By Grey Pepper Editorial
Merck has spent years developing a liver-disease strategy around an unusual idea: combine GLP-1 receptor activation with glucagon receptor activation in the same peptide, and investigate whether the two signals can produce meaningful improvements in metabolic liver disease.
A Phase 2b clinical trial published in The Lancet on November 9, 2026, provides the clearest evidence yet for that approach in patients with metabolic dysfunction-associated steatohepatitis, or MASH, and moderate-to-advanced liver fibrosis.
Among adults receiving efinopegdutide, an investigational once-weekly GLP-1/glucagon receptor co-agonist, up to 63% achieved MASH resolution without worsening of liver fibrosis after 52 weeks of treatment.
Only 13% of participants receiving placebo achieved the same endpoint.
But the more interesting result concerned liver scarring.
At 7 mg, efinopegdutide improved fibrosis by at least one stage without worsening steatohepatitis in 52% of participants. At the higher 10 mg dose, the corresponding response rate was only 34%.
The 7 mg result was statistically significant against placebo. The 10 mg result was not.
That does not establish that 7 mg is inherently more effective than 10 mg, but it challenges the assumption that a higher dose must produce a larger benefit across every disease outcome.
The study also included an open-label semaglutide reference arm, which makes the results tempting to read as a comparison between two competing treatment strategies.
That interpretation requires caution. The trial’s formal efficacy comparisons were against placebo, not designed to establish superiority over semaglutide.
For Merck, the study supplies a promising clinical signal. For researchers studying MASH, it raises a more complicated question: what happens when resolving liver inflammation and improving liver fibrosis do not follow the same dose-response pattern?
What Efinopegdutide Is, and Where It Came From
Efinopegdutide, also known as MK-6024, is an investigational peptide administered through a once-weekly subcutaneous injection.
Unlike medicines that activate only the GLP-1 receptor, efinopegdutide activates both the glucagon-like peptide-1 receptor and the glucagon receptor.
The Lancet paper describes a relative receptor potency balance of approximately 2:1 between the two receptor activities.
The scientific rationale involves two overlapping metabolic pathways.
GLP-1 receptor activation can reduce appetite, support bodyweight reduction and improve aspects of glucose regulation.
Glucagon receptor activation has direct effects on liver metabolism, including pathways involved in lipid handling and energy expenditure.
Combining the two is intended to produce complementary effects on metabolic dysfunction and the accumulation of fat in the liver.
But those mechanisms should not be confused with proof of direct reversal of liver fibrosis. The processes connecting altered metabolism to changes in liver inflammation and scar tissue remain complex.
Efinopegdutide did not originate at Merck.
The compound was initially developed by South Korea’s Hanmi Pharmaceutical under the designation HM12525A.
On August 4, 2020, Merck announced an exclusive licensing agreement to develop and commercialize the investigational molecule.
Hanmi received an upfront payment of $10 million and became eligible for up to $860 million in development, regulatory and commercial milestone payments, along with royalties on potential future sales.
That arrangement gave Merck control of a peptide program with a different mechanism from GLP-1-only treatments.
It also placed the company in a growing field of dual and triple receptor agonists designed to influence several metabolic pathways simultaneously.
Grey Pepper previously explored the broader strategy in our analysis of retatrutide and triple-receptor agonist science.
Efinopegdutide’s development is more specifically focused on metabolic liver disease, where the goal is not simply weight loss but measurable improvement in the injured liver.
How the Phase 2b MASH Trial Was Run
The Phase 2b study, registered as NCT05877547 and identified by Merck as MK-6024-013, was a randomized, multicenter clinical trial conducted at 176 academic and community research centers across 26 countries.
The study ran between June 23, 2023, and December 29, 2025.
Researchers screened 1,704 adults and randomly assigned 386 participants. Of those, 381 received at least one dose of study treatment and were included in the reported analysis.
All participants had biopsy-confirmed MASH with stage F2 or F3 liver fibrosis.
Stage F2 indicates significant fibrosis, while F3 represents more advanced bridging fibrosis. Neither classification is equivalent to established cirrhosis, which is generally designated F4.
