cintirorgon (LYC-55716) / Lycera, BMS - LARVOL DELTA

A Novel RORγ-Selective Agonist Facilitates the Infiltration of Effector T Cells and Innate Immune Cells into Tumor Tissue, Demonstrating Antitumor Efficacy. (PubMed, Biol Pharm Bull) - "Although a RORγ agonist (LYC-55716) has been under clinical evaluation, the precise effects of RORγ agonists on immune cells within tumor environments remain unclear...Moreover, the addition of Th17-derived cytokines to MC38 cells stimulated the release of CXCL10, a chemokine crucial for immune cell recruitment. These results offer valuable insights into the immunomodulatory and therapeutic potential of RORγ agonists in cancer immunotherapy, highlighting their role in enhancing immune cell infiltration and activity within tumors."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CD4 • CD8 • CXCL10 • GZMB • IFNG • IL17A

A Concise and Modular Approach to Generate Novel RORγ Agonists. (PubMed, J Med Chem) - "A variety of RORγ inhibitors have been identified, including clinical compounds such as VTP-43742 and JTE-151. In contrast, RORγ agonists have been less explored and LYC-55716 is, to the best of our knowledge, the sole example reached a human clinical investigation...This scaffold was subjected to final optimization by attaching function-oriented modules retaining druglike properties. After multiparameter optimization, novel selective RORγ agonists were discovered, and their in vivo effects were confirmed in a syngeneic mouse model after oral administration."

Journal

RORγt agonist LYC-55716 potentiates IFN-α's efficacy in hepatocellular carcinoma through enhancing cytotoxicity of Tc17 cells and infiltration of CD8+ T cells. (PubMed, Biochem Pharmacol) - "Moreover, our mechanistic studies revealed that the observed synergistic antitumor effect was mediated by enhanced CD8+ T cell tumor infiltration, which was facilitated by the C-X-C motif chemokine ligand 10 (Cxcl10)- C-X-C motif chemokine receptor 3 (Cxcr3) interaction. Collectively, these findings support a novel immunoregulatory strategy that leverages RORγt agonists to enhance the efficacy of IFN-α in HCC therapy."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8 • CXCL10 • CXCR3 • IFNA1 • IL17A

Type 3 immune response protects against Salmonella Typhimurium infection in the small intestine of neonatal rats. (PubMed, Emerg Microbes Infect) - "Furthermore, cintirorgon treatment during early life, the agonist of RORγt, significantly enhanced IL-17A-secreting type 3 immune response and alleviated the symptoms. Our data reveal targeting RORγt and IL-17A pathways may offer a promising therapeutic strategy for bacterial infections in neonatal populations."

Journal • Preclinical • Gastrointestinal Disorder • Infectious Disease • IL17A

THE BILE ACIDS METABOLITES PRODUCED BY THE INTESTINAL MICROBIOTA ACT AS GPBAR1 AGONIST AND RORΓT INVERSE AGONIST DETERMINING THE COURSE OF INFLAMMATORY BOWEL DISEASE (DDW 2024) - "Th17-inducing agents, cintirorgon or IL-23, exacerbated colitis emphasizing the role of Th17 in IBD pathogenesis, while 3-oxo-DCA exhibited a protective effect (Figure 2I, J). Conclusions. Our study clarifies some aspects of the intricate relationship between BAs derivatives, gut microbiota, and immune responses in IBD pathogenesis, highlighting the potential of 3-oxo-DCA as novel candidates for IBD management."

Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis • IL23A

Astragalus regulates the intestinal immune response during sepsis by mediating ILC3 proliferation through RORγt. (PubMed, Heliyon) - "RT-PCR revealed that astragalus and the retinoic acid-related orphan receptor γt (RORγt) agonist LYC-55716 both promote the expression of interleukin (IL)-17A, IL-17F, IL-22, interferon-γ, and granulocyte-macrophage colony-stimulating factor mRNA. Mechanistically, astragalus promotes the proliferation of ILC3 through RORγt, thereby reducing intestinal inflammatory damage. Astragalus, via RORγt, promotes the generation of ILC3, improves the inflammatory environment in rats with sepsis."

