Clinical Development of HC-5404


In preclinical studies, we have observed anti-tumor activity with HC-5404 in different tumor models, including primary tumors as well as those that metastasized to the lung and liver. Preclinically, we have observed robust combinatorial benefit with standard of care therapeutic agents in animal models of renal cell carcinoma, gastric cancer, and several other tumor types. HC-5404 is under investigation in a Phase 1a trial as a monotherapy for the treatment of advanced solid tumors enriched for patients with renal cell carcinoma (RCC) and gastric cancer.

Following completion of our Phase 1 trial, we plan to initiate a Phase 1b trial in combination with standard of care therapeutic agents in the first half of 2023.

PERK and the Unfolded Protein Response

HC-5404 is a differentiated, orally bioavailable investigational small molecule inhibitor of PERK (PKR-like endoplasmic reticulum kinase). PERK is a kinase of the Unfolded Protein Response (UPR), an adaptive cellular program used by cancer cells to survive by facilitating adaptation to harsh tumor microenvironments characterized by hypoxia, nutrient deprivation and oxidative stress.  Hypoxia drives the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress and activation of PERK.

Preclinically, we have observed that various standard care cancer therapies further amplify stress in tumors and activate PERK as a survival mechanism.  In these settings, we have observed that inhibition of the adaptive UPR via PERK inhibition blocks tumor resistance to standard of care agents, resulting in combinatorial activity in multiple cancer types.