GLP-1 drugs penetrate the fatty liver market

Novo Nordisk recently announced that its heavyweight weight loss drug Wegovy (semaglutide 2.4mg) has received accelerated approval from the FDA for a new indication: treatment of adult patients with metabolic associated fatty liver disease (MASH) accompanied by moderate to severe liver fibrosis (F2-F3 stage).

This marks the first formal entry of GLP-1 into the fatty liver treatment field.

MASH, the "New Continent" of a Trillion-Dollar Market

The capital market has a keen sense of smell. With the news of Wegovy's approval for the MASH indication, Novo Nordisk's stock price rose sharply, while on the other side of the market, the scene was starkly different.

Madrigal Pharmaceuticals' stock price faced immense pressure. Just recently, this company made history by having its developed drug Rezdiffra become the first FDA-approved MASH drug in nearly 40 years, breaking the silence in this field.

Madrigal's Rezdiffra is a selective thyroid hormone receptor-β (THR-β) agonist, a "specialty drug" focused on the liver pathway for MASH. In contrast, Novo Nordisk's Wegovy® is a "platform drug" with broad metabolic regulatory effects, and its evidence for weight loss and cardiovascular benefits is already well established.

For doctors and payers, the choice becomes simple. When a drug can simultaneously address obesity, reduce cardiovascular risk, and improve liver health, its appeal far exceeds treatment plans that require the combined use of multiple "specialty drugs." The market is betting that Wegovy will erode Rezdiffra's market share with its multiple benefits.

However, in this battle of giants, unexpected winners have emerged. A "water seller" company has seen its stock price soar, most notably the A-share listed company Furuya Co., Ltd. This company provides a non-invasive liver diagnostic device called FibroScan, used to measure liver stiffness and the degree of fatty degeneration.

The approval of MASH treatment drugs has created a more urgent demand: how to identify those in need of treatment among hundreds of millions of potential patients? MASH has almost no symptoms in its early stages, and the gold standard for diagnosis—liver biopsy—is not suitable for large-scale screening due to its invasiveness and high cost.

This has created a significant diagnostic bottleneck.

With the emergence of effective treatment options (whether Rezdiffra or Wegovy), the motivation for large-scale screening is unprecedented. Non-invasive testing (NITs) technologies like FibroScan from Furuya Co., Ltd. precisely address this pain point. They are repeatedly mentioned in clinical trials and treatment guidelines, becoming key tools for identifying high-risk patients and monitoring treatment responses.

Regardless of whether Novo Nordisk or Madrigal ultimately dominates the market, the demand for diagnostics will experience explosive growth. In this gold rush, diagnostic tool companies are steadily selling the most essential "shovels and pickaxes."

The enormous potential of the MASH market is undeniable. It is a serious progressive disease, with over 250 million patients worldwide, a significant portion of whom are derived from the obese population It is predicted that by 2030, the global MASH drug market will exceed $30 billion.

However, the enormous market also comes with significant challenges.

The MASH field is known as the "graveyard of drug development." Over the past decade, many pharmaceutical giants, including Pfizer and Gilead, have failed here. Behind this are multiple insurmountable obstacles.

First, the disease mechanism is extremely complex, involving metabolic disorders, inflammation, fibrosis, and other factors, making single-target drugs often miss the mark. Second, the aforementioned diagnostic issue, namely the reliance on invasive liver biopsies, greatly increases the difficulty of patient recruitment and evaluation costs in clinical trials. In addition, the significant placebo effect (with an improvement rate of about 20%) in MASH clinical trials often makes it difficult to statistically verify the true efficacy of drugs.

In such a harsh context, the successive approvals of Rezdiffra and Wegovy are particularly precious. They not only bring hope to patients but also prove that humanity has finally found two distinctly different yet effective paths in tackling this stubborn disease.

How Semaglutide "Targets the Problem"

ESSENCE is a global, multicenter, double-blind, placebo-controlled Phase 3 clinical trial by Novo Nordisk, planned to be conducted in two stages. The accelerated approval is based on the interim analysis results of the first phase of the trial involving 800 randomly assigned patients. These patients were confirmed to have MASH through biopsy, and their liver fibrosis was at F2 or F3 stage.

The core of the trial design lies in its dual primary endpoints: Compared to placebo, Wegovy can improve liver fibrosis (with no worsening of steatohepatitis), showing statistical significance and superiority; it can also improve steatohepatitis (with no worsening of liver fibrosis).

After 72 weeks of treatment, the data from the first phase of the ESSENCE trial clearly demonstrated the efficacy of semaglutide.

At week 72, 36.8% of participants receiving Wegovy achieved improvement in liver fibrosis with no worsening of steatohepatitis, while this proportion was 22.4% in the placebo group.

62.9% of participants receiving Wegovy showed improvement in steatohepatitis with no worsening of liver fibrosis, compared to 34.3% in the placebo group. Both endpoints achieved statistically significant differences, with clear advantages.

In terms of safety, the trial results are consistent with numerous studies of semaglutide in weight loss and diabetes. The most common adverse reactions are transient gastrointestinal events such as nausea and diarrhea, with a very low discontinuation rate due to adverse events. This demonstrates its feasibility for long-term use in the MASH patient population.

The Future of GLP-1: From "Weight Loss" to "Healthy Weight Gain"

The approval of the MASH indication is a result of Novo Nordisk systematically expanding the core molecule semaglutide into various chronic disease areas driven by obesity.

• Cardiovascular Benefits: It has been approved to reduce the risk of major adverse cardiovascular events (MACE) in adults with obesity or overweight who have cardiovascular disease
• Chronic Kidney Disease (CKD): Has been approved for reducing the risk of kidney disease progression and mortality in patients with type 2 diabetes accompanied by CKD.
• Broader Frontiers: Research is also underway in areas such as obstructive sleep apnea (OSA) and Alzheimer's disease.

Obesity is a common root cause of a series of diseases including type 2 diabetes, heart disease, kidney disease, and fatty liver. By demonstrating efficacy in each area, Novo Nordisk is integrating the previously separate treatment models of different specialties and multiple medications into a unified GLP-1-based solution.

As GLP-1 drugs advance rapidly, their inherent limitations are gradually surfacing.

A core issue is that during rapid weight loss, not only fat is consumed, but also a significant amount of lean body mass such as muscle. Research shows that 25% to 40% of the weight lost with GLP-1 drugs may come from muscle.

Thus, a new paradigm of "high-quality weight loss" has emerged.

The next wave of innovation in the industry is focusing on addressing the issue of muscle loss. The mainstream approach is to combine GLP-1 drugs with medications that can protect or even increase muscle. Among these, the Activin Receptor Type II (ActRII) pathway is one of the most closely watched targets.

Taking Bimagrumab as an example, this monoclonal antibody targeting ActRII, when used in conjunction with semaglutide, has shown remarkable effects: achieving significant fat loss while effectively protecting muscle tissue. Some biotech companies, including LaiKai Pharmaceuticals, are also actively laying out plans in this field.

This means that the competitive dimension of the future weight loss drug market will undergo fundamental changes. The focus of competition will no longer be solely on the percentage of weight loss, but on the "quality" of weight loss components—the ratio of fat to muscle reduction.

A drug combination that achieves a 15% weight loss, with 90% being fat, will have far greater clinical value than a single drug that achieves a 20% weight loss, but with 40% being muscle. This drives drug development from simple "subtraction" to more refined metabolic remodeling.

The journey of GLP-1 drugs began with blood sugar control and then conquered weight management. Now, it is systematically challenging various complex chronic diseases driven by metabolic disorders