GNS561 Granted Orphan Drug Designation by FDA in Second-Line Cholangiocarcinoma


The FDA has granted orphan drug designation to second-line GNS561 following the completion of a phase 1/2a trial evaluating the novel PPT1 inhibitor in liver cancer and cholangiocarcinoma.

The palmitoyl protein thioesterase­–1 (PPT1) inhibitor GNS561 (ezurpimtrostrat) has received an orphan drug designation as a second-line treatment for cholangiocarcinoma from the FDA, according to a press release from GENFIT.

The agent was evaluated as part of a multi-label, multi-center, uncontrolled, repeat dose phase 1/2a trial (NCT03316222) in patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma. A phase 2 trial is expected to begin later this year, with the first patient visit set to occur in 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 GNS561 was granted Orphan Drug Designation by the FDA,” Mark Yarchoan, MD, an associate professor of oncology at John Hopkins Medicine, said in the press release. “There is a real path forward for new options for second line treatment in cholangiocarcinoma, and GNS561 represents a strong second-line therapy candidate and hope to patients.”

GNS561 is a PPT1 inhibitor that blocks late-stage autophagy by entering cell lysosomes and binding to its target, thereby causing cell death. Prior to this trial, GNS561 had completed pre-clinical studies and a phase 1b trial providing a rationale for targeting cholangiocarcinoma.

The multicenter, open-label study enrolled 50 patients to receive escalating doses of GNS561 until the occurrence of unacceptable toxicity or disease progression, or withdrawal of consent. The study was designed to determine the safety profile and the recommended phase 2 treatment dose using a 3+3 dose escalation design. The dose limiting toxicity (DLT) observation period was 28 days. Patients were instructed to take their assigned doses at the same time every morning and evening after a meal. The primary end point was DLT measured by adverse effects by dose level.

Patients were required to have histologically confirmed, locally advanced or metastatic cholangiocarcinoma or HCC that was ineligible for treatment with curative therapy. Patients also needed to have a life expectancy of 12 weeks or greater and an ECOG performance status of 0 or 1 to be included. Adequate hematologic, renal, and hepatic function prior to the first dose were among the other inclusion criteria. Participants with liver cancer needed to have a liver tumor burden of 50% or less per investigator judgement.

Patients were excluded from the study if they presented with grade 2 or higher residual toxicities, or underwent major surgery, open biopsy, or traumatic injury within 4 weeks or less prior to the first dose of GNS561. Other exclusion criteria included having known untreated or symptomatic brain metastases, clinically significant ascites or paracentesis, and known esophageal varices with recent bleeding. Any history of encephalopathy was also grounds for exclusion.


FDA grants GENFIT’s GNS561 orphan drug designation for the treatment of cholangiocarcinoma. News Release. GENFIT. September 13, 2022. Accessed September 22, 2022.

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