FDA Grants ODD to Ezurpimtrostat for Hepatocellular Carcinoma


The first-in-class PPT-1 inhibitor ezurpimtrostat has been granted an orphan drug designation by the FDA for patients with hepatocellular carcinoma.

The FDA has granted an orphan drug designation to ezurpimtrostat (GNS561) for the treatment of patients with hepatocellular carcinoma (HCC), according to Genoscience Pharma.1

Ezurpimtrostat is a first-in-class, first-in-human autophagy, PPT-1 (palmitoyl protein thioesterase-1) inhibitor. In vivo models of HCC and human cancer cell lines with the agent have shown high liver tropism and potent anti-tumor activity when used as a single agent or in combination with checkpoint inhibitors. Recent data have also shown that the addition of autophagy inhibitors to checkpoint inhibitors may lead to increased efficacy, thus reinforcing the benefit of the in vivo models of ezurpimtrostat.

Additionally, preliminary data from a phase 1b trial (NCT03316222) support this orphan drug designation as treatment with ezurpimtrostat was feasible and well-tolerated in patients with primary and secondary liver tumors.2

“FDA orphan drug designation is a significant milestone for both Genoscience and for our product, ezurpimtrostat. It recognizes that our treatment has the potential to improve the lives of individuals living with HCC,” said Philippe Halfon, MD, PhD, chief executive officer of Genoscience Pharma, in a press release. “We have recently launched our phase 2b clinical trial using ezurpimtrostat in conjunction with the standard atezolizumab/bevacizumab treatment. We are looking forward to sharing the intermediate results in 2024.”

Liver cancer is the sixth most common cancer worldwide. In 2019, there were 35,563 new cases of primary liver cancer reported as well as 27,958 deaths. When advanced progressive HCC is left untreated, the median survival ranges from 4-8 months for patients.

Currently, the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is approved and revealed more than a doubled life expectancy for this patient [population. While the combination has improved patient-reported outcomes, progression-free survival remains short and new treatment options are needed.3

In the phase 1b trial of ezurpimtrostat for patients with primary and secondary liver tumors2, patients were administered doses ranging from 50 mg to 400 mg every 3 weeks and 200 mg to 300 mg twice daily to evaluate the primary end point of evaluating dose-limiting toxicities.

There were 26 patients evaluable for safety. Among them, no dose-limiting toxicities were reported, and adverse events (AEs) consisted of grade 1/2 gastrointestinal events. Primarily, these AEs included nausea and vomiting, which occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Moreover, there were 7 grade 3 AEs of diarrhea, decreased appetite, fatigue, alanine aminotransferase, and aspartate aminotransferase increase reported.

Every 3-week administration was associated with limited exposure, favoring the twice daily schedule. At 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 mean liver to plasma ratio of 9559 (range, 149-25759) after a median of 28 days of administration. These findings were similar with previously observed preclinical data after repeated administration.

A total of 20 patients were evaluable for efficacy, in which investigators noted reduced PPT1 expression in cancer tissues in the liver following treatment with ezurpimtrostat. No complete or partial responses occurred, although five patients experienced stable disease (25%), including one minor response (-23%).

Now, the agent is being investigated in the phase 2b ABE-Liver trial (NCT05448677) as a first-line treatment option in combination with an anti–PD-L1 and an anti-angiogenic agent. Approximately 196 patients with unresectable HCC will be enrolled in the study that has an estimated completion date of December 2025.4

  1. Genoscience Pharma receives FDA orphan drug designation for ezurpimtrostat to treat hepatocellular carcinoma (HCC). News release. Genoscience Pharma. February 1, 2023. Accessed February 27, 2023. https://bit.ly/3kpUIkR
  2. 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. 2022;11(3):268-277. doi:10.1159/000522418
  3. Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(suppl 3):267. doi:10.1200/JCO.2021.39.3_suppl.267
  4. Ezurpimtrostat autophagy inhibitor in association with atezolizumab-bevacizumab in first line treatment of unresectable hepatocellular carcinoma (ABE-LIVER). ClinicalTrials.gov. Updated December 27, 2022. Accessed February 27, 2023.
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