Who Are the Gold Diggers and Winners in the $40 Billion Metabolic Battlefield?

The metabolic disease sector is experiencing unprecedented fervor. At the recently concluded European Association for the Study of the Liver (EASL) Annual Meeting, various NASH therapeutics took center stage: Madrigal Pharmaceuticals announced the pivotal Phase III clinical trial results for Resmetirom, demonstrating superior efficacy and heralding it as a promising first-in-class drug; among FGF21-targeted agents, 89bio, Akero Therapeutics, and Boston Pharmaceuticals each reported notable achievements; meanwhile, GLP-1 receptor agonists, exemplified by Merck’s efinopegdutide, are also vying for a share of the NASH market.

In the field of liver disease, the annual European Association for the Study of the Liver (EASL) Congress and the American Association for the Study of Liver Diseases (AASLD) Annual Meeting serve as key industry bellwethers. Professor Wu Jian from the School of Basic Medical Sciences at Fudan University has been attending the AASLD Annual Meeting since 1997. After 2015, with the advent of new treatments for hepatitis C and the availability of vaccines and novel drugs for hepatitis B, interest in these two diseases began to wane, while attention toward non-alcoholic steatohepatitis (NASH) rose significantly. Since then, most major pharmaceutical companies that had previously focused on viral hepatitis have shifted their focus to NASH.

“NASH carried significant weight at this year’s EASL Congress. For many hepatologists, NASH remains an area requiring further exploration, as it involves more metabolic factors compared with previous liver disease research,” said Liu Que, Chief Medical Officer of Hepagene Therapeutics, in an interview with VCBeat News. He attended the current EASL Congress to present the company’s latest research on NASH.

The $40 billion market door is ready to open at any time.

Yet, during the EASL conference, Intercept—the frontrunner most likely to cross the finish line first—announced its exit from the NASH field. After a 40-year R&D black hole, obeticholic acid failed twice just before approval and has now officially become another casualty on the verge of breakthrough. At the ADA meeting immediately following EASL, Eli Lilly released striking Phase II data for retatrutide: hepatic steatosis resolved in over 85% of patients at 48 weeks, further intensifying competition in the NASH landscape.

VBInsight previously projected the potential arrival of a “NASH Year” in 2023 back in March this year. In light of the latest data released intensively in recent days, we once again turn our focus to this high-potential sector—or perhaps we should call itThe New Battlefield in Metabolism。

The challenge of NASH is first reflected in the understanding of the disease. Most patients with NAFLD or NASH have one or more cardiometabolic risk factors, yet these two terms focus on excluding excessive alcohol consumption as the cause, which obscures the contributing factors and also affects the definition of the patient population.

During this year’s EASL, a consensus statement led by AASLD, EASL, and ALEH, with contributions from 53 experts worldwide, was officially released. It stated that nonalcoholic fatty liver disease (NAFLD) has been renamed metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for nonalcoholic steatohepatitis (NASH).

From NASH to “MASH,” metabolism has become the keyword in the spotlight.

“I believe that renaming the condition will facilitate its treatment. In addition to weight loss, managing metabolic factors that affect liver function—such as correcting obesity, hyperlipidemia, and dysglycemia—will also be incorporated into the treatment regimen as a secondary clinical endpoint.”Professor Wu Jian told VBInsight. Professor Wu Jian is one of the co-founders of the China NASH New Drug Alliance, which was renamed the China Liver Disease New Drug Alliance in 2022.

Naming diseases is no easy task. In fact, discussions around renaming NAFLD or NASH have been ongoing for a long time. The official change to MASLD or MASH will emphasize the importance of metabolic dysfunction in the development and progression of fatty liver disease and its related conditions, helping doctors, patients, and society gain a clearer understanding of the causes and pathogenesis. This will also advance drug development in the field of NASH.

For instance, Madrigal Pharmaceuticals delivered on expectations at the EASL Congress. Its THR-β agonist, resmetirom, works by regulating hepatic metabolism. Phase III results demonstrated that resmetirom met both primary clinical endpoints. Non-invasive assessment of liver fat content using magnetic resonance imaging (MRI)-based techniques showed that after 52 weeks of treatment with 100 mg of resmetirom, patients experienced a mean reduction of 51% in liver fat levels. Significant reductions were also observed in various lipid and lipoprotein parameters, including low-density lipoprotein cholesterol (LDL-C).

Madrigal is set to file an NDA for Resmetirom shortly. The arrival of the first drug marks a robust validation of the metabolic target THR-β.

Revisiting the Failure of Obeticholic Acid. On June 22, Intercept Pharmaceuticals announced that it had received a Complete Response Letter (CRL) from the FDA regarding its New Drug Application for obeticholic acid in the treatment of NASH. Consequently, Intercept decided to halt all investments in the NASH field and refocus on rare diseases and infectious liver diseases. As early as May 19, the FDA Advisory Committee voted 12-2 against the accelerated approval of obeticholic acid as the first drug for NASH; therefore, the FDA’s refusal was expected.

