HC-7366 / HiberCell - LARVOL DELTA

Phase 1b study of HC-7366 alone and in combination with venetoclax and azacitidine in relapsed/refractory Acute Myeloid Leukemia (ASH 2025) - P1 | "Initiation of triplet dose escalation is planned for Q3 2025. (NCT06285890)Funding: MDACC NCI Cancer Center Support Grant, HiberCell, Inc."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Central Nervous System Leukemia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • MCL1

Activation of GCN2 By HC-7366 Results in Significant Anti-Tumor Efficacy As Monotherapy and Overcomes Resistance Mechanisms When Combined with Venetoclax in AML (ASH 2023) - P1 | "Venetoclax (anti-BCL2) is approved for elderly patients with acute myeloid leukemia (AML) in combination with hypomethylating agents such as azacitidine or decitabine. Our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity in AML as a single agent and in combination with venetoclax. The potential of HC-7366 to counteract multiple known resistance mechanisms to venetoclax could provide a viable treatment option for patients with relapsed/refractory AML when used in combination with venetoclax."

Clinical • IO biomarker • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ATF4 • FLT3 • PSAT1 • S100A8

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). (ASCO 2025) - P1 | "in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson pmattson@hibercell.com, 651.312.5831."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

HiberCell Announces Successful Completion of Dose Escalation and Enrollment Update for Ph1b Study Evaluating HC-7366 in Combination with WELIREG (belzutifan) in Advanced ccRCC (The Manila Times) - "HiberCell, Inc...today announced the successful completion of the dose escalation portion of its Phase 1b study evaluating HC-7366—an activator of the integrated stress response (ISR) kinase GCN2—in combination with...WELIREG (belzutifan) for the treatment of advanced clear cell renal cell carcinoma (ccRCC)....All three dose levels tested cleared the respective dose-limiting toxicity (DLT) evaluations. Based on the favorable safety and PK/PD profile, the 40 mg and 60 mg doses of HC-7366 were selected for further evaluation in combination with belzutifan....Enrollment for the 60 mg cohort is ongoing and is expected to complete before the end of the second quarter of 2025."

Trial status • Clear Cell Renal Cell Carcinoma

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). (ASCO-GU 2025) - P1 | "in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson pmattson@hibercell.com, 651.312.5831."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

RCC-TIP: A Hibercell phase I study of HC-7366 and belzutifan (DAVAGU 2024) - No abstract available.

HiberCell Receives FDA Fast Track Designation for HC-7366 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (AML) (GlobeNewswire) - "HiberCell, Inc...is pleased to announce that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to HC-7366 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia."

Fast track • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC-7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605 (KCRS 2024) - P1 | "Abstract 4615. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA"

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • VHL

Congratulations | Pharmaron Holds Eleventh Annual Symposium [Google translation] (Sina Corp) - "Pharmaron held its 11th Symposium on Synthetic and Medicinal Chemistry on the 21st September, 2024, in Beijing, China....Mr. Chris Thomas, Pharmaron, UK, disclosed the medicinal chemistry path to 'The Discovery of HC-7366: An Orally Bioavailable and Efficient GCN2 Kinase Activator ', in a collaboration between HiberCell and Pharmaron, which has successfully entered into phase 1b clinical trial."

Clinical • Oncology

HiberCell Announces First Patient Dosed in Phase 1b Clinical Trial, Evaluating HC-7366 in Combination with Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia (AML) (GlobeNewswire) - "HiberCell, Inc...is pleased to announce the first patient dosed in a clinical trial evaluating HC-7366 in combination with standard of care agents venetoclax and azacitidine for advanced acute myeloid leukemia (AML)....The initiation of this study along with our recently announced study of HC-7366 in clear cell renal cell carcinoma marks the continued advancement of HC-7366 and HiberCell....We look forward to seeing data for these studies throughout 2024 and 2025....The study aims to determine the recommended Phase 2 dose (RP2D) of HC-7366 in combination with venetoclax and azacitidine in a R/R AML population. The study will enroll up to 18 patients."

P1 data • Trial status • Acute Myelogenous Leukemia • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Malignancies • Oncology

Phase I Study of HC-7366 With Azacitidine and Venetoclax for Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Aug 2024 ➔ May 2024

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

HiberCell Announces First Patient Dosed in Clinical Collaboration with Merck, Evaluating HC-7366 in Combination with WELIREG (belzutifan) in patients with advanced ccRCC (GlobeNewswire) - "HiberCell...is pleased to announce the dosing of the first patient in a Phase 1b study evaluating HC-7366, an activator of integrated stress response (ISR) Kinase GCN2, in combination with Merck’s oral hypoxia-inducible factor-2α (HIF-2α) inhibitor WELIREG (belzutifan) for the treatment of advanced clear cell renal cell carcinoma (ccRCC). The Phase 1b study (NCT06234605) will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in combination with belzutifan in patients with advanced ccRCC. This trial will also determine a recommended Phase 2 dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd."

Trial status • Clear Cell Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

HC-7366, a potent GCN2 kinase activator, augments osimertinib therapy to delay resistance in EGFR mutant NSCLC models (AACR 2024) - P1 | "We found a proliferation reduction by Ki67 and an increase in apoptotic proteins CHOP, PUMA, and cleaved caspase 3. Taken together, these data reveal that combination of HC-7366 and osimertinib, and potentially other EGFR TKIs, may be an effective treatment strategy at targeting adaptive resistance mechanisms."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF4 • CASP3 • CCND1 • CDK4 • EGFR • HIF1A • TIMM17A

HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models (AACR 2024) - P1 | "Belzutifan is currently being tested in indications beyond RCC, so we evaluated the combination in VHLwt endometrial cancer model, MFE-280. Consistent with RCC models, the combination of HC-7366 and belzutifan resulted in tumor stasis with activation of ISR, enhanced inhibition of HIF and cell cycle markers in the combination vs belzutifan monotherapy.Together, these findings suggest that HC-7366 enhances belzutifan activity and serves as a rationale supporting clinical evaluation of this therapeutic combination."

