MK-3795 / Merck (MSD) - LARVOL DELTA

Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade. (PubMed, Cell Mol Life Sci) - "Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model...Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness."

Checkpoint inhibition • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • EPAS1 • HAVCR2

Hypoxia-inducible factor 2α mediates nonesterified fatty acids and hypoxia-induced lipid accumulation in bovine hepatocytes. (PubMed, J Dairy Sci) - "Meanwhile, normal or NEFA-treated hepatocytes were cocultured with or without PT2385, a specific HIF-2α inhibitor, showing that hypoxia promoted steatosis through HIF-2α...Overall, these data suggest that NEFA-induced hepatic hypoxia significantly contributes to the progression of hepatic steatosis which in turn, intensifies hypoxia and leads to a self-perpetuating cycle of reciprocal causation, further exacerbating hepatic lipid deposition. Additionally, accumulated HIF-2α plays a critical role in this complex-origin steatosis, potentially through ATF4."

Journal • Metabolic Disorders • ATF4 • EPAS1 • TCF4

In Obesity, Esophagogastric Junction Fat Impairs Esophageal Barrier Function and Dilates Intercellular Spaces via HIF-2α. (PubMed, Gastroenterology) - "We have elucidated molecular mechanisms whereby visceral fat of obese patients can impair esophageal barrier integrity by secreting substances that generate ROS, which activate HIF-2α in esophageal epithelial cells. These mechanisms could render the esophagus of obese individuals vulnerable to damage by acid and other noxious agents."

Journal • Gastroesophageal Reflux Disease • Genetic Disorders • Obesity • EPAS1 • IL1B • IL1R1

RO4929097 inhibits NICD3 to alleviate pulmonary hypertension via blocking Notch3/HIF-2α/FoxM1 signaling pathway. (PubMed, In Vitro Cell Dev Biol Anim) - "RO4929097 and plasmids including overexpression-NICD3 (oe-NICD3) and NICD3 small interfering RNA (siRNA) were used to alter the expression of NICD3, and HIF-2α inhibitor PT-2385 was used to alter the expression of HIF-2α. Our data suggest that RO4929097 regulates the Notch3/HIF-2α/FoxM1 signaling pathway by inhibiting the expression of NICD3, thereby inhibiting hypoxia-induced proliferation of HPASMCs. In vivo experiments also confirmed that RO4929097 could alleviate PH as a potential therapeutic strategy."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1 • FOXM1 • NOTCH3

IRON REGULATORY PROTEIN 2 CONTRIBUTES TO ANTIMICROBIAL IMMUNITY BY PRESERVING LYSOSOMAL FUNCTION IN MACROPHAGES (AASLD 2024) - "Tfeb mislocalization was reversed by Hif2 inhibitor PT2385 and, independently, through the inhibition of lactic acid production...Tfeb mislocalization was reversed by Hif2 inhibitor PT2385 and, independently, through the inhibition of lactic acid production. Our study highlights a mechanism whereby IRP2 preserves macrophage lysosomal function in antimicrobial activity to protect the liver against gut-originated bacterial invasion, shedding light on therapeutic intervention for patients with PLA."

Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Oncology • Solid Tumor • LDHA • TFEB

A pH-responsive novel delivery system utilizing carbon quantum dots loaded with PT2385 for targeted inhibition of HIF-2α in the treatment of osteoarthritis. (PubMed, Int J Pharm) - "The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis.This strategy opens new avenues for osteoarthritis treatment."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • EPAS1 • MMP13

Genetic and Epigenetic Regulation of Cortactin (CTTN) by Inflammatory Factors and Mechanical Stress in Human Lung Endothelial Cells. (PubMed, Biosci Rep) - "CTTN transcriptional is significantly influenced by inflammatory factors and promoter variants. Cortactin, essential in mitigating inflammatory edema, presents a promising therapeutic target to alleviate severe inflammatory disorders."

Journal • Inflammation • CTTN • EPAS1 • HIF1A • TNFA

The 'ABC' of split-nanoluciferase HIF heterodimerization bioassays: Applications, benefits & considerations. (PubMed, Biochem Pharmacol) - "This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols."

