Obesity and MASH Drug Development: What Comes After Weight Loss?

Obesity drug development is no longer defined by weight loss alone. In recent years, GLP-1-based therapies and other next-gen metabolic medicines have reshaped expectations for what obesity treatments can achieve. As more candidates enter clinical trials, companies are facing a higher bar: demonstrating not only meaningful weight reduction, but also tolerability, metabolic benefits and a clear path to differentiation.

Hyung Heon Kim
CEO and President
MetaVia

For Hyung Heon Kim, CEO and President of MetaVia, the next stage of obesity and metabolic dysfunction-associated steatohepatitis (MASH) drug development will not be defined by weight loss alone. Instead, he sees the field moving toward therapies that can better address tolerability, glycemic control, liver-related disease and the broader metabolic complications that often accompany obesity.

MetaVia is a clinical-stage biotech company focused on cardiometabolic diseases, with programs in obesity and MASH. Its pipeline includes DA-1726, an oxyntomodulin analogue being evaluated for obesity and MASH, and vanoglipel, also known as DA-1241, a GPR119 agonist being evaluated for MASH.

In an interview with Xtalks, Kim discussed the unmet needs in obesity care and the challenges in conducting clinical trials for obesity and MASH. He also shared why differentiation has become essential for clinical-stage biotech companies working in highly competitive metabolic disease markets.

Tolerability Remains a Major Unmet Need in Obesity

While recent therapies have reshaped expectations for obesity treatment, Kim said tolerability remains one of the biggest unmet needs for patients.

A key issue, according to Kim, is titration. Some currently approved therapies require patients to gradually escalate to the maximum dose over several months. That process can be burdensome for patients and payers, particularly when patients are paying for treatment while still working toward the dose intended to deliver the full therapeutic effect.

“When you look at the approved drugs, it takes about six months to get to the max dose,” Kim said. “That six months means that people are spending their money while going up in dose, and insurance, they’re paying money for that titration period.”

Dose escalation can also be accompanied by GI side effects, which may affect whether patients are willing or able to stay on treatment. For Kim, a next-gen obesity therapy should ideally require fewer titration steps while also reducing side effects.

“We need a drug that has at least fewer titration steps to save money and insurance and all that, but plus fewer side effects,” he said.

That combination could have important implications for treatment uptake and persistence. If a therapy is easier to start and stay on, more patients may be able to access treatment and remain on it long enough to achieve meaningful clinical benefit.

Why Obesity Trials Can Be Difficult to Run

From a clinical development perspective, Kim said one of the challenges in obesity trials is identifying the right study population.

Early obesity studies may seek to enroll patients who are obese but otherwise healthy. In practice, that can be difficult.

“Just finding that obese, otherwise healthy population is kind of a challenge because typically and sadly, overweight or obese patients do have complications,” Kim said.

Those complications can include type 2 diabetes and liver-related disease. Kim noted that obesity studies can involve different patient populations, including patients with obesity alone, patients with obesity and type 2 diabetes and patients with obesity or overweight who also have liver complications.

That complexity matters because it affects how therapies are studied and how their clinical value is interpreted. A drug that produces weight loss in otherwise healthy adults may not necessarily address the broader needs of patients who also have impaired glucose control, fatty liver disease, liver inflammation or fibrosis.

Placebo-controlled studies also create unique challenges in obesity. Patients often enroll in a trial because they want to lose weight, but in a double-blind study, some will be assigned to placebo.

“These people come into this study thinking they’ll be getting drugs, GLP-1s, or dual agonists or triple agonists, and they signed up to lose weight,” Kim said.

When patients assigned to placebo see others in the study losing weight, they may become discouraged. Some may drop out. Others may try to lose weight through dieting during the study, which can create protocol deviations and complicate interpretation of the data.

For sponsors, these issues can affect study conduct, retention and data quality. They also underscore how obesity trials can differ from studies in some other therapeutic areas, as the effects of treatment assignment may become more visible to participants when weight loss is a key outcome.

The Next-Gen Obesity Therapy May Need to Do More Than Reduce Weight

Weight loss and waist circumference remain important measures in obesity trials. However, Kim said the next generation of obesity therapies will need to demonstrate broader metabolic effects.

One major consideration is glycemic control. Kim noted that many patients with obesity also have metabolic comorbidities, including type 2 diabetes, making glucose-related outcomes important when evaluating future therapies.

Liver-related disease is another important signal, particularly because obesity and metabolic dysfunction are closely linked with metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. Kim said liver complications can range across fibrosis stages, with many patients in the broader metabolic disease population presenting with earlier-stage fatty liver disease and inflammation.

“Almost about the same amount of people have some kind of liver complication, whether it’s F1 to F4, but typically F1 to F2 with fatty liver disease with inflammation on it,” he said. “So you have to have that signal as well.”

In Kim’s view, the market may become increasingly difficult for therapies that only produce weight loss without addressing other metabolic or hepatic drivers.

“I don’t believe that in the next five years there’ll be room for a drug that only causes weight loss,” he said.

This reflects a broader shift in cardiometabolic drug development. Obesity is increasingly being understood not as an isolated condition, but as part of an interconnected disease spectrum involving insulin resistance, type 2 diabetes, dyslipidemia, fatty liver disease, inflammation and cardiovascular risk.

