INCB59872 / Incyte - LARVOL DELTA

Combination Therapy and Dual-Target Inhibitors Based on LSD1: New Emerging Tools in Cancer Therapy. (PubMed, J Med Chem) - "Over two decades, numerous LSD1 inhibitors have been reported, especially some of which have entered clinical trials, including eight irreversible inhibitors (TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289, ORY-2001, TAK-418, and LH-1802) and two reversible inhibitors (CC-90011 and SP-2577)...LSD1 multitarget inhibitors have also been reported, exampled by clinical dual LSD1/histone deacetylases (HDACs) inhibitors 4SC-202 and JBI-802. Herein, we present a comprehensive overview of the combination of LSD1 inhibitors with various antitumor agents, as well as LSD1 multitarget inhibitors. Additionally, the challenges and future research directionsare also discussed, and we hope this review will provide new insight into the development of LSD1-targeted anticancer agents."

Combination therapy • Journal • Review • Oncology

Lysine-Specific Demethylase 1 (LSD1) Inhibitors: Peptides as an Emerging Class of Therapeutics. (PubMed, ACS Chem Biol) - "The advent of LSD1 inhibitor-based clinical utility began with tranylcypromine, and it is now considered an inevitable scaffold in the search for other irreversible novel LSD1 inhibitors (IMG-7289 or bomedemstat, ORY1001 or iadademstat, ORY-2001 or vafidemstat, GSK2879552, and INCB059872). Moreover, numerous reversible inhibitors for LSD1 have been reported in the literature, including clinical candidates CC-90011 (pulrodemstat) and SP-2577 (seclidemstat)...For the first time, we comprehensively organized the peptide-based LSD1 inhibitors from the design strategy. Peptide inhibitors of LSD1 are classified as H3 peptide and SNAIL1 peptide derivatives, along with miscellaneous peptides that include naturally occurring LSD1 inhibitors."

Journal • Review • Oncology • SNAI1

Recent advances of LSD1/KDM1A inhibitors for disease therapy. (PubMed, Bioorg Chem) - "Nine LSD1 inhibitors including tranylcypromine, ORY-1001, ORY-2001, GSK-2879552, IMG-7289, INCB059872, TAK-418, CC-90011 and SP-2577 have entered clinical stage for disease treatment as either mono- or combinational therapy. The influence of the stereochemistry on the potency against LSD1 and its homolog LSD2 is briefly discussed. Finally, the challenges and prospects of LSD1-targeted drug discovery are also given."

Journal • Review • Hematological Disorders • Hematological Malignancies • Oncology

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials. (PubMed, Front Pharmacol) - "Seven of them (tranylcypromine, iadademstat (ORY-1001), bomedemstat (IMG-7289), GSK-2879552, INCB059872, JBI-802, and Phenelzine) covalently bind the FAD cofactor, and two are non-covalent LSD1 inhibitors [pulrodemstat (CC-90011) and seclidemstat (SP-2577)]. Another TCP-based LSD1/MAO-B dual inhibitor, vafidemstat (ORY-2001), is in clinical trial for Alzheimer's diseases and personality disorders. The present review summarizes the structure and functions of LSD1, its pathological implications in cancer and non-cancer diseases, and the identification of LSD1 covalent and non-covalent inhibitors with different chemical scaffolds, including those involved in clinical trials, highlighting their potential as potent and selective anticancer agents."

Journal • Review • Acute Myelogenous Leukemia • Alzheimer's Disease • CNS Disorders • Esophageal Cancer • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Leukemia • Mood Disorders • Oncology • Personality Disorder • Solid Tumor

An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=116 | Terminated | Sponsor: Incyte Corporation | Active, not recruiting ➔ Terminated; Strategic Business Decision

Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Comprehensive in Vitro Characterization of the LSD1 Small Molecule Inhibitor Class in Oncology. (PubMed, ACS Pharmacol Transl Sci) - "A host of classical amine oxidase inhibitors such as tranylcypromine, pargyline, and phenelzine together with LSD1 tool compounds such as SP-2509 and GSK-LSD1 have been extensively utilized in LSD1 mechanistic cancer studies. Additionally, several optimized new chemical entities have reached clinical trials in oncology such as ORY-1001 (iadademstat), GSK2879552, SP-2577 (seclidemstat), IMG-7289 (bomedemstat), INCB059872, and CC-90011 (pulrodemstat)...Herein, we characterize the whole LSD1 small molecule compound class as inhibitors of LSD1 catalytic activity, disruptors of SNAIL/GFI1 (SNAG)-scaffolding protein-protein interactions, inducers of cell differentiation, and potential anticancer treatments for hematological and solid tumors to yield an updated, unified perspective of this field. Our results highlight significant differences in potency and selectivity among the clinical compounds with iadademstat being the most potent and reveal that most of the tool compounds..."

Journal • Preclinical • Hematological Disorders • Oncology • Solid Tumor

[VIRTUAL] Pre-Clinical Efficacy of Co-Targeting GFI1/KDM1A and BRD4 or JAK1/2 Against AML and Post-MPN Secondary AML Blast Progenitor Cells (ASH 2020) - "CRISPR-mediated GFI1-KO ± the irreversible LSD1 inhibitor (LSD1i) (INCB059872, INCB), repressed GFI1 levels, yet enhanced expressions of PU.1, p21 and CD11b and significantly increased % morphologic differentiation. Notably, co-treatment with INCB (1.5 mg/kg) and ruxolitinib (20 mg/kg) or OTX015 (50 mg/kg), administered orally for 21 days, compared to ruxolitinib alone or vehicle control, significantly reduced the sAML burden and improved survival of immune-depleted mice engrafted with luciferized sAML HEL92.1.7 xenografts (p < 0.01). Collectively, these findings support further pre-clinical development of LSD1i-based combinations with ruxolitinib and BETi against post-MPN sAML."

IO biomarker • Inflammation • BCL2 • CDK6 • CDKN1A • DNMT1 • HDAC1 • IRF8 • ITGAM • JAK1 • JAK2 • KIT • MYB • MYC • RUNX1

[VIRTUAL] The LSD1 inhibitor INCB059872 is a possible therapeutic option for venetoclax-resistant AML (AACR 2021) - "The high response rate of AML patients receiving venetoclax in combination with azacitidine as first line AML therapy means differentiation therapy with LSD1 inhibitors would be more acceptable either in combination with venetoclax, or post-venetoclax treatment. Venetoclax resistant MLL-AF9 driven AML was also resistant to INCB059872, but the combination of venetoclax and INCB059872 was able to slow the onset of venetoclax resistant MLL-AF9 driven AML significantly. The data presented here suggest that inhibition of LSD1 with INCB059872 may alter the expression of apoptotic machinery of AML cells leading to combinatorial therapeutic benefit when co-administered with venetoclax, and that INCB059872 combined with venetoclax may overcome acquired venetoclax resistance in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MCL1

Azacitidine Combined With Pembrolizumab and Epacadostat in Subjects With Advanced Solid Tumors (ECHO-206) (clinicaltrials.gov) - P1/2; N=70; Terminated; Sponsor: Incyte Corporation; Completed ➔ Terminated; Study terminated by Sponsor

Biomarker • Clinical • Combination therapy • Trial termination • Tumor microenvironment • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • BRAF • EGFR • KRAS • NRAS

An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=116; Active, not recruiting; Sponsor: Incyte Corporation; Terminated ➔ Active, not recruiting; Trial completion date: Jun 2020 ➔ May 2022; Trial primary completion date: Jun 2020 ➔ May 2022

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Incyte Announces Data from Multiple Programs Within its Oncology Portfolio Accepted for Presentation at the AACR Annual Meeting 2021 (Businesswire) - "Incyte...announced that multiple abstracts from across its oncology portfolio will be presented during Week 1 of the upcoming American Association for Cancer Research (AACR) Annual Meeting 2021, held virtually from April 10-15, 2021....'At AACR 2021, we look forward to sharing clinical and pre-clinical data from INCB106385, our novel A2A/A2B adenosine receptor antagonist, and INCA00186, our novel CD73 monoclonal antibody—both of which highlight our ongoing efforts targeting the adenosine pathway. Presentations at the congress will also feature updated data from our LIMBER development program, including results from our Phase 2 combination study of ruxolitinib, a janus kinase (JAK1/JAK2) inhibitor, and parsaclisib, a potent, highly selective oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ)'"

Clinical data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Lung Cancer • Myelofibrosis • Non Small Cell Lung Cancer • Oncology

The FAD-directed LSD1 specific inhibitor, INCB059872, inhibits cell migration and metastasis by suppressing premetastatic niche formation in a spontaneous metastasis mouse model (AACR 2018) - "Notably, analyses of molecular pathways using RNA-Seq identified that components of the EMT associated pathway are also downregulated in tumors treated with INCB059872, which further supports the role of INCB059872 in the inhibition of metastasis. Taken together, these preclinical data suggest that inhibition of LSD1 with INCB059872 can suppress metastasis through multiple molecular and cellular mechanisms, notably by inhibition of the formation of the pre-metastatic niche by modulating the population of MDSCs in the primary tumor and distal tissues."

Preclinical • Triple Negative Breast Cancer

The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of T-ALL (AACR 2018) - "Combination efficacy studies of INCB059872 with standard care of agents or targeted therapeutic agents in T-ALL models are currently being evaluated. These data suggest exploring the potential clinical development of INCB059872 as a therapy for T-ALL patients."

IO Biomarker • Preclinical • Acute Lymphocytic Leukemia

INCB059872, a novel FAD-directed LSD1 Inhibitor, is active in prostate cancer models and impacts prostate cancer stem-like cells (AACR 2018) - "These data suggest that INCB059872 could be a valid addition to the current treatment strategies for prostate cancer. INCB059872 is currently in phase1/2 clinical studies"

Preclinical • Prostate Cancer

Clinical efficiency of epigenetic drugs therapy in bone malignancies. (PubMed, Bone) - "Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102, inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 and Tamezostat. To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers."

Clinical • Journal • Ewing Sarcoma • Immune Modulation • Inflammation • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EZH2

Tranylcypromine based LSD1 inhibitor: Summary and Prospective. (PubMed, J Med Chem) - "To date, six trans-2-phenylcyclopropylamine (TCP)-based LSD1 inhibitors (including TCP, ORY-1001, GSK-2879552, INCB059872, IMG-7289 and ORY-2001) that covalently bind to the flavin adenine dinucleotide (FAD) within the LSD1 catalytic cavity have already entered into clinical trials. Here, we provide an overview about the structures, activities and structure-activity relationship (SAR) of TCP-based LSD1 inhibitors that mainly covers the literatures from 2008 to date. The opportunities, challenges and future research directions in this emerging and promising field are also discussed."

Clinical • Journal • Oncology

An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=116; Terminated; Sponsor: Incyte Corporation; N=215 ➔ 116; Trial completion date: Dec 2021 ➔ Jun 2020; Recruiting ➔ Terminated; Trial primary completion date: Jun 2021 ➔ Jun 2020; Strategic Business Decision

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

LSD1/KDM1A inhibitors in clinical trials: advances and prospects. (PubMed, J Hematol Oncol) - "Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field."

Clinical • Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lung Cancer • Oncology • Small Cell Lung Cancer • Thoracic Cancer

A Study of INCB059872 in Relapsed or Refractory Ewing Sarcoma (clinicaltrials.gov) - P1b; N=25; Terminated; Sponsor: Incyte Corporation; Trial completion date: Jun 2021 ➔ Jun 2020; Recruiting ➔ Terminated; Trial primary completion date: Dec 2020 ➔ Jun 2020; Strategic Business Decision

Clinical • Trial completion date • Trial primary completion date • Trial termination • Ewing Sarcoma • Oncology • Sarcoma • Small Cell Lung Cancer • Solid Tumor

Nascent transcript and single-cell RNA-seq analysis defines the mechanism of action of the LSD1 inhibitor INCB059872 in myeloid leukemia. (PubMed, Gene) - "INCB059872 is in phase I clinical trials, and we evaluated a pre-treatment bone marrow sample of a patient who showed a clinical response to INCB059872 while being treated with azacitidine. Finally, we treated mice with INCB059872 and performed scRNA-seq of lineage-negative bone marrow cells, which showed that INCB059872 triggered accumulation of megakaryocyte early progenitor cells with gene expression hallmarks of stem cells. Accumulation of these stem/progenitor cells may contribute to the thrombocytopenia observed in patients treated with LSD1 inhibitors."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia

Incyte’s targeted therapy and immuno-oncology portfolio to be featured in 20 Abstracts at the AACR Annual Meeting 2017 (Incyte Press Release) - "Incyte...announces that 20 abstracts from its research and development portfolio will be presented at the upcoming 2017 [AACR Annual Meeting]...These abstracts include a clinical data presentation from the dose-escalation phase of the Company’s ongoing trial of its selective FGFR 1/2/3 inhibitor (INCB54828), and well as preclinical data from its small molecule inhibitor programs targeting PI3Kδ (INCB50465), LSD1 (INCB59872), JAK1 (INCB52793), BRD/BET (INCB54329 and INCB57643) and FGFR4 (INCB62079) and from its epacadostat, OX40 (INCAGN1949) and GITR (INCAGN1876) immuno-oncology programs."

Anticipated clinical data • Anticipated conference • Anticipated preclinical • Oncology

Incyte: Q4 & YE FY 2015 Results (Incyte) - Anticipated initiation of P1/2 trial in advanced malignancies in H1 2016

Anticipated new P1/2 trial • Oncology

The evaluation of INCB059872, an FAD-directed covalent inhibitor of LSD1, in preclinical models of Ewing sarcoma (AACR 2017) - "Studies identifying potential candidate molecular mechanisms are underway. Together, these data suggest that INCB059872 may be therapeutically efficacious in a subset of Ewing sarcoma patients."

Biosimilar • Oncology • Sarcoma

An Open-Label, Dose-Escalation/Dose-Expansion Safety Study of INCB059872 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=108; Not yet recruiting; Sponsor: Incyte Corporation

New P1/2 trial • Biosimilar • Oncology

The FAD-directed LSD1 specific inhibitor, INCB059872, is a promising epigenetic agent for AML therapy by inducing differentiation of leukemic stem/progenitor cells (AACR 2018) - "Furthermore, INCB059872 induced the differentiation of early hematopoietic progenitors, CD34+/CD38- to more committed CD34+/CD38+ multipotent/oligopotent progenitors, which in turn gave rise to lineage specific progenitors in the human AML PDX models. These studies support further exploration of INCB059872 as a promising novel epigenetic agent for AML therapy whose mechanism of action lies in part through the induction of differentiation of leukemic stem/progenitor cells to more committed hematopoietic lineages."

IO Biomarker • Acute Myelogenous Leukemia