HiberCell Initiates Phase 1a Clinical Trial of HC-5404-FU, an ER Stress Modulator

HiberCell recently announced the initiation of a Phase 1a multicenter, open-label, dose escalation trial of its orally administered HC-5404-FU in patients with selected metastatic solid tumors. HC-5404-FU is an endoplasmic reticulum (ER) stress modulator, and the Investigational New Drug (IND) application received the greenlight from the U.S. Food and Drug Administration (FDA) in late 2020.

The Phase 1a trial is designed as a dose escalation study across patients with specific tumor types, inclusive of renal cell carcinoma (RCC), gastric cancer (GC), breast cancer (MBC), and small-cell lung cancer (SCLC).  The primary endpoints are to establish HC-5404-FU’s Maximum Tolerated Dose (MTD) and to monitor its safety and tolerability in patients with selected, advanced solid tumors. The secondary endpoints are intended to determine the pharmacokinetic (PK) parameters of HC-5404-FU and to preliminarily assess potential antitumor activity, as evaluated by overall response rate (ORR), duration of response (DOR) progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS). ORR, DOR, PFS and TTF will be assessed per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). Exploratory objectives of the study include immunophenotyping of peripheral blood cells and evaluation of local antitumor effects, microenvironment changes, and associated pharmacodynamic (PD) markers in tumor biopsies by multiplex immunohistochemistry (IHC).

“While targeted therapy and immunotherapy have extended the timeline horizon for cancer patients with solid tumors, stress-mediated tumor recurrence, therapeutic resistance, and cancer relapse remain significant barriers in the management of advanced cancer,” said Alan Rigby, PhD, Chief Executive Officer at HiberCell. “The initiation of this first-in-human study is a significant milestone for HiberCell as we move our platform of stress modulators into the clinic.”

Stress is omnipresent in cancer. Endoplasmic reticulum (ER) mediated stress resulting from activation of the unfolded protein response (UPR) pathway creates an immunosuppressive tumor microenvironment, while simultaneously endowing cancer cells with survival advantages. Protein kinase R–like endoplasmic reticulum kinase (PERK) is a primary UPR sensor that plays a central role in tumor angiogenesis and survival. Modulation of the PERK pathway in a hypoxic or nutrient deprived, “stressed” environment leads to cell apoptosis and tumor growth inhibition. HC-5404-FU is a highly selective, potent PERK inhibitor (PERKi) oral candidate with demonstrable monotherapy anti-tumor activity.

“In preclinical studies across species, HC-5404-FU was well tolerated. Beyond HC-5404-FU, our PERK drug discovery and chemistry campaign has identified several potent, selective, drug-like compounds. These and other data in support of inhibiting PERK in cancer have published in a recently accepted manuscript in Bioorganic Medicinal Chemistry Letters (Calvo et al., Bioorg. Med. Chem. Lett. 43 (2021), 128058),” said José Iglesias, MD, Consultant Chief Medical Officer at HiberCell. “We are excited to move HC-5404-FU into the clinic. Its mechanism of action allows us to explore several novel possibilities to interdict tumor growth, given the observed synergy with immunotherapeutic and antiangiogenic agents.”

HiberCell is biotechnology company dedicated to developing therapeutic molecules that overcome foundational scientific barriers that prevent patients from living longer, cancer-free lives. The company views cancer as a chronic disease and is working to develop novel therapies that address the most common cause of cancer mortality: relapse and metastasis. To that end, HiberCell is developing therapies that blunt the omnipresent stress-mediated adaptive response of cancer cells. HC-5404-FU is the first therapeutic candidate from the HiberCell’s “stress modulator” platform that has direct anti-tumor activity while simultaneously reprogramming the immunosuppressive tumor microenvironment that is foundational to cancer cell survival.