In January 2015, obeticholic acid was granted Breakthrough Therapy designation by the FDA for the treatment of patients with nonalcoholic steatohepatitis (NASH) accompanied by liver fibrosis. After eight years, this first NASH drug globally to enter Phase III clinical trials has reached its endpoint, and Intercept’s stock price has fallen to $11. This once again demonstrates that:The Absolute Importance of the FDA as the Market “Gatekeeper” to the Market Capitalization of Innovative Drug Companies.

Obeticholic acid has demonstrated positive data results. 2019 marked a highlight for Intercept, with its stock price surging to as high as $127. However, safety concerns have remained a persistent weakness for obeticholic acid. Patients receiving obeticholic acid treatment experienced relatively severe pruritus, with an incidence rate of 51% in the high-dose group compared to 19% in the placebo group. Additionally, obeticholic acid therapy carries potential cardiovascular risks.

NASH patients require long-term medication, necessitating stricter standards for drug safety and adherence. Over the subsequent three years, obeticholic acid continually attempted to demonstrate its long-term efficacy and safety to the FDA but ultimately failed. The FDA cited a lengthy list of safety risks and practical barriers to patient acceptance of liver biopsies, highlighting drug-induced liver injury as a “serious signal.” It concluded that the risks of 25 mg obeticholic acid outweighed the benefits for NASH patients with stage F2 or F3 fibrosis.

FXR modulation readily translates FXR ligand signaling into alterations in gene expression, thereby inducing changes in multiple genes involved in bile acid, glucose, and lipid metabolism, which subsequently leads to the emergence of adverse effects.

However, FXR is not necessarily rendered ineffective. Obeticholic acid represents an “older therapy,” and next-generation FXR agonists are being developed to address issues of side effects and efficacy. HPG1860 from Hepagene Therapeutics is a next-generation non-bile acid FXR agonist, distinct from the first-generation bile acid-based obeticholic acid. In completed Phase II clinical trials, HPG1860 has demonstrated superior safety and efficacy compared with obeticholic acid.

After 12 weeks of treatment with HPG1860, the incidence of pruritus in the 3 mg, 5 mg, and 8 mg dosing groups was only 9.1%, 9.5%, and 27.3%, respectively. This is also why Yachuang’s research garnered widespread attention during the EASL Congress.

Arterial New Medicine previously highlighted two emerging NASH companies, Akero and 89bio, in a special report on NASH. Both companies have heavily invested in the FGF21 target, leveraging capital support and high-quality clinical trials to rapidly unlock the value of their pipelines.

At this year’s EASL, 89bio presented oral data from the Phase IIb clinical trial of pegozafermin, which was selected as one of the best abstracts of the EASL Congress. The results were also published in the New England Journal of Medicine (NEJM). In this trial, 222 patients were assigned to three dosing regimens—15 mg once weekly (QW), 30 mg QW, and 44 mg every two weeks (Q2W)—and a placebo group. At 24 weeks of treatment, the proportions of patients achieving ≥1-stage improvement in fibrosis were 22%, 26%, and 27% in the three dose groups, respectively, compared with 7% in the placebo group. The proportions of patients achieving NASH resolution without worsening of fibrosis were 37%, 23%, and 26%, respectively, versus 2% in the placebo group. The trial also included 14 patients with F4 fibrosis; 12 underwent follow-up biopsy at Week 24, among whom 11 showed no worsening of NASH and ≥1-stage improvement in fibrosis.

Also based on 24-week data, Akero announced positive results for EFX (Efruxifermin) in the Phase IIb HARMONY study last September. Both the 28 mg and 50 mg dose groups of EFX met the primary endpoint of improving liver fibrosis as well as multiple secondary endpoints. Specifically, 39% and 41% of patients, respectively, achieved at least a one-stage improvement in liver fibrosis without worsening of NASH, compared to only 20% in the control group. The study also met a key secondary endpoint, with 47% and 76% of patients receiving EFX 28 mg and 50 mg, respectively, achieving NASH resolution without worsening of liver fibrosis. Furthermore, 29% and 41% of patients, respectively, achieved both endpoints: improvement in liver fibrosis and NASH resolution.

Another competitor targeting FGF21 is BOS-580 from Boston Pharmaceuticals. Phase IIa data presented during the EASL conference showed that ≥70% of patients receiving a total monthly dose of ≥150 mg achieved a ≥50% reduction in liver fat, compared with only 3% in the placebo group. Given that the trial lasted only 12 weeks and patient responses may deepen over time, this could suggest superior efficacy for BOS-580; however, no data on improvement in fibrosis have been released to date.

Phase IIb Data from Akero and 89bio, and Phase IIa Data from Boston Pharmaceuticals: The Chart Displays Only the Two Highest Doses from Each Trial. Data Compilation and Charting: Evaluate

Both Akero and 89bio are awaiting discussions with the FDA regarding their Phase III clinical trial plans. The efficacy of FGF21 and the shorter trial duration may facilitate faster regulatory approval and market launch. If all goes well, the NASH field could see the availability of drugs targeting two major pathways—THR-β and FGF21—within three to five years.

