▎WuXiEdited by Kant Content Team

Eli Lilly and Company announced positive results from the Phase 2 clinical trial, SYNERGY-NASH, of its重磅 GLP-1 class drug tirzepatide for the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) patients at this year's European Association for the Study of the Liver (EASL) annual meeting. Analysis shows,Compared with placebo, 73.3% of patients receiving the highest dose of tirzepatide achieved the primary endpoint of MASH resolution without worsening of liver fibrosis, and more than half of the patients showed ≥1 stage significant improvement in liver fibrosis.

MASH, formerly known as nonalcoholic steatohepatitis (NASH), is the advanced form of nonalcoholic fatty liver disease (NAFLD).MASH is the leading cause of liver-related mortality, imposing an increasingly heavy burden on global health systems. Moreover, MASH patients, especially those with more metabolic risk factors (hypertension, coexisting type 2 diabetes), face an elevated risk of cardiovascular adverse events, along with increased morbidity and mortality.

SYNERGY-NASH is a multicenter, double-blind, randomized, placebo-controlled Phase 2 dose-finding trial that enrolled 190 patients with biopsy-confirmed MASH who had stage 2 or 3 liver fibrosis and a Nonalcoholic Fatty Liver Disease Activity Score (NAS) ≥4. Participants were randomly assigned in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary endpoint was resolution of MASH with no worsening of liver fibrosis at 52 weeks. Secondary endpoints included improvement in fibrosis by ≥1 stage with no worsening of MASH, as well as a reduction in NAS by ≥2 points with at least two NAS components decreasing by ≥1 point.

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Analysis showed that, out of the 155 subjects who completed treatment and underwent evaluable biopsies,51.8%, 62.8%, and 73.3% of subjects receiving 5 mg, 10 mg, and 15 mg tirzepatide, respectively, achieved the primary endpoint, compared to only 13.2% in the placebo group (p<0.001 for all doses).

In addition,The proportions of patients treated with 5 mg, 10 mg, and 15 mg tirzepatide who achieved MASH non-worsening and ≥1 stage fibrosis improvement were 54.9%, 51.3%, and 51.0%, respectively, with differences of 21.3-25.2% compared to the placebo group (29.7%) (all doses p<0.05).In the three tirzepatide dose groups, 71.7-78.3% of patients had a NAS reduction of ≥2 points, compared to 36.7% in the placebo group (p<0.001 for all doses).

Patients can lose up to 17.3% of their body weight after using tirzepatide. Additionally, compared with the placebo group,Reduction in liver enzymes and liver fat, as well as liver inflammation and fibrosis in the tirzepatide groupSerum andImaging biomarkers also showed significant improvement (p<0.01).

The adverse events of Tirzepatide are mainly gastrointestinal adverse events, with severity ranging from mild to moderate.

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Tirzepatide is aGlucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonist, which can simultaneously activate the GLP-1 receptor and GIP receptor-mediated signaling pathways.GIP and GLP-1 are natural incretin hormones that regulate blood sugar. Tirzepatide was approved by the United States in May 2022.FDA Approval(Product name: Mounjaro) Used in conjunction with controlled diet and exercise to improve blood sugar control in adult patients with type 2 diabetes. In November last year, tirzepatide received another approval.FDA Approval(Product name: Zepbound), used to help obese or overweight adult patients lose weight and maintain stable weight.

According to information from Eli Lilly and Company's official website and ClinicalTrials.gov, tirzepatide is currently undergoing multiple Phase 3 clinical trials, with research scopes including evaluating the drug's efficacy in treatingObstructive Sleep Apnea (OSA), heart failure with preserved ejection fraction (HFpEF), reducing the incidence and mortality of obesity, and decreasing adverse cardiovascular outcomes in patients with type 2 diabetes, etc. At the same time, Eli Lilly and Company is conducting multiple phase 2 clinical trials, which are respectively exploring the effects of higher doses of tirzepatide on obese and type 2 diabetes patients, as well as the efficacy of tirzepatide in treating MASH and type 1 Wolfram syndrome. In addition, a clinical trial of tirzepatide for the treatment of moderate to severe hidradenitis suppurativa has recently been initiated. In April this year, Eli Lilly and Company announced twoPhase 3 Trial ResultsDisplay,Tirzepatide can significantly improve snoring in obese patients with moderate to severe OSA.Regardless of whether the patient is wearing a ventilation device for treatment. Based on this positive result,Eli Lilly Plans to Submit Relevant Regulatory Applications.

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MThe development of ASH therapy has been a focus of the industry in recent years.In March this year,U.S. FDAAccelerated ApprovalMadrigal PharmaceuticalsRezdiffra (resmetirom) in combination with diet and exercise for the treatment of patients with moderate to severe liver fibrosis (F2 to F3 stage)MASHAdult patients.According to the press release,This is the first MASH therapy to receive FDA approval, marking a significant milestone in the field.

Also focusing on MASH are89bio. Last September, its development ofFibroblast Growth Factor 21 (FGF21) AnalogResults of the Phase 2b Trial of Pegozafermin for the Treatment of MASH PublishedThe New England Journal of Medicine, the analysis shows that 37% of 15 mgPegozafermin Treatment Group Shows MASH Resolution, Compared to Only 2% in the Placebo Group; Phase 3 Trial for MASH Treatment Has Been Initiated.Sagimet Biosciences announced in January this year that its researchOral FASN Small Molecule InhibitorDenifanstat for the treatment of MASHClinicalPhase 2b TrialAchieved the primary endpoint and multiple secondary endpoints, the company is expected toPhase 3 trial to be launched in the second half of this year. AndAkero Therapeutics'Investigational drug efruxifermin (EFX)Phase 3 trials for the treatment of MASH have also been initiated.