FDA Grants Orphan Drug Designation to Ezurpimtrostat for Cholangiocarcinoma

The FDA has granted an orphan drug designation to the novel autophagy/palmitoyl protein thioesterase-1 inhibitor ezurpimtrostat for the treatment of patients with cholangiocarcinoma.

The FDA has granted an orphan drug designation to the novel autophagy/palmitoyl protein thioesterase-1 (PPT1) inhibitor ezurpimtrostat (GNS561) for the treatment of patients with cholangiocarcinoma.1

Ezurpimtrostat has completed preclinical studies and a phase 1b trial (NCT03316222), the results of which support the rationale for targeting cholangiocarcinoma. A phase 2 trial is expected to begin in the fourth quarter of 2022, and the first patient visit is planned for the first quarter of 2023.

“Cholangiocarcinoma is a rare cancer with a high mortality rate. Patients have limited treatment options, particularly following first line therapy. This is why new therapies are urgently needed and is one of the reasons that [ezurpimtrostat] was granted orphan drug designation by the FDA. There is a real path forward for new options for second line treatment in cholangiocarcinoma, and [ezurpimtrostat] represents a strong second-line therapy candidate and hope to patients,” Mark Yarchoan, MD, an associate professor of oncology at Johns Hopkins Medicine, stated in a press release.

Ezurpimtrostat is a first-in-class, oral, small molecule PPT-1 inhibitor that prevents autophagy in tumor cells, leading to cell death.

The agent was evaluated in a phase 1, open-label, dose-escalation trial with a 3 + 3 design. Two dosing schedules of ezurpimtrostat were evaluated: once daily 3 times a week every 3 weeks and twice daily continuous administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis.2

The primary objective was to determine the recommended phase 2 dose (RP2D) and schedule of ezurpimtrostat. Secondary objectives included the evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity the agent.

Dose escalation ranged from 50 mg to 400 mg every 3 weeks and 200 mg to 300 mg twice daily.3 Among 26 patients who were evaluable for safety, 20 were evaluable for efficacy.

Notably, no dose-limiting toxicity occurred. Regarding safety, adverse effects (AEs) included gastrointestinal grade 1/2 events; nausea and vomiting occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea occurred in 11 (42%) patients. Seven (7) grade 3 AEs were reported and included diarrhea, decreased appetite, fatigue, and increased alanine aminotransferase and aspartate aminotransferase.

Every 3-week administration was associated with limited exposure, and the twice daily schedule was preferred. With 200 mg of twice daily ezurpimtrostat, plasma and liver concentrations were similar to active doses in animal models. Liver trough concentrations were significantly higher than in plasma, with a median time of 28 days of administration with a mean liver to plasma ratio of 9559 (range, 149-25759).

Additionally, PPT1 expression was diminished in malignant liver tissue following treatment with ezurpimtrostat.

Despite no documented cases of complete or partial response, 5 patients experienced stable disease (25%), including one minor response (-23%).

Based on these findings, the RP2D of ezurpimtrostat was set at 200 mg twice daily.


  1. FDA grants GENFIT’s GNS561 orphan drug designation for the treatment of cholangiocarcinoma. News release. GENFIT. September 13, 2022. Accessed September 19, 2022. https://bit.ly/3BRaDOP
  2. Study of GNS561 in patients with liver cancer. ClinicalTrials.gov. Updated May 2, 2022. Accessed September 19, 2022. https://clinicaltrials.gov/ct2/show/NCT03316222
  3. Liver cancer, phase 1b clinical results publication. News release. Genoscience Pharma. Accessed September 19, 2022. https://bit.ly/3UkiyeI