Approximately 63% of treated participants had F2 fibrosis and 37% had F3 fibrosis.
The average participant age was 53 years, and approximately 51% were women.
Participants were assigned to five groups: efinopegdutide at 4 mg, 7 mg or 10 mg; placebo; or an active reference group receiving semaglutide 2.4 mg.
All treatments were administered by subcutaneous injection once weekly.
The efinopegdutide and placebo groups were blinded, meaning the participants and study personnel were not told which of those treatments had been assigned.
The semaglutide reference arm was open-label. Participants and investigators knew when semaglutide was being administered.
That distinction matters when interpreting the active reference results.
The trial’s primary endpoint was MASH resolution without worsening of fibrosis at week 52.
This is a specific histological outcome. It requires the liver biopsy to show that steatohepatitis has resolved according to the study’s scoring criteria while the fibrosis stage has not become worse.
It does not require existing scar tissue to disappear.
The key secondary histological endpoint asked a different question: whether fibrosis improved by at least one stage without worsening steatohepatitis.
Both endpoints were evaluated through blinded independent central review of liver biopsies.
Missing end-of-treatment biopsies were considered treatment failures for the primary analysis, according to the published abstract.
Merck reported that 349 of the 381 treated participants, approximately 92%, completed the study.
That is a strong completion rate for a year-long trial involving a chronic metabolic disease and repeat liver-biopsy assessments.
But the number completing the study is not the same as the number included in every histological analysis. The published abstract reports different denominators for the primary and key secondary endpoints, which makes careful interpretation of the percentages essential.
The MASH Resolution Results—and the Fibrosis Surprise
The primary endpoint produced a consistent result across all three efinopegdutide doses.
At week 52, MASH resolution without worsening fibrosis occurred in 56% of participants receiving 4 mg, 63% receiving 7 mg and 61% receiving 10 mg.
Among participants receiving placebo, the response rate was 13%.
All three efinopegdutide doses demonstrated statistically significant superiority to placebo, with reported p values below 0.0001.
The estimated difference between the 7 mg group and placebo was 49.5 percentage points, with a 95% confidence interval from 31.4 to 64.2 percentage points.
These findings provide evidence that efinopegdutide can improve biopsy-defined MASH activity over one year in adults with F2–F3 fibrosis.
They do not establish permanent disease remission, reversal of all liver damage or a reduction in future clinical events such as cirrhosis and liver failure.
The key secondary fibrosis endpoint produced a less straightforward picture.
Fibrosis improved by at least one stage without worsening steatohepatitis in 43% of participants receiving efinopegdutide 4 mg, 52% receiving 7 mg and 34% receiving 10 mg.
The corresponding response rate with placebo was 21%.
For the 4 mg group, the difference versus placebo was 21.7 percentage points, with p=0.0038.
For the 7 mg group, the difference was 30.4 percentage points, with a 95% confidence interval from 15.4 to 44.3 percentage points and p below 0.0001.
For the 10 mg group, the difference was 13.0 percentage points. Its confidence interval extended from −1.2 to 26.8 percentage points, and the reported p value was 0.072.
That means the highest dose did not demonstrate a statistically significant improvement over placebo on the fibrosis endpoint under the study’s reported testing.
It does not mean the 10 mg dose had no biological effect. Its observed response rate remained numerically higher than placebo.
Nor does the trial establish that 7 mg is definitively superior to 10 mg. The results were not presented as a formal demonstration of superiority between those active doses.
Nevertheless, the pattern is clinically interesting.
The 7 mg dose produced the highest observed fibrosis response rate, while the 10 mg dose produced a smaller response rate and more treatment discontinuations because of adverse events.
That combination of efficacy and tolerability findings helps explain why the investigators identified 7 mg as having the most favorable observed benefit-risk profile.
Every efinopegdutide dose beat placebo on MASH resolution. On fibrosis improvement, the middle dose produced the strongest observed response.
The unexpected dose ordering also raises questions that the published summary cannot fully resolve.
Was the difference influenced by gastrointestinal tolerability and treatment discontinuation?
