GLP-1 receptor agonists (GLP-1 RAs), such as semaglutide, and GLP-1 dual/triple receptor agonists, such as Tirzepatide, have shown significant efficacy in treating type 2 diabetes and obesity. Beyond these conditions, the application of GLP-1 RAs in the field of non-alcoholic fatty liver disease (NAFLD) has also garnered widespread attention.

NAFLD includes a range of conditions from simple steatosis to a more serious form called non-alcoholic steatohepatitis (NASH). NASH occurs when fat deposits cause the liver to become swollen and damaged. If NASH worsens, it can lead to severe liver scarring (cirrhosis) and even liver cancer.

NASH is a major cause of liver-related deaths and is placing an increasing burden on healthcare systems globally. Moreover, patients with NASH, particularly those with advanced metabolic risk factors like hypertension or type 2 diabetes, face a higher risk of adverse cardiovascular events and increased morbidity and mortality. When NASH progresses to moderate to advanced liver fibrosis (stages F2 to F3 fibrosis), the risk of serious liver problems rises significantly.

Figure 1. The pathological spectrum of NAFLD. [1]

However, treatment options for NASH are limited. There is an urgent need to develop effective treatments to address this global health issue.

GLP-1RAs for NASH

GLP-1RAs have significantly improved the clinical, biochemical, and histological markers of hepatic steatosis, inflammation, and fibrosis in patients with NAFLD.  Currently, dozens of GLP-1 RAs are under development for the treatment of NASH.

Table 1. GLP-1 RAs under development for NASH

Semaglutide

Semaglutide showed a significant dose-dependent NASH resolution without worsening of fibrosis in a phase 2 randomized controlled trial (RCT) involving patients with NASH and stage 1–3 fibrosis. A phase 3 trial of semaglutide for NASH-related fibrosis (ESSENCE trial) is underway.

Results from the Phase II clinical trial (NCT02970942) showed that after 72 weeks, 59% of patients in the 0.4 mg semaglutide group achieved NASH resolution without worsening liver fibrosis, a statistically significant result compared to 17% in the placebo group, meeting the primary clinical endpoint. However, the secondary clinical endpoints were not met. Additionally, a reduction in liver enzyme levels was observed.

Figure 2. NCT02970942 results [2]

Among patients treated with semaglutide, those in the 0.4 mg group experienced an average weight loss of 13%, compared to 1% in the placebo group. The most common gastrointestinal side effects in the 0.4 mg group included nausea, constipation, decreased appetite, vomiting, and abdominal pain, occurring more frequently than in the placebo group. Additionally, 15% of patients in the semaglutide group developed tumors, compared to 8% in the placebo group (with 3% having malignant tumors in the semaglutide group, and none in the placebo group).

Semaglutide shares 94% homology with human GLP-1 and is structurally similar to liraglutide but with two additional modifications. The first modification is the replacement of alanine at position 8 with α-amino isobutyric acid, which helps prevent degradation by DPP-4. The second modification involves attaching a C18 di-acid side chain to the lysine at position 26 using a short polyethylene glycol (PEG) spacer and a γ-glutamic acid linker. This change increases its binding to albumin, reducing renal clearance and extending its half-life to 165–184 hours.

Tirzepatide

Tirzepatide is a GIPR and GLP-1R agonist that activates the body's receptors for GIP and GLP-1. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. Tirzepatide is being studied as a potential treatment for people with obesity and/or overweight with metabolic dysfunction-associated steatohepatitis (MASH). 

At the EASL Congress 2024, Eli Lilly and Company presented positive results from the Phase II clinical trial, SYNERGY-NASH, of their tirzepatide for treating patients with biopsy-proven MASH with stage 2 or 3 fibrosis. The analysis showed that, compared to the placebo, 73.3% of patients treated with the highest dose of tirzepatide achieved an absence of MASH with no worsening of fibrosis on liver histology compared  to 13.2% of participants on placebo at 52 weeks of treatment, meeting the study's primary endpoint. Additionally, more than half of the patients experienced a significant improvement of at least one stage in liver fibrosis.