Mining metabolic diseases has been one of the main themes in innovative drug development over the past two years. GLP-1 receptor agonists, which have already seen widespread success, also hold significant promise in the field of non-alcoholic steatohepatitis (NASH). There is a high degree of overlap among patients with obesity, NASH, and diabetes; nearly all NASH patients exceed their ideal body weight by more than 10%, and approximately one-third of NASH patients have type 2 diabetes.

Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide are not content with merely leading the market in weight loss and diabetes; these two potential blockbusters are also seeking to break into the NASH indication.

Merck & Co.’s dual GLP-1 and glucagon receptor agonist, efinopegdutide (MK-6024), was presented at this year’s EASL Congress. The presentation highlighted a 24-week Phase IIa clinical trial in which 145 patients were randomized to receive either efinopegdutide (10 mg once weekly) or semaglutide (1 mg once weekly). Results showed a 72.7% reduction in liver fat levels in the efinopegdutide group, compared with 42.3% in the active control group.

On the other hand, combination therapy with GLP-1 receptor agonists (GLP-1 RAs) represents a promising strategy. Akero Therapeutics announced Phase IIb data evaluating efruxifermin (EFX) in combination with GLP-1 RAs for patients with NASH and type 2 diabetes (T2D). The study compared EFX against placebo in patients who were already receiving GLP-1 RAs such as semaglutide at baseline. Over 12 weeks, liver fat decreased by 65% in the EFX group versus 10% in the placebo group. Furthermore, significant improvements were observed across multiple endpoints, including fibrosis, liver injury, insulin sensitivity, and weight loss.

Lilly’s Phase II clinical results for retatrutide, a triple agonist targeting GLP-1R, GIPR, and GCGR, announced at the ADA conference on June 26, were also highly significant. The data showed that at therapeutic doses of 8 mg and 12 mg, the mean relative reduction in liver fat exceeded 80%, and hepatic steatosis resolved in more than 85% of patients after 48 weeks of treatment.

Obviously, GLP-1 has already“The Flames of War” Have ReachedNASHfield.However, it remains unclear how the excellent weight-loss and lipid-lowering effects of GLP-1-related drugs will translate into benefits for improving liver fibrosis, which is a key endpoint for FDA approval of NASH therapeutics.

“NASH is a complication of obesity and diabetes. The weight-loss and lipid-lowering effects of GLP-1 may make it a more acceptable therapeutic option; however, the potential risk associated with GLP-1 lies in an increased incidence of tumors, particularly thyroid tumors. Whether regulatory authorities will approve it as a treatment for NASH remains contingent upon the results of Phase III clinical trials,” pointed out Professor Wu Jian.

Multinational corporations (MNCs) have consistently made substantial investments in the NASH field. Gilead has 18 NASH projects in development, Pfizer has launched 7 projects, while Novo Nordisk, AstraZeneca, and Boehringer Ingelheim each have 6 projects in their pipelines. Naturally, MNCs are also poised for mergers and acquisitions, ready to take over subsequent market education and volume ramp-up tasks.

“We believe that products from companies such as Madrigal and Akero are highly likely to be acquired, with multinational corporations (MNCs) leveraging these deals to bolster their pipelines,” pointed out Dr. Li Bonan, Executive Director at CEC CAPITAL.

CEC Capital began covering projects in the NASH field two to three years ago, including: recently assisting Chengyi Biopharma in completing a RMB 180 million Series B capital increase; Hepagene Therapeutics, whose Phase II clinical data for the FXR agonist HPG1860 was presented at this year’s EASL, and whose THRβ agonist HPG7233 is expected to receive IND approval shortly; Hejia Biopharma, which is developing unique innovative NASH drugs using siRNA technology and is currently conducting Phase I clinical trials; and Zeta Peptide Bio, a metabolic disease-focused innovative pharmaceutical company that leverages its proprietary peptide conjugation technology to link GLP-1 and FGF21, two key targets involved in glucose and lipid metabolism, while also incorporating synthetic biology technologies.

“Currently, the NASH field in China is primarily adopting a fast-follow strategy, while some companies are also exploring relatively unique technological approaches and targets. As a major metabolic disease, NASH presents a large market with broad demand, allowing for a relatively high number of leading players. We look forward to companies in this sector sequentially announcing their clinical progress and mid-to-late stage data to the market.”

For instance, Hepagene Therapeutics boasts an experienced clinical team capable of conducting clinical trials in both China and the United States. The company is actively preparing for a clinical study on NASH involving combination therapy with FXR and THRβ agonists—a therapeutic approach widely regarded as the future trend in NASH treatment.

Another example is Junshengtai Pharmaceuticals, which also attended EASL. The Phase IIa data of its HTD1801 demonstrated therapeutic potential for NASH, and the company has currently submitted an IPO application to the Hong Kong Stock Exchange.

“The entire field of metabolic diseases is receiving increasing attention. As more pivotal clinical data are disclosed in areas such as NASH, the domestic NASH market is becoming increasingly active. CEC CAPITAL is very optimistic about this sector. We believe that innovative NASH drugs developed by Chinese companies will achieve pivotal breakthroughs within the next three to four years, providing new treatment options for patients in China and around the world,” summarized Dr. Li Bonan.