Did differences in baseline disease characteristics, biopsy variability or random variation contribute to the observed results?
Could higher glucagon receptor stimulation alter the balance of benefit and tolerability in ways that affect the final outcome?
These are reasonable hypotheses, not findings established by the trial.
The results also need to be read in light of the different analysis denominators reported in the abstract.
For example, the 7 mg primary endpoint was reported in 31 of 49 participants, whereas the fibrosis endpoint was reported in 39 of 75.
The abstract does not fully explain why those populations differ. The complete methodology and supplementary analysis are needed before drawing conclusions from the denominator changes.
The most defensible conclusion is therefore narrower than a claim that the highest dose performed worse overall.
Efinopegdutide demonstrated meaningful MASH-resolution efficacy at all three tested doses. The 7 mg dose delivered the strongest observed fibrosis response and a more favorable tolerability profile than 10 mg.
A higher dose did not produce a better observed result on every endpoint. That is a finding worth investigating, not a final explanation of the underlying biology.
Why the Semaglutide Comparison Needs Care
The trial included a fifth treatment group receiving semaglutide 2.4 mg once weekly.
At week 52, 53% of participants in that group achieved MASH resolution without worsening fibrosis.
Fibrosis improvement of at least one stage without worsening steatohepatitis occurred in 25%.
Placed beside the efinopegdutide results, those figures appear to favor the 7 mg dual agonist on both endpoints.
But a visual comparison between percentages is not the same as a statistically supported head-to-head conclusion.
The semaglutide group was open-label, while the efinopegdutide and placebo groups were blinded.
The trial’s formal efficacy testing focused on efinopegdutide versus placebo. It was not designed or reported as a definitive comparison establishing superiority over semaglutide.
Group sizes were also modest, particularly for the histological endpoint populations.
The presence of an active reference group provides useful context, but the differences between treatment arms should not be interpreted as proving that the dual agonist is a better treatment.
There is another important point that changes how the trial fits into the broader MASH field.
Semaglutide already has regulatory evidence supporting its use in MASH.
In August 2025, the U.S. Food and Drug Administration granted accelerated approval to injectable Wegovy (semaglutide 2.4 mg) for adults with noncirrhotic MASH and moderate-to-advanced fibrosis.
That approval was supported by the ESSENCE trial, which demonstrated improvements in both MASH resolution and liver fibrosis.
At week 72, approximately 63% of semaglutide-treated participants achieved MASH resolution without worsening fibrosis, compared with approximately 34% receiving placebo.
Fibrosis improvement without worsening steatohepatitis occurred in approximately 37% of participants receiving semaglutide, versus 22% receiving placebo.
These figures should not be compared directly with efinopegdutide’s week-52 Phase 2b results to establish which treatment is more effective.
The studies differed in duration, sample size, population characteristics, trial procedures and statistical design.
But the existence of an approved GLP-1 treatment means it would be misleading to frame efinopegdutide as succeeding where GLP-1-only drugs have failed.
The scientific question is instead whether dual GLP-1/glucagon activation can provide additional, reproducible benefits beyond what established therapies achieve.
That will require appropriately designed comparative studies.
Grey Pepper previously covered the evolving MASH treatment landscape in its analysis of Wegovy, Rezdiffra and liver-disease evidence.
Efinopegdutide now joins that landscape with promising clinical evidence, but its position relative to approved alternatives remains unresolved.
The semaglutide arm offers context, not a verdict. A higher response percentage in this trial does not establish a superior treatment.
Side Effects, Dose Selection and the Road Ahead
The safety findings provide another reason to examine the three efinopegdutide doses separately.
As with other incretin-based medicines, gastrointestinal adverse events were common.
Nausea occurred in 29% of participants receiving 4 mg, 39% receiving 7 mg and 44% receiving 10 mg.
Among participants receiving semaglutide, nausea occurred in 39%, compared with 11% receiving placebo.
Vomiting occurred in 20%, 8% and 28% of the efinopegdutide groups in ascending dose order, compared with 15% in the semaglutide arm and 3% on placebo.