Efinopegdutide (MK-6024, HM12525A)

Efinopegdutide is a chemical conjugate of a synthetic GLP-1/GCG peptide with a human IgG Fc via a PEG linker. In June 2023, The FDA granted fast track designation to efinopegdutide for the treatment of NASH.

Figure 3. Structure of Efinopegdutide 

In June 2023, Merck announced the results of a Phase IIa clinical trial of efinopegdutide for the treatment of NASH. Efinopegdutide significantly reduced liver fat content (LFC)  in patients compared to GLP-1 RA semaglutide. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly greater with efinopegdutide (72.7%) than with semaglutide (42.3%).

Survodutide

Survodutide, developed jointly by Boehringer Ingelheim and Zealand Pharma, is an investigational long-acting, GCGR/GLP-1R agonist targeting obesity by increasing energy expenditure and reducing food intake and MASH.

In a Phase II trial, up to 83% of adults with MASH treated with survodutide (BI 456906) showed statistically significant improvement compared to 18.2% in the placebo group [response difference: 64.8%, (CI 51.1% - 78.6%), p<0.0001]. The trial met its primary endpoint, showing a biopsy-proven improvement in MASH after 48 weeks, without worsening of fibrosis stages F1, F2 and F3 (mild to moderate or advanced scarring). Survodutide also achieved all secondary endpoints, including statistically significant improvement in liver fibrosis.

Pemvidutide

Pemvidutide (ALT-801) is a dual GLP-1R/GCGR agonist with a 1:1 ratio of GLP-1 to GCGR, providing an optimal balance of efficacy and safety. Additionally, its structure includes the EuPort™ domain, a proprietary technology that extends the plasma halflife for weekly dosing and slows the entry of Pemvidutide into the bloodstream, enhancing tolerability.

​

Figure 4. Pemvidutide Structure [6]

On November 13, 2023, Altimmune presented the results of their Phase II clinical trial (NCT05292911) for Pemvidutide in the treatment of NAFLD at the American Association for the Study of Liver Diseases (AASLD) Annual Meeting. After 24 weeks of treatment, the trial showed a relative reduction in liver fat content (LFC) by 76.4%, a decrease in serum ALT (alanine aminotransferase) by 15.2 IU/L, and a drop in cT1 levels by 149.7 ms.

Conclusion

Currently, there is a large population of NAFLD/NASH patients who require long-term treatment, yet there is only one approved drug specifically for NASH, Rezdiffra (resmetirom), indicating that the clinical need is far from being fully met.

GLP-1 RAs have opened a new frontier in the treatment of NASH, and more companies are expected to enter this field in the future. Based on the clinical trial data released so far, the new GLP-1 RAs for NASH show promising potential and are indeed worth further investment and research.

Biopharma PEG supplies polyethylene glycol (PEG) derivatives, and custom PEG derivative synthesis from R&D through GMP commercial quantities, for preclinical, clinical trials, and commercial products for pharma, biotech, medical devices, and diagnostics. 

References:
[1] Ferguson, D., Finck, B.N. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 17, 484–495 (2021). https://doi.org/10.1038/s41574-021-00507-z
[2] Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021 Mar 25;384(12):1113-1124. doi: 10.1056/NEJMoa2028395. Epub 2020 Nov 13. PMID: 33185364.
[3] https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-was-superior-placebo-mash-resolution-and-more
[4] Romero-Gómez M, Lawitz E, Shankar RR, Chaudhri E, Liu J, Lam RLH, Kaufman KD, Engel SS; MK-6024 P001 Study Group. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J Hepatol. 2023 Oct;79(4):888-897. doi: 10.1016/j.jhep.2023.05.013. Epub 2023 Jun 22. PMID: 37355043.
[5] Survodutide Phase II trial shows 83% of adults treated achieved groundbreaking results in liver disease due to MASH, with significant improvements in fibrosis https://www.boehringer-ingelheim.com/human-health/metabolic-diseases/survodutide-top-line-results-mash-fibrosis  
[6] https://ir.altimmune.com/static-files/82fc1b1b-18f6-4a1a-a7ca-6cbcae33d8d9