First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers

Abstract

Introduction - GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1). Methods - This phase I, open-label, dose-escalation trial (3+3 design) explored two GNS561 dosing schedules: one single oral intake three times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561. Results - Dose escalation ranged from 50-400mg Q3W to 200-300mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1-2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients respectively, and diarrhea in 11 (42%) patients. Seven (7) grade 3 adverse events were reported (diarrhea, decreased appetite, fatigue, ALT and AST increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9559 (Min 149-Max 25759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (-23%). Conclusion - Based on a favourable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200mg BID. Studies to evaluate the antitumor activity of GNS561 in HCC and iCCA are to follow. NCT 03316222

Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors

“…The compound binds to PPT1 and reduces not only its enzymatic activity but its expression as well. GNS561 successfully completed a phase 1b trial in patients with primary and secondary liver cancer, highlighting the safety of the molecule [ 91 ]. GNS561 is now entering a phase 2 clinical trial in association with standard-of-care atezolizumab–bevacizumab as a first-line treatment in patients suffering from unresectable hepatocellular carcinoma (NCT05448677) ( Table 1 ).…”

Diverse Roles of Protein Palmitoylation in Cancer Progression, Immunity, Stemness, and Beyond

“…For instance, in oral squamous cell carcinomas (OSCC), the expression level of PPT1 can be reduced by erianin, a natural bibenzyl compound, although the molecular mechanism was not fully characterized [ 189 ]. GNS561, a specific PPT1 inhibitor, by itself, is able to effectively inhibit the progression of liver cancer [ 177 , 190 ]. Furthermore, another selective and potent PPT1 inhibitor, DC661, not only impaired tumor growth [ 180 ] but also enhanced the response of liver cancer cells to treatment of sorafenib, a multi-kinase inhibitor [ 191 ], and enhanced the antitumor activity of the anti-PD-1 antibody in melanoma [ 192 ].…”

Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma

“…Ezurpimtrostat is a quinoline derivative exerting an in vitro antiproliferative activity that blocks autophagic activity and the relocalisation of mTOR in HCC cells [76]. Preliminary in vivo results of an ezurpimtrostat monotherapy showed an excellent tolerance but absent objective responses [77]. Consequently, ezurpimtrostat is now being evaluated in association with atezolizumab-bevacizumab in the ABE-LIVER Phase 2 trial (NCT05448677).…”