The vomiting pattern was not perfectly dose-dependent. The 7 mg group reported a lower rate than either the 4 mg or 10 mg group.
Diarrhea was reported in 29%, 26% and 22% across the three efinopegdutide groups, compared with 22% on semaglutide and 20% on placebo.
These findings demonstrate why safety profiles cannot always be summarized as a simple increase with dose.
However, discontinuation because of adverse events was highest in the 10 mg group.
Adverse events led to treatment discontinuation in 3% of participants receiving efinopegdutide 4 mg, 4% receiving 7 mg and 11% receiving 10 mg.
Only 1% of participants receiving placebo or open-label semaglutide discontinued because of adverse events.
That difference is relevant to dose selection, particularly for a medicine being developed to treat a chronic disease over potentially prolonged periods.
But the trial does not establish that discontinuations caused the lower fibrosis response observed at 10 mg.
The dose-response pattern remains a question for additional investigation.
The broader clinical limitations are equally important.
The trial involved 381 treated adults, with approximately one year of follow-up. Its principal efficacy outcomes were changes in liver-biopsy findings.
Histological improvement is clinically meaningful and is used by regulators when evaluating MASH treatments.
However, changes in liver inflammation or fibrosis after 52 weeks do not directly establish fewer cases of cirrhosis, liver failure, liver cancer, transplantation or death.
Those outcomes require larger studies with substantially longer follow-up.
Efinopegdutide remains investigational and is not an approved MASH medicine.
Merck has received FDA Fast Track designation for efinopegdutide in MASH, but that designation does not constitute regulatory approval or demonstrate that a treatment will eventually meet approval requirements.
The company is also evaluating the molecule in a separate clinical study involving people with compensated cirrhosis caused by steatohepatitis, registered as NCT06465186.
That population represents a more advanced stage of liver disease than the F2–F3 patients included in the Phase 2b study.
Whether efinopegdutide can provide meaningful benefits in that setting remains to be established.
For Merck, the Phase 2b findings support further development of a molecule licensed from Hanmi Pharmaceutical six years earlier.
For the wider field, the results strengthen the rationale for investigating GLP-1/glucagon co-agonism in metabolic liver disease.
They also provide a reminder that dose selection is not simply a competition to administer the largest possible amount.
In this trial, the 7 mg group achieved the highest observed response rates for both MASH resolution and fibrosis improvement, with fewer treatment discontinuations than the 10 mg group.
That is a promising signal, but not a definitive explanation for the unexpected dose-response pattern.
The next studies will need to determine whether these results are reproducible, how the drug compares with established therapies and whether favorable biopsy findings eventually translate into better long-term outcomes for patients.
Efinopegdutide demonstrated a meaningful one-year response in MASH. The unanswered question is why its middle dose performed better on fibrosis than its highest dose—and whether that pattern will survive larger trials.
Sources and Further Reading
- Lawitz E, Wong VW, Shankar RR, et al. Efficacy and Safety of Efinopegdutide in Adults With Metabolic Dysfunction-Associated Steatohepatitis and Stage 2–3 Fibrosis: A Phase 2b, Randomised, Placebo-Controlled Study. The Lancet, November 9, 2026. PMID: 43003105.
- The Lancet. Original Efinopegdutide Phase 2b Research Publication. DOI: 10.1016/S0140-6736(26)02043-X.
- Merck & Co. Positive Phase 2b Results for Efinopegdutide in MASH With Stage 2–3 Fibrosis. November 9, 2026.
- ClinicalTrials.gov. Efinopegdutide in Participants With Precirrhotic Nonalcoholic Steatohepatitis (MK-6024-013). NCT05877547.
- Merck & Co. Merck and Hanmi Pharmaceutical Enter Into Licensing Agreement to Develop Efinopegdutide. August 4, 2020.
- U.S. Food and Drug Administration. FDA Approves Wegovy for Adults With Noncirrhotic MASH and Moderate-to-Advanced Fibrosis. August 2025.
- ClinicalTrials.gov. Efinopegdutide in Participants With Compensated Cirrhosis Due to Steatohepatitis (MK-6024-017). NCT06465186.
