Senolytic drug combination improves fibrosis in small MASH trial

A small randomized clinical trial has found that intermittent treatment with dasatinib and quercetin improved liver fibrosis in people with fibrotic metabolic dysfunction-associated steatohepatitis, or MASH. The combination also produced higher rates of MASH resolution than placebo, although adverse events were more common among participants receiving the drugs.

The findings, reported by nature.com, come from a phase 2, double-blind, randomized, placebo-controlled study. Thirty-one people took part, with a median age of 56. Men made up 76% of the participants, and 58% had type 2 diabetes. The participants were assigned in equal proportions to receive either the drug combination or placebo.

How the treatment was given

The experimental treatment combined dasatinib, at 100 milligrams per day, with quercetin, at 1,000 milligrams per day. Participants took the two medicines on three consecutive days each week for three weeks. This schedule was repeated during three seven-week treatment cycles.

The study examined whether targeting cellular senescence could help people whose MASH was accompanied by liver fibrosis. Cellular senescence has been linked to inflammation and fibrosis in the liver, but its value as a treatment target in human MASH had not previously been established by this trial.

Researchers assessed the main outcome using paired liver biopsies taken at different points in the study. The primary endpoint required an improvement of at least one fibrosis stage without worsening of MASH. This outcome was recorded in 47% of participants given dasatinib and quercetin, compared with 7% of those given placebo. The reported difference was statistically significant, with a P value of 0.02.

Improvements in MASH and fibrosis

MASH resolution was also more frequent in the treatment group. It occurred in 53% of participants receiving dasatinib and quercetin, versus 7% in the placebo group, again with a P value of 0.02.

The researchers also measured changes in the NAFLD Activity Score, a liver-disease measure used in the trial. The average reduction was 1.43 points, with a standard deviation of 1.22, among those receiving the drug combination. The placebo group had an average reduction of 0.39 points, with a standard deviation of 0.77. The difference had a P value of 0.012.

These results mean the treatment group showed improvement across the study’s biopsy-based fibrosis endpoint, the assessment of MASH resolution and the activity score. Because the study involved only 31 participants, the results provide an early clinical signal rather than a definitive assessment of the treatment’s effectiveness.

Additional laboratory analysis supported the biopsy findings. Single-nucleus RNA sequencing showed lower signatures associated with cellular senescence and fibrosis in the dasatinib-and-quercetin group. The same analysis found fewer cell populations associated with fibrogenesis, the process involved in the development of fibrosis.

Side effects and next steps

Adverse events affected 82% of participants who received dasatinib and quercetin, compared with 43% in the placebo group. The study reported that all of these events were self-limiting. The article did not identify a persistent adverse-event problem, but the higher frequency in the treatment group remains relevant when considering further testing.

The results do not establish that senolytic treatment should be used broadly in people with MASH. Instead, they provide clinical evidence for the idea that removing or reducing the effects of senescent cells may influence both liver inflammation-related activity and fibrosis. The study’s limited size and proof-of-principle design leave the approach requiring evaluation in future trials.

Nature.com reports that the investigators concluded the findings support further research into senolytic therapy for fibrotic MASH. The trial is registered on ClinicalTrials.gov under identifier NCT05506488.