FDA Grants Denifanstat Breakthrough Therapy Designation for Treatment of MASH

Positive trial results laid the groundwork for the designation.

The FDA has granted breakthrough therapy designation (BTD) to Sagimet Biosciences for denifanstat (TVB-2640; Sagimet Biosciences), an oral, selective fatty acid synthase (FASN) inhibitor, to treat patients with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis, according to a news release from Sagimet Biosciences.^1,2

Photomicrograph of liver biopsy in a patient with cirrhosis, showing bridging septal fibrosis and regenerative nodules.

Cirrhosis can result from severe MASH. | Image credit: © David A Litman | stock.adobe.com

The designation was granted based on positive results from the phase 2b FASCINATE-2 clinical trial evaluating denifanstat in patients with biopsy-confirmed MASH with stage 2 or 3 fibrosis. Results were announced earlier this year, with 36% of patients who were treated with denifanstat 50 mg (n = 81) achieving disease resolution without worsening of fibrosis, compared with 13% of patients who were treated with placebo (n = 45).³

Furthermore, 41% of patients who were treated with denifanstat reported an improvement of their fibrosis by 1 stage or more, with no corresponding worsening of MASH, compared with 18% among placebo-treated patients. Importantly, safety data indicated that the treatment was generally well tolerated among participants.³

“As the only fat synthesis inhibitor that directly targets the three main drivers of MASH—fat accumulation, inflammation, and fibrosis—we believe denifanstat is well-positioned to offer a leading treatment option for patients living with MASH,” David Happel, CEO of Sagimet, said in the news release.¹

More than 100 million individuals worldwide are affected by MASH, a progressive and severe liver disease, and it is the most common chronic liver disease in the United States. The disease leads to cirrhosis, which through the replacement of healthy liver tissue with scar tissue, becomes severe and irreversible.^1,4

About the Trial

Trial Name: Study of TVB-2640 in Subjects With Nonalcoholic Steatohepatitis (NASH)

ClinicalTrials.gov ID: NCT04906421

Sponsor: Sagimet Biosciences Inc

Study Completion Date: October 2, 2023

Currently, the only available treatment for the disease is resmetirom (Rezdiffra; Madrigal Pharmaceuticals), which was granted an accelerated approval from the FDA earlier this year. The once-daily, oral thyroid hormone receptor-β agonis showed positive results in the phase 3 MAESTRO-NASH trial; however, investigators cautioned that further verification of its effectiveness would be necessary.^1,5

New trials have been initiated to evaluate other treatments for MASH. One such trial analyzed tirzepatide (Zepbound; Elil Lilly) in participants with biopsy-proven MASH, and found that at 5 mg, 10 mg, and 15 mg dosages, there was a demonstratable absence of MASH with no worsening liver fibrosis.⁶

The action by the FDA today is poised to accelerate the process for which denifanstat can be evaluated for full FDA approval. BTDs are granted to treatments that target a serious or life-threatening disease. Preliminary clinical evidence surrounding the drug must indicate that it leads to a significant improvement over existing therapies on 1 or more clinically significant end points.¹

REFERENCES

1. Sagimet Biosciences. Sagimet receives FDA Breakthrough Therapy Designation for denifanstat in MASH. News Release. Released October 1, 2024. Accessed October 1, 2024. https://www.globenewswire.com/news-release/2024/10/01/2955945/0/en/Sagimet-Receives-FDA-Breakthrough-Therapy-Designation-for-Denifanstat-in-MASH.html

2. ClinicalTrials.gov. Study of TVb-2640 in subjects with nonalcoholic steatohepatitis (NASH). National Library of Medicine. Last Updated December 26, 2023. Accessed October 1, 2024. https://clinicaltrials.gov/study/NCT04906421

3. Sagimet Biosciences. Sagimet Biosciences announces positive topline results from phase 2b FASCINATE-2 clinical trial of denifanstat in biopsy-confirmed F2/F3 NASH. News Release. Released January 22, 2024. Accessed October 1, 2024. https://ir.sagimet.com/news-releases/news-release-details/sagimet-biosciences-announces-positive-topline-results-phase-2b

4. Halpern L. NASH affects millions, but the future for treatment remains brighter than ever. Pharmacy Times. Published July 24, 2024. Accessed October 1, 2024. https://www.pharmacytimes.com/view/nash-affects-millions-but-the-future-for-treatment-remains-brighter-than-ever

5. Hippensteele A. FDA grants accelerated approval of resmetriom for noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis. Pharmacy Times. Published March 14, 2024. Accessed October 1, 2024. https://www.pharmacytimes.com/view/fda-grants-accelerated-approval-of-resmetirom-for-noncirrhotic-nonalcoholic-steatohepatitis-with-moderate-to-advanced-liver-fibrosis

6. Gallagher A. Tirzepatide shows improvements in MASH without worsening fibrosis. Pharmacy Times. Published July 4, 2024. Accessed October 1, 2024. https://www.pharmacytimes.com/view/tirzepatide-shows-improvements-in-mash-without-worsening-fibrosis