The small molecule palmitoyl-protein thioesterase 1 (PPT1) inhibitor GNS561 (ezurpimtrostat) successfully completed its phase 1 clinical trial in patients with primary and secondary liver cancers including cholangiocarcinoma (CCA), advanced hepatocellular carcinoma (HCC), and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis.

GNS561 showed a favorable safety profile, exposure level, and a preliminary signal of activity, as published in Liver Cancer. The investigators now plan to initiate further studies in patients with HCC and intrahepatic CCA.

“Further studies are scheduled in patients with advanced HCC and [intrahepatic CCA] to evaluate the expression of PPT1 and the antitumor activity of GNS561,” the authors said.

Continue Reading

A twice a week (BID) dosing schedule at 200 mg was determined to be optimal for further phase 2 testing based on the results of this dose-escalation trial (NCT03316222). During the trial, patients received doses ranging from 50-400 mg 3 times a week to 200-300 mg BID.

Read more about CCA experimental therapies

Liver biopsies showed that PPT1 expression levels were reduced after exposure to GNS561. No patients during the study experienced complete or partial response during the study but efficacy was not a primary endpoint due to low patient numbers receiving the recommended dosing and the patient population being highly pre-exposed or resistant to prior therapies.

Sustained tumor stabilization was observed in 5 patients, however, including 1 patient with intrahepatic CCA who experienced a minor response. No dose-limiting toxicities were encountered during the trial in any of the 26 patients evaluable for safety.

No treatment-related deaths occurred during the study, and the most commonly experienced adverse events (greater than 10% of patients) were nausea, vomiting, diarrhea, fatigue, and decreased appetite. A total of 7 grade 3 adverse events were reported including diarrhea, decreased appetite, fatigue, asthenia, and increased alanine aminotransferase and aspartate aminotransferase levels.

Pharmacokinetic analysis showed linear plasma exposure with increasing doses. A dose level of 200 mg BID was needed to achieve plasma trough levels above the active exposure target of 50 ng/mL which was previously determined in a rat cancer model.


Harding JJ, Awada A, Roth G, et al. First-in-human effects of PPT1 inhibition using the oral treatment with GNS561/ Ezurpimtrostat in patients with primary and secondary liver cancers. Liver Cancer. Published online February 15, 2022. doi:10.1159/000522418