HC-5404 / HiberCell, LG Chem - LARVOL DELTA

AVEO Oncology…and HiberCell…announced today that the companies have entered into an exclusive development and option agreement to develop HiberCell's first-in-human human...PERK inhibitor, HC-5404, alone and in combination with AVEO's potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor FOTIVDA (tivozanib) (PRNewswire) - "Under the terms of the agreement, AVEO is responsible for conducting initial stage clinical development. During the Phase 2 clinical trial, AVEO will have the option to obtain an exclusive license for the development, manufacturing, and commercialization of HC-5404 in all therapeutic indications worldwide for an undisclosed option fee."

Licensing / partnership • Renal Cell Carcinoma

A multicenter, open‑label, phase 1a study of HC‑5404 in patients with advanced solid tumors. (ASCO 2024) - P1 | "HC-5404 showed a favorable safety profile and encouraging preliminary efficacy in heavily pretreated patients with advanced solid tumors. Safety and exposure-response analyses support further exploration of the 25-100 mg dose level of HC-5404, as monotherapy and in novel combinations. Clinical trial information: NCT04834778."

Clinical • Metastases • P1 data • Cardiovascular • Diabetes • Fatigue • Genito-urinary Cancer • Myocardial Infarction • Oncology • Renal Cell Carcinoma • Solid Tumor • Xerostomia • PERK

A Study of HC-5404-FU to Establish the Maximum Tolerated Dose (MTD) (clinicaltrials.gov) - P1 | N=23 | Completed | Sponsor: HiberCell, Inc. | Recruiting ➔ Completed | Phase classification: P1a ➔ P1 | N=36 ➔ 23

Enrollment change • Metastases • Phase classification • Trial completion • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Hepatocellular Cancer • HER2 Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Thyroid Gland Papillary Carcinoma • HER-2

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors. (PubMed, Clin Cancer Res) - "By disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard of care therapies in RCC."

Journal • Preclinical • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EIF2AK3 • PERK

HiberCell Announces Successful Completion and Interim Results of Phase 1 Study of Novel PERK Inhibitor, HC-5404, in Solid Tumors and Maps Forward Path as Monotherapy and in Combinations (GlobeNewswire) - "HiberCell...announced...two pre-clinical publications in one of the leading journals of AACR, Clinical Cancer Research (CCR)....HiberCell announced the publication of 'PERK inhibition by HC-5404 sensitizes renal cell carcinoma tumor models to antiangiogenic tyrosine kinase inhibitors,' illustrating significant anti-tumor activity when combined with standard of care VEGFR TKIs. HC-5404, by disrupting PERK-mediated adaptive stress response evoked by VEGFR-TKIs, presents a potential opportunity to address the acquired resistance mechanism of the TKIs....Albert Einstein College of Medicine also announced a second publication relating to HiberCell’s HC-5404 titled 'A PERK specific inhibitor blocks metastatic progression by limiting integrated stress response-dependent survival of quiescent cancer cells'."

Preclinical • Renal Cell Carcinoma

HiberCell Announces Successful Completion and Interim Results of Phase 1 Study of Novel PERK Inhibitor, HC-5404, in Solid Tumors and Maps Forward Path as Monotherapy and in Combinations (GlobeNewswire) - P1 | N=36 | NCT04834778 | Sponsor: HiberCell, Inc. | "HiberCell...announced the successful completion of its Phase 1 study of the novel PERK inhibitor, HC-5404, in solid tumors....The Phase 1 trial (NCT04834778) was designed to study the safety and tolerability, MTD, and pharmacokinetics (PK)/pharmacodynamics (PD) of HC-5404 in multiple solid tumor types....Notably, the MTD was not determined in the population evaluable for safety (N=23).....HC-5404 demonstrated dose-dependent exposure and pharmacodynamic responses consistent with pathway engagement even at the starting dose of 25 mg. Preliminary signs of efficacy included one patient who achieved a durable partial response (with a duration of response of greater than two years and ongoing), multiple patients demonstrating stable disease, and four patients (17.4%) remaining on therapy for >180 days."

P1 data • Trial completion • Breast Cancer • Gastric Cancer • Renal Cell Carcinoma • Small Cell Lung Cancer

Inhibition of PERK by HC-5404 sensitizes clear cell renal cell carcinoma tumor models to anti-angiogenic tyrosine kinase inhibitors (AACR 2023) - P1a | "Furthermore, the approvals for VEGFR-targeting receptor tyrosine kinase inhibitors (VEGFR-TKIs), cabozantinib in second-line, and tivozanib in third-line RCC patients were based on modest objective response rates and median progression-free survival...We demonstrate that axitinib, cabozantinib, lenvatinib, and sunitinib all activate PERK in 786-O ccRCC xenografts in a dose-responsive manner...The combination treatment significantly improved TGI relative to either monotherapy, resulting in tumor regression of ~20%. Taken together, these findings highlight that by disrupting an adaptive stress response evoked by VEGFR-TKIs, HC-5404 presents a clinical opportunity to enhance the anti-tumor effects of well-established standard of care therapies in ccRCC."

Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Combination therapy using PERK and PD1/PD-L1 inhibitors reprograms tumor associated macrophages and reduces tumor burden (AACR 2023) - P1a | "We hypothesized that inhibition of PERK would improve responses to ICI therapy by reprogramming TAM from immunosuppressive to immunoactivating cells. To investigate if ER-stress underlies resistance to PD-1/PD-L1 targeted therapies, we utilized ex vivo assays to investigate ER-stress regulation of macrophage phenotype, and in vivo syngeneic murine models of melanoma growth, with HC-5404 (PERKi), a selective and potent first-in-human small molecule PERK inhibitor currently in a phase 1 clinical trial for solid tumors (NCT04834778). Treatment with PERKi sensitized αPD-1/PD-L1 mAb-resistant melanoma tumors (Y1.7/YR1.7) to PD-1/PD-L1 blockade with concomitant increase in tumor infiltrating leukocytes, TH1- reprogrammed TAM, and cytotoxic CD8+ T cells... The combination therapy targeting PERK and PD-1/PD-L1 signaling increased adaptive immune responses, reprogramed TAMs and reduced tumor growth kinetics. Results from these studies highlight a role for ER-stress..."

Combination therapy • IO biomarker • Melanoma • Oncology • Solid Tumor • CD8 • PERK

HiberCell to Present Pre-clinical Data on its Novel GCN2 Activator and PERK Inhibitor Programs at the American Association for Cancer Research (AACR) Annual Meeting 2023 (GlobeNewswire) - "HiberCell...announced three pre-clinical poster presentations which will be highlighted at the American Association for Cancer Research (AACR) Annual Meeting 2023, taking place April 14-19 in Orlando, Florida....'At the upcoming AACR meeting, we will be presenting data on HC-5404, which has shown remarkable activity in models of clear cell Renal Cell Carcinoma (RCC) in combination with anti-angiogenic VEGFR Tyrosine Kinase Inhibitors, an important component of standard of care in this setting. We will also present data on HC-7366, which have shown robust anti-tumor activity both as a monotherapy in and in combination with standard of care agents in several tumor types."

Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

PERK inhibitor HC-5404 demonstrates immune-activation and anti-tumor efficacy in combination with anti-PD1 immune checkpoint inhibitor antibody (SITC 2022) - P1a | "MDSCs also showed a reduced inhibition of T-cells in the presence of HC-5404 in vitro. Conclusions Collectively, these data demonstrate the efficacious and immuno-stimulatory effects of HC-5404 coadministered with anti-PD1 mAb and outline its potential application in ICI-treated cancers."

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CALR • CD69 • CD8 • IFNAR1 • IFNAR2

A Study of HC-5404-FU to Establish the Maximum Tolerated Dose (MTD) (clinicaltrials.gov) - P1a | N=36 | Recruiting | Sponsor: HiberCell, Inc. | Trial completion date: Jul 2023 ➔ Mar 2024 | Trial primary completion date: Jan 2023 ➔ Oct 2023

Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Hepatocellular Cancer • HER2 Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Thyroid Gland Papillary Carcinoma • HER-2

HiberCell to Present Preclinical Data from Novel GCN2 Activator and PERK Inhibitor Programs at The Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting (GlobeNewswire) - "HiberCell...announced two clinical abstract poster presentations at the upcoming Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting taking place November 8-12, 2022 in Boston, MA....The posters will present the immunomodulatory mechanisms of HC-7366, a differentiated selective, orally bioavailable activator of GCN2 (general controlled nonderepressible 2), and HC-5404, a differentiated highly selective, orally bioavailable inhibitor of key stress response protein kinase PERK (protein kinase RNA-like endoplasmic reticulum kinase)."

Preclinical • Oncology • Solid Tumor

A Study of HC-5404-FU to Establish the Maximum Tolerated Dose (MTD) (clinicaltrials.gov) - P1a | N=36 | Recruiting | Sponsor: HiberCell, Inc. | N=24 ➔ 36 | Trial completion date: Apr 2022 ➔ Jul 2023 | Trial primary completion date: Mar 2022 ➔ Jan 2023

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Hepatocellular Cancer • HER2 Breast Cancer • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Thyroid Gland Papillary Carcinoma • HER-2

HiberCell Receives Fast Track Designation from FDA for First-in-Human Studies of PERK Inhibitor (PERKi) HC-5404-FU (GlobeNewswire) - “HiberCell…announced today that the U.S. Food and Drug Administration (FDA) has granted the company Fast Track designation for HC-5404-FU, an orally administered PERK inhibitor (PERKi) for patients with solid tumors. 'This Phase 1a study will be expanded into a Phase 1b/2a through a protocol amendment with the dose and tumor type(s) identified in Phase 1a as the most appropriate for further clinical development.'"

Clinical protocol • Fast track designation • Oncology • Solid Tumor

HiberCell Initiates Phase 1a Clinical Trial of HC-5404-FU, an ER Stress Modulator (GlobeNewswire) - "HiberCell...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."

Enrollment status • Oncology • Solid Tumor