Journal • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Septic Shock • IFNG • IL22

RORγ agonist LYC-55716, a novel small molecule immunotherapy: Rationale for clinical evaluation in non-small cell lung cancer based on translational and bioinformatic evaluation. (ASCO-SITC 2018) - P1/2; "Bioinformatic analyses of RORγ expression/biology, correlation with improved survival, plus in vitro findings support inclusion of NSCLC in an ongoing Phase 2 clinical trial of LYC-55716."

Clinical • Non Small Cell Lung Cancer

LYC-55716, a first-in-class ROR agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies (AACR 2018) - P1/2; "In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule ROR agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer.Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine model Anti-PD1 alone Anti-CTLA4 alone ROR agonist alone ROR agonist + anti-PD1 ROR agonist + anti-CTLA4H22 (Liver) 30-50% >50%* 10-30% >50%* >50%*Pan02 (Pancreas) <10% 10-30% <10% 10-30%* 10-30%*CT26 (Colon) 10-30% <10% <10% <10% 30-50%B16F10 (Melanoma) 10-30% 10% 10-30% 10-30% 30-50%A230 (Lymphoma) <10% <10% 10-30% 30-50% 10%Renca (Renal) <10% 10-30% 30-50%* 30-50%* 30-50%*P<.05 vs ve

IO biomarker • PD(L)-1 Biomarker • Lymphoma • Melanoma • Non Small Cell Lung Cancer

ROR_ agonist LYC-55716 in combination with pembrolizumab to treat metastatic non–small cell lung cancer: an open-label, multicenter Phase 1b trial (ESMO 2018) - P1; "The LYC-55716 safety profile and clinical activity as a monotherapy agent support investigation of L+P to treat patients with metastatic NSCLC."

Clinical • Combination therapy • IO biomarker • P1 data • PD(L)-1 Biomarker • Non Small Cell Lung Cancer

ABCB1 restricts brain accumulation of the novel RORγ agonist cintirorgon, while OATP1A/1B and CYP3A limit its oral availability. (PubMed, Eur J Pharm Biopharm) - "Moreover, oral availability of cintirorgon was limited by CYP3A. These insights could help optimizing cintirorgon's clinical application."

IO biomarker • Journal • Oncology • Solid Tumor • ABCB1 • ABCG2 • CYP3A4

RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers. (PubMed, J Exp Clin Cancer Res) - "Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8 T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers."

IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • CCL20 • CCR6 • CD8 • CXCL10

Development and validation of an LC-MS/MS assay for the quantification of cintirorgon (LYC-55716) in mouse plasma and tissue homogenates. (PubMed, J Pharm Biomed Anal) - "Quantification could be accomplished within a linear validated concentration range of 5-4,000 ng/mL (10-4,000 ng/mL in brain homogenates) with an intra- and inter-day precision between 4.6-14.7% and 5.1-15.6% (including the LLOQ), respectively, and accuracies between 89.1%-111.2%. The method was successfully applied to a preclinical study with cintirorgon in mice."

Journal • Preclinical • Oncology

Safety and dose selection for LYC-55716, a first-in-class ROR agonist to treat solid tumors: Phase I results from an open-label, multicenter Phase I/IIa trial (AACR 2018) - P1/2; "Phase I data support the safety of LYC-55716 and selection of a BID dosing regimen for the ongoing Phase 2a phase of the trial in patients with non-small cell lung, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers."

Clinical • IO Biomarker • P1/2 data • Non Small Cell Lung Cancer • Ovarian Cancer

A phase 2A open-label, multicenter trial of the safety and efficacy of LYC-55716, a first-in-class oral, small-molecule ROR agonist to treat select solid tumors. (ASCO 2018) - P1/2; "Immune markers of interest will be evaluated using a NanoString platform and immunohistochemistry. Results will be analyzed using descriptive and summary statistics."

Clinical • IO biomarker • P2a data • PD(L)-1 Biomarker • Non Small Cell Lung Cancer • Ovarian Cancer

Novel Small-Molecule ROR_ Agonist Immuno-oncology Agent LYC-55716: Safety and Efficacy in a Phase 2A Open-Label, Multicenter Trial (ESMO 2018) - P1/2; "The ongoing Phase 2A trial of the first-in-class small-molecule RORγ agonist LYC-55716 will determine the ORR, duration of response, and effects of treatment on survival and immune biomarkers in patients with advanced NSCLC, SCCHN, GE, RCC, UC, and OC."

