numidargistat (INCB001158) / Calithera - LARVOL DELTA

The role of Arginase 1 in immune infiltration in the pre-metastatic tumor microenvironment (SITC 2025) - "We hypothesized that its increase in the aged TME is significant as it may play a role in allowing outgrowth of proliferative cells, unabated by the immune system.Methods To investigate how Arg1 enables metastatic progression in a growth restrictive metastatic TME, we treated C57BL/6 young male mice with recombinant Arg1 (HY-P71833, 100ug/mL) via intraperitoneal injection (IP) injection while aged mice were treated with an inhibitor of ARG1, Numidargistat (CB-1158, 100 mg/kg/mouse), given via oral gavage twice daily...ARG1 inhibition in aged mice decreased outgrowth and increased NK cell infiltration into both tissues. PROS1 overexpression also significantly increased metastatic colonization across both tissues and increased myeloid specific expression of ARG1.Conclusions This provides strong evidence that age induced pre-metastatic increase in Arg1 myeloid cells, coupled with secretion of PROS1 from reactivated melanoma cells in the aged metastatic lung and liver..."

Biomarker • Metastases • Tumor microenvironment • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • ARG1 • ITGAM • PROS1

Induction of T cell immunity against arginase 1 (Arg1)+ myeloid cells is a unique feature that differentiates tumor growth suppression of Arg1 immune-modulatory vaccines from that of Arg1 inhibitors (SITC 2025) - "Direct comparison of Arg1 peptide vaccination and Arg1 inhibitor CB-1158 showed that while both treatments led to comparable tumor growth control, Arg1 vaccination promotes a pro-inflammatory TME with significant reduction in Arg1 within TAMs and MDSCs than those observed in mice Arg1 inhibitor-treated mice...These findings provide a strong rationale for future clinical development of an Arg1-based vaccine as a potential therapeutic strategy for solid tumors.Ethics Approval The animal experiments were reviewed and approved by the Danish Animal Experimentation Council and performed under license number 2022-15-0201-01209. All animal experiments were conducted following national regulations and ethical guidelines."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • ARG1 • CD14 • IFNG • S100A8 • S100A9

EvSec22, a SNARE Protein, Regulates Hyphal Growth, Stress Tolerance, and Nematicidal Pathogenicity in Esteya vermicola. (PubMed, J Fungi (Basel)) - "Overall, the EvSec22 gene is associated with the virulence of E. vermicola CBS115803 against B. xylophilus, and its deletion also affects the normal growth of E. vermicola and its tolerance to abiotic stress. This study providing new insights into SNARE protein functions in fungal biocontrol agents."

Journal • Infectious Disease

First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours. (PubMed, BMJ Oncol) - P1 | "Overall, the limited antitumour activity of arginase inhibition observed suggests that the role of arginine depletion in cancer is multifaceted. NCT02903914."

IO biomarker • Journal • P1 data • Colorectal Cancer • Fatigue • Head and Neck Cancer • Oncology • Renal Disease • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

KEYNOTE 741: Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=260 | Completed | Sponsor: Incyte Corporation | Phase classification: P1/2 ➔ P1

Combination therapy • Metastases • Phase classification • Bladder Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Melanoma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

PD-1 inhibition with retifanlimab and/or arginase inhibition with INCB001158 in Japanese patients with solid tumors: A phase I study. (PubMed, Cancer Med) - "Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients."

Journal • P1 data • Endocrine Disorders • Oncology • Solid Tumor

Establishing Gene Expression and Knockout Methods in Esteya vermicola CBS115803. (PubMed, Mol Biotechnol) - "Moreover, we successfully implemented a split-marker strategy to delete the EvIPMD gene in E. vermicola CBS115803. In summary, our findings present valuable experimental methodologies for gene function analysis in E. vermicola CBS115803."

Journal • Gene Therapies

The Essential Role of Arginine Biosynthetic Genes in Lunate Conidia Formation, Conidiation, Mycelial Growth, and Virulence of Nematophagous Fungus, Esteya vermicola CBS115803. (PubMed, Pest Manag Sci) - "This investigation confirms the essential role of two arginine biosynthesis genes in lunate conidia formation in E. vermicola CBS115803. The findings also suggest that the supplementation of arginine to the culture medium can enhance the lunate conidia yield. These insights contribute significantly to the application of E. vermicola CBS115803 in managing B. xylophilus infections."

Journal • Infectious Disease

Arginase-1 promotes lens epithelial-to-mesenchymal transition in different models of anterior subcapsular cataract. (PubMed, Cell Commun Signal) - "ARG1 can regulate EMT in EMT-associated cataracts. Based on the pathogenesis of ASC, these findings are expected to provide new therapeutic strategies for patients."

Journal • Cataract • Oncology • Ophthalmology • ARG1 • FN1 • TGFB1 • TGFB2 • TJP1 • VIM

ARGININE DEPRIVATION INDUCES ACQUISITION OF A SENESCENT PHENOTYPE AND FAVORS GENOMIC INSTABILITY IN MULTIPLE MYELOMA PLASMA CELLS (EHA 2023) - "Our previous work showed that in vivo the treatment with arginase inhibitor CB1158 could reduce MM growth while increasing serum arg concentrations without affecting the infiltrates of myeloid cells... Taken together, our findings suggest that arginine deprivation, while inducing immune dysfunction, conveys a complex adaptive response which causes a chromatin remodeling that leads to the acquisition of a senescencephenotype to select the most fit clone and favors genomic instability, providing new insights to improve immunotherapy and induce synthetic lethality in MM."