Journal • Hematological Disorders • Oncology • HIF1A

Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages. (PubMed, Proc Natl Acad Sci U S A) - "Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation."

Journal • Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Oncology • Solid Tumor • Ulcerative Colitis • LYZ • TFEB

Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia. (PubMed, Eur J Pharm Sci) - "This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC."

Journal • Inflammation • EPAS1

The role of hypoxia inducible factor modulation and defatting in discarded steatotic human livers preserved with normothermic machine perfusion (NMP): observations from an ex-situ whole blood transplant model (TTS 2024) - "We have previously reported dosing schedules for pharmacological HIF modulators including deferoxamine (DFO, a potent activator of both HIF-1a & HIF-2a) with selective HIF-2a inhibition using PT2385 (a HIF-2a dimerisation inhibitor) during NMP. The aim of the present study was to compare the effect of an established NMP defatting protocol (DeFat, comprising of insulin/glucose reduction, L-carnitine, NKH477 and lipid filter) with and without the adjunct of HIF modulators (DeFat-HIF, addition of DFO & PT2385) during ex-situ perfusion. Six sequential discarded livers (DeFat, n=3 and DeFat-HIF, n =3) were perfused with pRBC using the OrganOx metra over 12h, flushed and reperfused for 6h with whole blood (ex-situ transplant model), (Table1)... The DeFat-HIF protocol demonstrated a decrease in the presence of Ld-MaS and comparable perfusion biochemistry to the established DeFat protocol. The effect of these interventions on ischaemia-reperfusion injury remain to be..."

Reperfusion Injury • Transplantation • EPAS1 • HIF1A

PET Imaging of HIF-2a in Renal Cancer (KCRS 2024) - P1 | "PT2977 DoD CDMRP/KCRP Awards (FY2022) differs from PT2385 in that it consists of a vicinal difluoro group instead of a germinal one in PT2385. If successful, the theranostic method developed in this project may become transformative not only in oncology, but also in other diseases such as cardiac ischemia or strokes. FY22 KCRP Focus Area Addressed: Identify and develop new strategies for screening, early-stage detection, and accurate diagnosis and prognosis prediction of kidney cancers, with examples including biomarkers and imaging Principal Investigator: SUN, XIANKAI Institution Receiving Award: UNIVERSITY OF TEXAS SOUTHWESTERN Program: KCRP Proposal Number: KC220060 Award Number: HT9425-23-1-0903 Funding Mechanism: Translational Research Partnership Award Award Amount: $834,798"

IO biomarker • Cardiovascular • Clear Cell Renal Cell Carcinoma • Coronary Artery Disease • Ischemic stroke • Kidney Cancer • Myocardial Ischemia • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

A Phase 1, Dose-Escalation Trial of PT2385 Tablets In Patients With Advanced Clear Cell Renal Cell Carcinoma (MK-3795-001) (clinicaltrials.gov) - P1 | N=110 | Active, not recruiting | Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2024 ➔ Nov 2026

Metastases • Trial completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Epithelial HIF Activation Impairs Distal Airway Derived Alveolar Repair (ATS 2024) - "Roxadustat, a prolyl-hydroxylase inhibitor, was used to activate HIF-driven signaling...Administration of HIF2α inhibitor (PT-2385) attenuated emergence of IPF-like cell states, which based on RNA-trajectory analysis were derived from distal-airway progenitors... Persistent HIF activation in the alveolar epithelium prevents maturation and terminal differentiation of regenerating AT2 cells from airway progenitors through suppression of essential AT2 biosynthetic components and metabolic machinery. HIF2 inhibition represents a novel therapeutic target to enhance alveolar repair."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • ACACA • ACSL1 • ACSL4 • FASN • KRT17 • KRT5 • LPCAT1

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling. (PubMed, Cell Host Microbe) - "Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • EPAS1

Renal Surgery following HIF2α Antagonist Therapy: Growth Kinetics and Surgical Outcomes (AUA 2024) - "Two HIF2α inhibitors, PT2385 and PT2977 (Belzutifan), have shown efficacy and led to the recent FDA approval for Belzutifan in patients with tumors from VHL syndrome. This is the first study to detail the growth kinetics and surgical outcomes of renal tumors removed after HIF2α antagonist exposure. There was no significant difference between the growth rates of the index tumor before, during, or after HIF2α antagonist therapy (p=0. 79)."

