat in organs like the liver, which can prevent it from working optimally. She adds: “The fat is stored in the wrong place; the liver isn’t meant for fat storage, and this can eventually cause inflammation and fibrosis.”

Metabolic, mechanical and mental complications

Possible comorbidities / increased risk factors

Body Weight Lowering (BWL) required for beneficial effect on complication

The numbers reflect that: One in three people with obesity develop MASH over their lifetime. And it’s a growing concern. MASH is predicted to be the leading cause of liver transplantation by 2030. The liver also plays an important role as a key regulator of metabolic health. Yet unfortunately for more than 250 million people worldwide already living with MASH, there are limited treatment options available.

Balancing act: The science behind survodutide peptide

Based on the phase II data, the survodutide peptide has shown a direct impact on both MASH and obesity—results the team is especially optimistic about. “We spent a lot of time getting the ratio between the two components of survodutide, so the glucagon and GLP-1 receptor, exactly right. We wanted the best molecule for both indications,” Heike explains on the research process.

The team spent a lot of effort, for example, on characterizing different candidate molecules with varying glucagon activity. Or, simply put, they tried to maximize the reduction of energy intake and increase in energy expenditure by finetuning the molecules’ properties. Too little glucagon activity meant not seeing much of an impact on energy expenditure. Too much, however, and that could trigger unwanted effects.

Physiological metabolism

Energy intake equals energy expenditure → weight stability

The team now believes they achieved their desired outcome based on two criteria: an optimized balance of the two hormones and a prolonged half-life, thus enabling less frequent drug administration.

As for the need for dual agonists, Heike remains convinced: “We need to look at patients holistically.” Obesity, for example, is a catalyst for metabolic dysfunction and its complications, which include conditions like MASH. By tackling the underlying causes of obesity, the liver could potentially get healthier too.

Nowadays, Heike and her team in EH&RBB focus on external innovation for different therapeutic areas altogether: eye health, neurodegeneration, and endometriosis. Connecting with partners to drive innovation forward seems an apt next step. After all, the development of survodutide was only possible through learning from Zealand’s initial research.

Shaping connections

We connect obesity and liver health in a dual- agonist approach—and connect disciplines, partners and data across our pipeline. By uniting two pathways, we pursue care that reflects how metabolic dysfunction behaves: as a catalyst for cascading metabolic complications. Our goal is real-world benefits that help people manage complexity with one coherent therapy.