FDA Grants Orphan Drug Designation to Ezurpimtrostat for HCC


The FDA has granted an orphan drug designation to ezurpimtrostat, a PPT-1 inhibitor for the treatment of patients with hepatocellular carcinoma.

The FDA has granted an orphan drug designation (ODD) to ezurpimtrostat (GNS561), a PPT-1 (palmitoyl protein thioesterase-1) inhibitor for the treatment of patients with hepatocellular carcinoma (HCC), according to an announcement from Genoscience Pharma.1

“FDA Orphan Drug Designation is a significant milestone for both Genoscience and for ourproduct, ezurpimtrostat. It recognizes that our treatment has the potential to improve the lives of individuals living with HCC,” Philippe Halfon, MD, PhD, chief executive officer of Genoscience Pharma, said 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, with 35,563 new cases of primary liver cancer reported in 2019 and 27,958 deaths. The FDA grants ODD to drugs and biologics developed for the treatment, prevention, or diagnosis of a rare disease or condition affecting fewer than 200,000 people in the United States.

If advanced progressive HCC is left untreated, the median survival for patients ranges from 4 to 8 months. Although the approved combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has more thandoubled this life expectancy and improved patient-reported outcomes, progression-free survival remains short and new treatment options are needed. 2

Ezurpimtrostat is a first-in-class, first-in-human autophagy inhibitor with anticancer activity stemming from PPT-1 inhibition. In in vivo models of HCC and human cancer cell lines, the agent has shown high liver tropism and potent anti-tumor activity as a single agent and in combination with checkpoint inhibitors. This is in keeping with data showing that the addition of autophagy inhibitors to checkpoint inhibitors may lead to increased efficacy.

Preliminary data from a phase 1b trial (NCT03316222) demonstrated that treatment with single-agent ezurpimtrostat was feasible and well tolerated in primary and secondary liver tumors.3

In the trial, dose escalation ranged from 50 mg to 400 mg every 3 weeks and 200 mg to 300 mg twice daily. Among 26 patients evaluable for safety, no dose-limiting toxicity occurred. Adverse effects (AEs) included grade 1/2 gastrointestinal events, primarily nausea and vomiting, which occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Seven grade 3 AEs of diarrhea, decreased appetite, fatigue, alanine aminotransferase and aspartate aminotransferase increase were 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) following a median of 28 days of administration, similar to prior preclinical data observed 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%).

The agent is currently being tested as a first-line treatment in combination with an anti–PD-L1 and an anti-angiogenic agent, in the phase 2b ABE-Liver trial (NCT05448677). Investigators are planning to enroll up to 196 patients.


  1. Genoscience Pharma receives FDA orphan drug designation for ezurpimtrostat to treat hepatocellular carcinoma (HCC). News release. Genoscience Pharma. February 1, 2023. Accessed February 8, 2023. https://www.genosciencepharma.com/wp-content/uploads/2023/02/230201-Genoscience-Pharma-FDA-ODD-EN.pdf
  2. 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
  3. 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
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