GRN-300 / Arrien, Greenfire Bio - LARVOL DELTA

Identification of pharmacodynamic biomarkers in PBMCs and cancer cells for SIK2 kinase inhibitor therapy (AACR 2024) - P1 | "SIK2 inhibitors synergistically enhance sensitivity of ovarian and breast cancer cells to paclitaxel, carboplatin and PARP inhibitors. Five genes - ID1, ID2, ID3, ID4 and TGFBI - are down-regulated in response to GRN-300 treatment in more than 10 of 13 cell lines. The decrease in HDAC4/5/7 phosphorylation, and alterations in mRNA markers we discovered could serve as PD biomarkers for clinical trials to evaluate the effects of SIK2 inhibitors and provide insights in the mechanisms of drug action."

Biomarker • PK/PD data • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Ovarian Cancer • Solid Tumor • AMPK • DDIT4 • HDAC4 • IL6 • MS4A6A • mTOR • RNASE1 • STK11 • TGFBI

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Suspended | Sponsor: Green3Bio, Inc. | Active, not recruiting ➔ Suspended

Combination therapy • Trial suspension • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Active, not recruiting | Sponsor: Green3Bio, Inc. | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300-001: First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1 | N=73 | Recruiting | Sponsor: Green3Bio, Inc. | Trial completion date: Mar 2023 ➔ Mar 2025 | Trial primary completion date: Dec 2022 ➔ Dec 2024

Combination therapy • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor

GRN300–001: Phase 1/1B evaluation of the safety, pharmacokinetics, and efficacy of GRN-300, a salt-inducible kinase inhibitor, alone and in combination with paclitaxel, in recurrent ovarian, primary peritoneal, and fallopian tube cancers. (ASCO 2022) - P1 | "The first 3 dose groups (100, 200, and 300 mg BID of GRN-300) have been completed without DLT and preliminary PK analysis indicate dose proportionality. Enrollment to dose group 4 (400 mg BID) began in February 2022."

Clinical • Combination therapy • P1 data • PK/PD data • Fallopian Tube Cancer • Oncology • Ovarian Cancer

Green3Bio Announces Publication of Pre-Clinical Data Demonstrating SIK2 Inhibition (including GRN-300) Enhances PARP Inhibitor Activity Synergistically in Ovarian and Triple Negative Breast Cancers. (PRNewswire) - "Green3Bio Announces Publication of Pre-Clinical Data Demonstrating SIK2 Inhibition (including GRN-300) Enhances PARP Inhibitor Activity Synergistically in Ovarian and Triple Negative Breast Cancers. The major findings from the preclinical research study include: 1. GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity; 2. The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300; 3. GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis; 4. Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC."

Preclinical • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer

SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers. (PubMed, J Clin Invest) - "We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC."

Journal • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • DRD • FANCD2 • HDAC4 • MEF2D • XRCC4

Greenfire Bio to update progress on Phase 1 Clinical Trial for SIK2/SIK3 inhibitor, GRN-300, in ovarian cancer at the ASCO Annual Meeting 2022 (PRNewswire) - P1 | N=64 | NCT04711161 | Sponsor: Green3Bio | "Greenfire Bio...will present an update on the ongoing first-in-human clinical trial of GRN-300 at the upcoming ASCO 2022 Annual Meeting. GRN-300 is a first-in-class, orally bioavailable novel small molecule inhibitor of the Salt Inducible Kinases 2 and 3 (SIK2/SIK3) that is highly expressed in ovarian cancer and has been identified to play a pivotal role in several other cancers. The transition of this emerging biologic pathway and a novel agent into the clinic marks a successful step in the progress of the GRN-300 program."

P1 data • Gynecologic Cancers • Oncology • Solid Tumor

A Novel Salt Inducible Kinase 2 Inhibitor, ARN-3261, Sensitizes Ovarian Cancer Cell Lines and Xenografts to Carboplatin. (PubMed, Cancers (Basel)) - "Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor

First-in-Human Evaluation of GRN-300 in Subjects With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers. (clinicaltrials.gov) - P1; N=64; Recruiting; Sponsor: Green3Bio, Inc.

Clinical • Combination therapy • New P1 trial • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Solid Tumor