Monotherapy • Clear Cell Renal Cell Carcinoma • Endometrial Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • EPAS1 • HIF1A

HiberCell Announces Recent Publication and Poster Presentations for its Novel GCN2 Activator, HC-7366 (GlobeNewswire) - "HiberCell...announced the publication of 'Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator' in the Journal of Medicinal Chemistry along with two poster presentations on this same molecule which will be highlighted at the American Association for Cancer Research (AACR) Annual Meeting 2024....'Our publication in the Journal of Medicinal Chemistry illustrates that that HC-7366 is a refined GCN2 activator with a superior PK/PD profile, enhanced selectivity, and robust preclinical efficacy'....Our first poster features the remarkable preclinical activity of HC-7366 as monotherapy and in combination with belzutifan in clear cell renal cell carcinoma models (ccRCC)....Our second presentation details preclinical data demonstrating the ability of HC-7366 to augment osimertinib therapy to counteract resistance mechanisms in models of EGFR mutant NSCLC."

Preclinical • Clear Cell Renal Cell Carcinoma • Non Small Cell Lung Cancer

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator. (PubMed, J Med Chem) - "Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition."

Journal • Oncology

Phase I Study of HC-7366 With Azacitidine and Venetoclax for Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center | N=58 ➔ 18

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Study of HC-7366 in Combination With Belzutifan (WELIREG™) in Patients With Renal Cell Carcinoma (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: HiberCell, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • VHL

A Study of HC-7366 to Establish the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) (clinicaltrials.gov) - P1 | N=35 | Terminated | Sponsor: HiberCell, Inc. | N=70 ➔ 35 | Trial completion date: Oct 2024 ➔ Mar 2024 | Recruiting ➔ Terminated; sponsor decision

Enrollment change • Metastases • Trial completion date • Trial termination • Bladder Cancer • Clear Cell Renal Cell Carcinoma • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

Phase I Study of HC-7366 With Azacitidine and Venetoclax for Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=58 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Study of HC-7366 in Combination With Belzutifan (WELIREG™) in Patients With Renal Cell Carcinoma (clinicaltrials.gov) - P1 | N=80 | Not yet recruiting | Sponsor: HiberCell, Inc.

New P1 trial • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • VHL

HiberCell Announces Presentation at ASH, Highlighting Preclinical Data for HC-7366 with Standard of Care Agents in Acute Myeloid Leukemia (AML) (GlobeNewswire) - "HiberCell...announced data from a poster presentation at the 65th ASH Annual Meeting and Exposition....'We look forward to providing additional information on our clinical development plans for HC-7366 in AML in 2024'....HC-7366 potently activates integrated stress response (ISR) signaling via GCN2 and shows single-agent antitumor activity in vivo in TP53-mutant AML CDX models....The combination of HC-7366 and venetoclax shows combination benefit, characterized by enhanced activation of ISR by the doublet and inhibition of several modes of venetoclax resistance. The triplet combination of low-dose HC-7366, venetoclax, and azacitidine is significantly more efficacious than the venetoclax/azacitidine doublet."

Clinical • Preclinical • Acute Myelogenous Leukemia

HiberCell, Inc. Announces Clinical Collaboration with Merck to Evaluate HC-7366, an Activator of ISR Kinase GCN2, in Combination with WELIREG (belzutifan) in a Phase 1b Study of Patients with Clear Cell Renal Cell Carcinoma (ccRCC) (GlobeNewswire) - "HiberCell...announced a clinical collaboration with Merck...to evaluate HC-7366, HiberCell’s first-in-class, potent and selective activator of the general control nonderepressible 2 (GCN2) kinase, in combination with WELIREG (belzutifan), Merck’s oral hypoxia-inducible factor-2α (HIF-2α) inhibitor, for the treatment of clear cell renal cell carcinoma (RCC). The Phase 1b study will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in combination with WELIREG in participants with ccRCC. With a focus on determining the recommended Phase 2 dose (RP2D), the study includes a dose-escalation phase followed by a dose-expansion phase and an independent HC-7366 monotherapy cohort. The study is planned to open in Q1 2024 and will enroll up to 80 participants at clinical sites..."

Licensing / partnership • New P1 trial • Clear Cell Renal Cell Carcinoma

Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy and in combination with multiple standard of care agents in various solid cancer models (AACR 2023) - P1 | "Furthermore, HC-7366 showed significant benefit in colorectal models when combined with DC101 (anti-VEGFR2 antibody), 5-fluorouracil (chemotherapy), alpelisib (PI3Kα inhibitor), or trametinib (MEK1/2 inhibitor). ATF4 and JUN transcriptional activity was enhanced with HC-7366 treatment consistent with activation of ISR. Collectively, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity across multiple solid tumor models as a monotherapy or in combination with standard of care agents."

Clinical • Combination therapy • Monotherapy • Preclinical • Oncology • Sarcoma • Solid Tumor • ATF4 • E2F1 • HIF1A • PIK3CA • PSAT1

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