For companies developing next-gen obesity therapies, this means clinical differentiation may increasingly depend on whether a candidate can show a broader metabolic profile, not only reductions in body weight or waist circumference.

That broader profile is also relevant to MASH, where obesity, insulin resistance, liver fat, inflammation and fibrosis often intersect.

MASH Trials Remain Expensive and Operationally Risky

MASH has long been one of the more challenging areas in clinical development. According to Kim, one of the biggest hurdles for biotech companies is the cost and complexity of biopsy-based studies.

“For a biotech company, the challenge is always raising capital,” he said. “Biopsy-led studies are very expensive.”

Liver biopsy has historically been central to MASH trials because it allows for histological assessment of steatosis, inflammation, ballooning and fibrosis. However, Kim said biopsies also introduce variability because they depend heavily on the operator and clinical site.

Some operators can perform high-quality biopsies for MASH studies, he said, while others may not have the same level of technique. That creates risk for sponsors because an expensive and important endpoint can still be affected by site-level variability.

“So while you’re spending so much money on it, it’s very dependent on the clinical site’s operation, which is very risky,” Kim said.

There is growing interest in noninvasive technologies for MASH assessment, including FibroScan-based measures and other liver-related biomarkers. Kim said he believes the field is moving in that direction, but that a full shift away from biopsy has not yet occurred.

“I do believe biopsy won’t be required at some point, but I’m not sure exactly when that will be,” he said.

For now, Kim said sponsors still need to plan carefully around biopsy-based evidence in Phase II and Phase III MASH development, even as noninvasive tools gain regulatory attention.

The Importance of Metabolic Signals Depends on Disease Stage

In MASH, Kim said the importance of metabolic outcomes depends on the disease stage and the therapeutic mechanism.

For later-stage MASH, particularly where fibrosis is the main clinical concern, the most important question is whether a therapy can address fibrosis. In that setting, additional metabolic effects may be useful but are not necessarily the core driver of differentiation.

In earlier-stage disease, for patients with F1, F2 or F3 disease, a therapy may need to show broader metabolic benefits. This can include glycemic control, liver fat reduction, inflammation effects or other cardiometabolic improvements.

That is because earlier-stage therapies may not be differentiated solely by anti-fibrotic effects. In those settings, a broader metabolic profile could be important for both clinical value and commercial positioning.

“You need additional benefits or else the drug won’t really have a competitive edge,” he said.

Kim also pointed out that some metabolic abnormalities, such as elevated lipids, can be treated with widely available oral generic medicines. This means a therapy’s overall profile needs to be considered in the context of its mechanism, target population and stage of disease.

“At the end of the day, I think it’s how you focus your drug, what is your mechanism of action?” he said.

For later-stage disease, where fibrosis is a central driver of clinical risk and regulatory evaluation, anti-fibrotic activity may be the dominant priority. For earlier-stage metabolic liver disease, targeting multiple angles may become more important, according to Kim.

For Biotechs, Differentiation Is a Development Necessity

Beyond the clinical science, Kim said one of the biggest challenges for companies like MetaVia is finding a clear competitive edge.

That challenge is especially acute in obesity and MASH, where many companies are pursuing overlapping mechanisms, patient populations and clinical endpoints. For a clinical-stage biotech, differentiation is not only a scientific issue; it can determine whether a company is able to raise capital and continue development.

“Unless a biotech has a competitive edge, the capital market hasn’t been really kind to biotechs in recent years,” Kim said.

He also emphasized the importance of adaptability. In fast-moving markets, companies need to watch the competitive landscape closely and be willing to refine their strategy as new data emerge.

“Competitive edge, you just have to be active in searching for it,” he said.

For MetaVia, that search for differentiation spans obesity, type 2 diabetes, MASH and potentially other forms of liver disease.

Looking Ahead to New Development Opportunities

Kim said MetaVia is actively evaluating where its programs could best address patient needs.

One area of interest is type 2 diabetes, particularly for patients who may have developed tolerance to GLP-1-based therapies. Kim noted that there is still an open question around whether such patients could benefit from another GLP-1-based therapy, dual agonist or triple agonist before moving to insulin.

“There is no study done yet on whether, once the patients start growing tolerance to GLP-1s, can we still use another GLP-1 or a dual or triple agonist and give them another opportunity to lower the HbA1c?” he said.

For Kim, this represents a potential area of clinical need because it could give patients with type 2 diabetes more treatment options.

“We want to give more optionality to the type 2 diabetes patient pool rather than going into insulin,” he said.

MetaVia is also looking at liver disease more broadly. “There is MASH, which used to be NASH. Is that everything? Or I think there’s a growing understanding and the need is growing for alcohol-induced liver damage,” he said.

As the field evolves, Kim said MetaVia is examining multiple development angles across obesity, diabetes and liver disease as it works to align its programs with areas of patient need and competitive differentiation.

For the broader industry, his comments point to a central shift in cardiometabolic drug development: the most competitive therapies may be those that address obesity as part of a larger metabolic disease continuum.

Weight loss will remain important, but the next generation of therapies may also need to demonstrate tolerability, practical dosing, glycemic benefits and meaningful liver-related signals.

In MASH, the balance between fibrosis, metabolic dysfunction and noninvasive assessment will continue to shape clinical trial strategy.

For clinical-stage biotechs working in this space, the challenge is not only to generate promising data, but to show where a therapy can fit in a crowded and rapidly changing therapeutic market.