Surgery • Cardiovascular • Kidney Cancer • Oncology • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization. (PubMed, J Cachexia Sarcopenia Muscle) - "Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Muscular Atrophy • Pulmonary Disease • Respiratory Diseases • EPAS1 • HIF1A

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation. (PubMed, Cell Death Dis) - "Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • FKBP10 • FKBP5 • LDHA

A Phase 1, Dose-Escalation Trial of PT2385 Tablets In Patients With Advanced Clear Cell Renal Cell Carcinoma (MK-3795-001) (clinicaltrials.gov) - P1 | N=110 | Active, not recruiting | Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2023 ➔ Nov 2024

Metastases • Trial completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P2 | N=4 | Completed | Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Active, not recruiting ➔ Completed | Trial primary completion date: Nov 2023 ➔ Aug 2023

Trial completion • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

High-Altitude Hypoxia Induces Excessive Erythrocytosis in Mice via Upregulation of the Intestinal HIF2a/Iron-Metabolism Pathway. (PubMed, Biomedicines) - "The HIF2α inhibitor PT2385 suppressed intestinal HIF2α expression, decreased iron hypermetabolism, and reduced excessive erythrocytosis in mice. These data support the hypothesis that exposure to high-altitude hypoxia can lead to iron hypermetabolism by activating intestinal HIF2α transcriptional regulation, and reduced iron availability improves EE by inhibiting intestinal HIF2α signaling."

Journal • Preclinical • Hematological Disorders • DMRT1 • EPAS1

Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma. (PubMed, J Neurooncol) - "PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied."

Journal • Brain Cancer • Cardiovascular • CNS Disorders • CNS Tumor • Diabetes • Glioblastoma • Heart Failure • Hematological Disorders • Oncology • Solid Tumor • EPAS1

Epithelial HIF Inhibition Enables Adaptive Repair and Alveolar Regeneration in Chronic Lung Injury (ATS 2023) - "Sftpc-Cre-ERT2 or Scgb1a1-Cre-ERT2 mice x Rosa-CAG-LSL-tdTomato mice treated with Tamoxifen were used for lineage labeling of type II alveolar epithelium (AT2) or airway secretory cells, respectively...Next, using implantable osmotic pumps to administer HIF2α inhibitor (PT-2385) during repetitive IT bleomycin injury, Scgb1a1-linage traced cells from PT-2385-treated mice contributed a larger fraction of repairing alveoli and an increased proportion of traced cells expressed mature alveolar markers (pro-Spc or Ager)... Persistent HIF2 activation in the alveolar epithelium prevents maturation and terminal differentiation of regenerating AT2 and AT1 cells arising from airway progenitors. HIF2 inhibition represents a novel therapeutic target to enhance alveolar repair."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • HIF1A

[18F]PT2385 PET/CT in Patients With Renal Cell Carcinoma (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: Orhan Kemal Oz | N=50 ➔ 80

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

THE ESOPHAGOGASTRIC JUNCTION FAT PAD OF OBESE INDIVIDUALS CAUSES ESOPHAGEAL SQUAMOUS CELLS TO SECRETE IL-1β AND IMPAIRS ESOPHAGEAL BARRIER FUNCTION VIA ACTIVATION OF HIF-2α (DDW 2023) - "ALI cultures were exposed to conditioned medium from EGJ fat of obese patients (CM-EGJ) with or without PT2385 (a HIF-2α specific inhibitor), or to control medium (CtrlM); we measured transepithelial resistance (TER, an index of barrier function) in ALI cultures on days 4, 6, and 8... Substances produced by EGJ fat of obese subjects impair esophageal barrier function and cause esophageal squamous cells to secrete the pro-inflammatory cytokine IL-1β via activation of HIF-2α. This suggests that, in obesity, visceral fat induces HIF-2α-dependent activation of caspase-1 to cause a GERD-independent esophageal inflammatory response that impairs esophageal barrier function."

Clinical • Gastroesophageal Reflux Disease • Genetic Disorders • Melanoma • Obesity • Oncology • Solid Tumor • AIM2 • EPAS1 • IL18 • IL1B