Clinical • IO biomarker • P2a data • Head and Neck Cancer • Non Small Cell Lung Cancer • Ovarian Cancer

Novel small-molecule RORγ agonist immuno-oncology agent LYC-55716: Tumor selection and evaluation of renal cell and bladder cancer for inclusion in phase 2a expansion. (ASCO-GU 2018) - P1/2; "Translational and bioinformatics studies of RORγ expression, biology, and tumor immune profiles support the inclusion of RCC and BC patients in an ongoing Phase 2a expansion trial of LYC-55716."

P2a data • Bladder Cancer • Renal Cell Carcinoma

A phase 1b trial of ROR agonist LYC-55716 in combination with pembrolizumab to evaluate safety, efficacy, and immune biomarker profiles in patients with metastatic non-small cell lung cancer. (ASCO 2018) - P1; "Secondary endpoints for the main cohort include profiling of immune biomarker changes, objective response rate and duration of response, and pharmacokinetics. Patients will be followed for progression-free and overall survival."

Biomarker • Clinical • Combination therapy • IO biomarker • P1 data • PD(L)-1 Biomarker • Non Small Cell Lung Cancer

Lyc-55716: A novel small-molecule RORγ agonist immuno-oncology agent: Rationale for tumor selection and clinical evaluation of gastric and esophageal carcinoma in phase 2a expansion. (ASCO-GI 2018) - P1/2; "Bioinformatics assessments of RORγ expression, biology, and tumor immune profiles support the inclusion of GC and EC patients in an ongoing Phase 2 clinical trial of LYC-55716."

Clinical • P2a data • Esophageal Cancer • Gastric Cancer

Novel immunooncology agent, small-molecule ror agonist lyc-55716Tumor selection process for phase IIa expansion and rationale for clinical evaluation in ovarian cancer following phase I dose finding (SGO 2018) - P1/2; "Preclinical activity in syngeneic tumor models, bioinformatics analyses of RORγ expression and biology, and their correlation with improved survival support the inclusion of OC in a phase 2a clinical trial of LYC-55716."

Clinical • IO biomarker • P2a data • Ovarian Cancer

Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer. (PubMed, J Med Chem) - "To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors."

Journal • Oncology • Solid Tumor • IL17A

RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-β signaling in cancer. (PubMed, Pharmacol Res) - "In tumors, JG-1 not only promotes Th17 cells differentiation and increases C-C Motif Chemokine Receptor 6 (CCR6)- Chemokine (C-C motif) ligand 20 (CCL20) expression, but also inhibits both the expression of transforming growth factor-β1 (TGF-β1) and the differentiation and infiltration of Treg cells. In summary, JG-1 is a lead compound showing a potent activity in vitro and robust tumor growth inhibition in vivo with synergetic effects with anti-CTLA-4."

IO biomarker • Journal • Oncology • CCL20 • TGFB1

Discovery of novel N-sulfonamide-tetrahydroisoquinolines as potent retinoic acid receptor-related orphan receptor γt agonists. (PubMed, Eur J Med Chem) - "In particular, LYC-55716 (cintirorgon), a small molecule RORγt agonist developed by Lycera, has entered the phase II clinical study...When the inverse agonist s27 bound with RORγt, the steric hindrance between s27 and H479 caused the destruction of the HYF triplet, leading to the collapse of H12, thus the transcription function of RORγt was interrupted due to the failure of recruiting a coactivator molecule. The triplet HYF in RORγt and the rigidity of 28 and s27 were identified to be the structural determinants for the functional switch of RORγt."

Journal • Oncology • STING

Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. (PubMed, Clin Cancer Res) - "These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a Phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers."

Biomarker • Clinical • Journal • P1 data • Breast Cancer • Fatigue • Gynecologic Cancers • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Disease • Sarcoma • Thoracic Cancer

Study of LYC-55716 With Pembrolizumab in Adult Subjects With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1; N=18; Recruiting; Sponsor: Lycera Corp.; Initiation date: Jan 2018 ➔ Mar 2018

Trial initiation date • Biosimilar • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study of LYC-55716 With Pembrolizumab in Adult Subjects With Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1; N=18; Recruiting; Sponsor: Lycera Corp.

New P1 trial • Biosimilar • Non Small Cell Lung Cancer