IO biomarker • Anemia • Hematological Disorders • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • BRCA2 • FANCI • IL18 • IL1B • NLRP3

Inhibition of murine myeloid suppressor cells increases CD8+ T cell activation in Vitro (AACR 2023) - "An ARG1 target is currently in clinical trials (INCB001158, CB-1158 from Calithera Biosciences) and was used as a target of interest in this study.MDSC generation from bone marrow cells (BM) was compared using GM-CSF and IL-6 or GM-CSF, IFNγ, and LPS...Similar trends were observed with CD69, PD-1, IFN-y, TNF-a and IL-2 expression in CD8+ T cells. Overall, the ability to monitor changes in T cell activation following MDSC has broad applications in in vitro screening of novel drug compounds that alter the TME as well as sets the experimental framework for ex vivo analysis of cells isolated from TME following treatment."

IO biomarker • Preclinical • Oncology • ARG1 • CD69 • CD8 • CSF2 • IFNG • IL2 • IL6 • PD-1 • TNFA

Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naïve diffuse large B-cell lymphoma. (PubMed, Exp Hematol Oncol) - "In treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy."

Biomarker • IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ARG1 • CD4 • CD8

INCB001158 Combined With Subcutaneous (SC) Daratumumab, Compared to Daratumumab SC, in Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=15 | Terminated | Sponsor: Incyte Corporation | Completed ➔ Terminated; This decision follows recruitment difficulties. No safety-related concerns impacted this decision.

Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Perioperative Arginine Immunonutrition Prevents Metastases by Accelerating Natural Killer Cell Recovery After Surgery (SSO 2020) - P=N/A | "In mice, pre-op depletion of myeloid cells (Gr1) or inhibition of Arginase-1 (with CB1158) prevented the drop in arginine, suggesting that MDSCs are regulators of post-op arginine... Peri-op arginine improves NK cells ability to recover after surgery-induced dysfunction in mice. We recently completed PERIOP-02 (NCT02987296) which investigates the importance of peri-op arginine on NK cells in colorectal cancer surgery patients."

Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Oncology • Solid Tumor • NKG2D

Drug-Induced Thrombocytopenia (SOHO 2019) - P1/2; "Immune thrombocytopenia caused by INCB01158 had never been described.Patient Hereby we describe the case of a 63 year old patient diagnosed with a high grade serous ovarian cancer treated in 2016 by surgical debullking with a residual disease followed by six cycles of Carboplatin and Paclitaxel; one year and a half later, patient had numerous retroperitoneal, iliac and peri-hepatic lymph nodes treated by Carboplatin and Gemcitabine coupled with Bevacizumab for nine cycles followed by Bevacizumab maintenance, an evaluation four months later showed disease progression and patient was started on liposomal Doxorubicin with Trabectidin for 3 cycles with no response, thereafter patient was included in a phase 1/2 study evaluating the safety, tolerability, and efficacy of INCB001158 in Combination With Chemotherapy, in Subjects With Advanced or Metastatic Solid Tumors [1]. Thereafter, patient was started on steroids with a marked improvement of the platelets count and currently...

Arginase 1 is a key driver of immune suppression in pancreatic cancer. (PubMed, Elife) - "Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8 T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting Arginine and inhibiting T cell activation."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Immune Modulation • Inflammation • Oncology • Pancreatic Cancer • Solid Tumor • ARG2 • CD8

Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma. (PubMed, Sci Transl Med) - "CB1158 and tadalafil are promising drugs in reducing radiation-induced lymphopenia in patients with glioblastoma. These results demonstrate the promise of using these classes of drugs to reduce treatment-related lymphopenia and immunosuppression."

Journal • Lymphopenia • Myeloid-derived suppressor cells • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Phase 1/2 Study of INCB001158 in Combination With Chemotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1/2 | N=149 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Biliary Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor

Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours (ESMO 2019) - P1/2; "Early data indicate that 1158 MT and CT w/ PEM was well tolerated and showed responses as MT and CT in pretreated MSS CRC pts. Updated safety and efficacy data will be presented. Clinical trial identification: NCT02903914 Posted to clinicaltrials.gov: September 16, 2016."

Clinical • Combination therapy • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

CX-1158-101: A first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors. (ASCO 2017) - P1; "CB-1158 is a first-in-class inhibitor of the myeloid-derived immunosuppressive enzyme arginase. CB-1158 has been well tolerated and achieves on-target inhibition resulting in increases in plasma arginine, an amino acid required for T-cell immune responses."

Checkpoint inhibition • Combination therapy • Monotherapy • P1 data • Biosimilar

KEYNOTE 741: Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=260 | Completed | Sponsor: Incyte Corporation | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Bladder Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Immune Modulation • Inflammation • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma. (PubMed, Front Oncol) - "Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation...To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2γc recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications."

Journal • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation

A Phase 1/2 Study of INCB001158 in Combination With Chemotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1/2 | N=149 | Active, not recruiting | Sponsor: Incyte Corporation | Trial primary completion date: Jun 2022 ➔ Dec 2022

Combination therapy • Trial primary completion date • Biliary Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor

A Phase 1/2 Study of INCB001158 in Combination With Chemotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - P1/2 | N=149 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Jun 2022 ➔ Dec 2022

Combination therapy • Trial completion date • Biliary Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Ovarian Cancer • Solid Tumor

KEYNOTE 741: Arginase Inhibitor INCB001158 as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=260 | Active, not recruiting | Sponsor: Incyte Corporation | Trial completion date: Mar 2022 ➔ Jun 2022

Combination therapy • Trial completion date • Bladder Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Immune Modulation • Inflammation • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer