tizaterkib (ATG-017) / AstraZeneca, Antengene - LARVOL DELTA

Discovering potential ERK1 inhibitors from natural products for therapeutic targeting of Alzheimer's disease. (PubMed, J Alzheimers Dis) - "The study suggested that Silandrin and Hydroxytuberosone can further be exploited as potential lead molecules for therapeutic development against ERK1-mediated AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation

ERASER: Safety and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1 | N=36 | Terminated | Sponsor: Antengene Therapeutics Limited | N=211 ➔ 36 | Recruiting ➔ Terminated; The study was terminated based on the internal need to re-prioritization the whole pipeline and phase 1 portfolio.

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial termination • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response. (PubMed, Int J Mol Sci) - "Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Oncology • Otorhinolaryngology • CD68 • PTPRC

Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors. (ASCO 2024) - P1 | "In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated."

Clinical • Metastases • P1 data • Dermatitis • Dermatology • Gastrointestinal Disorder • Immunology • Oncology • Ovarian Cancer • Retinal Disorders • Solid Tumor • KRAS

Antengene To Present One Oral and Four Abstracts at ASCO 2024 (PRNewswire) - P1 | N=211 | ERASER (NCT04305249) | Sponsor: Antengene Therapeutics Limited | "ATG-017, an oral and selective ERK1/2 inhibitor, was evaluated in a Phase I study to assess safety, pharmacokinetics, and MTD in patients with refractory advanced solid tumors; At the 20 mg BID level, no DLTs were observed, and pharmacokinetic analysis revealed effective ERK inhibition at this dose. Common treatment-emergent adverse events (TEAEs) were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events); Efficacy data showed that one patient (4.8%) achieved a PR, while 8 patients (38%) achieved stable disease (SD)."

P1 data • Oncology • Solid Tumor

ERASER: Safety and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1 | N=211 | Recruiting | Sponsor: Antengene Therapeutics Limited | Trial completion date: Dec 2024 ➔ Jun 2024 | Trial primary completion date: Jul 2024 ➔ Feb 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

ERASER: Safety and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1 | N=211 | Recruiting | Sponsor: Antengene Therapeutics Limited | Trial completion date: Aug 2023 ➔ Dec 2024 | Trial primary completion date: May 2023 ➔ Jul 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

Caffeic acid phenethyl ester mediates apoptosis in serum-starved HT29 colon cancer cells through modulation of heat shock proteins and MAPK pathways. (PubMed, Cell Biochem Funct) - "Molecular docking data demonstrates that CAPE shows a higher docking score of -5.35 versus -4.59 to known p38 inhibitor SB203580 as well as a docking score of -4.17 versus -3.86 to known ERK1/2 inhibitor AZD0364...These results suggest that stress induction via serum starvation in HT29 CRC cells leads to the induction of apoptosis and co-ordinated activation of MAPK-HSP pathways. Molecular docking studies support that CAPE could serve as an effective inhibitor to target p38 and MAPK compared to their currently known inhibitors."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • MAPK14

Self-assembled coating with a metal-polyphenolic network for intraocular lens modification to prevent posterior capsule opacification. (PubMed, Biomed Mater) - "Importantly, after in vivo implantation for 28 days with 8 rabbits PCO models in two groups, the TA(AZD0364/PTE) IOL group maintained clear refracting media and decreased the inflammatory reaction compared with the original IOL group(P＜0.05). This study provides a new applicable and economical strategy for preventing PCO and offers a reference for the next generation of IOLs that benefit cataract patients."

Journal • Cataract • Inflammation • Ocular Inflammation • Ophthalmology

Antengene Announces First Patient Dosed in the Nivolumab Combination Portion of the Clinical Study Evaluating the ERK1/2 Inhibitor ATG-017 in Patients with Advanced Solid Tumors in the United States (PRNewswire) - "Antengene Corporation Limited...announced that the first patient has been dosed in the United States in the combination portion of the Phase I ERASER trial to evaluate ATG-017 plus nivolumab. The objective of the combination segment of the study is to evaluate the safety/tolerability, pharmacokinetics, and preliminary efficacy of ATG-017 combination therapy with nivolumab in patients with advanced solid tumors....The monotherapy portion of the ERASER study is currently ongoing in Australia while the combination portion will be carried out in parallel in both the U.S. and Australia."

Trial status • Oncology • Solid Tumor

Synergistic effects of the combination of ERK1/2 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition for cancer treatment (AACR 2023) - "This study tested the in vivo antitumor effects induced by the combination of ATG-017, with EGFR inhibitor (Osimertinib), KRASG12C inhibitor (ATG-012), CDK4/6 inhibitor (Abemaciclib) or PD-L1 inhibitor (Atezolizumab), in preclinical tumor models. The in vivo combinations of the drugs were tested in NCI-H1975, NCI-H358 (non-small cell lung cancer) or EL4 (T cell Lymphoma) CDX mouse models. Strong synergism has been observed for the combination of ATG-017 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition, suggesting promising therapeutic strategies for cancer patients that warrants further investigation."

Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • CD4 • CD8 • EGFR • KRAS • MAP2K1

Antengene Announces Five Presentations at the 2023 American Association for Cancer Research Meeting (PRNewswire) - "This preclinical study was designed to test the in vivo anti-tumor effects induced by the combination of ATG-017, with EGFR inhibitor (osimertinib), KRASG12C inhibitor (ATG-012), CDK4/6 inhibitor (abemaciclib) or PD-L1 inhibitor (atezolizumab)...According to the results, ATG-017 demonstrated significant TGI (>60%) in the NSCLC models....These data suggest that the combination of ATG-017 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibitors have strong synergism and significantly improved TGI, thus represent promising therapeutic strategies for cancer patients."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Antengene Announces Five Upcoming Presentations at the 2023 American Association for Cancer Research Annual Meeting (PRNewswire) - "Five posters will showcase progress with multiple preclinical and clinical programs, including the clinical results of ATG-008 (mTORC1/2 inhibitor) and preclinical data of ATG-031 (anti-CD24 monoclonal antibody), ATG-037 (small molecule CD73 inhibitor), ATG-017 (ERK1/2 inhibitor), and ATG-034 (LILRB4 antagonist antibody)...Antengene Corporation Limited...announced the publication of abstracts for five posters that will be presented during the upcoming 2023 American Association for Cancer Research Annual Meeting (AACR 2023), taking place from April 14th to 19th at the Orange County Convention Center in Orlando, Florida, the United States."

P2 data • Preclinical • Gastrointestinal Cancer • Hematological Malignancies • Hepatocellular Cancer • Liver Cancer • Multiple Myeloma • Oncology • Solid Tumor

ERASER: Safety and Preliminary Efficacy of ATG-017 Monotherapy or Combination Therapy With Nivolumab in Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1 | N=211 | Recruiting | Sponsor: Antengene Therapeutics Limited | N=60 ➔ 211

Combination therapy • Enrollment change • Metastases • Monotherapy • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

Antengene Receives U.S. FDA Clearance of IND Application for Phase I Trial of Small Molecule ERK1/2 Inhibitor ATG-017 in Patients with Advanced Solid Tumors (PRNewswire) - "To date, the ATG-017 monotherapy dose escalation has been ongoning in Australia, which will continue to participate in the combination therapy portion of the trial. In addition to Australia and the U.S., Antengene also plans to conduct this Multi-Regional Clinical Trial(MRCT) in China....Antengene Corporation Limited...announced that the Investigational New Drug (IND) application for ATG-017 has received clearance from the U.S. Food and Drug Administration (FDA). The IND clearance enables Antengene to initiate the combination portion of the Phase I 'ERASER' clinical trial in the United States (U.S.) to evaluate the safety, pharmacokinetics, and preliminary efficacy of ATG-017 combination therapy with nivolumab in patients with advanced solid tumors....'We look forward to initiating patient enrollment of the ERASER trial in the U.S'."

IND • Trial status • Hematological Malignancies • Oncology • Solid Tumor

Antengene Receives U.S. FDA Clearance of IND Application for Phase I Trial of Small Molecule ERK1/2 Inhibitor ATG-017 in Patients with Advanced Solid Tumors (PRNewswire) - "The clinical collaboration between Antengene and Bristol Myers Squibb to evaluate ATG-017 in combination with nivolumab builds on Antengene's preclinical data. The data, including studies presented at the Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting & Pre-conference Programs in November 2021, has demonstrated that the combination of an ERK1/2 inhibitor and an immune checkpoint inhibitor (ICI) worked synergistically to produce improved efficacy in preclinical ICI-resistant in vivo mice models."

Licensing / partnership • Preclinical • Oncology

Antengene Announces Interim 2022 Financial Results and Provides Corporate Update (PRNewswire) - "...Before the end of the year, we intend to report critical clinical data on two mid-stage programs - ATG-016 (eltanexor), a next generation XPO1 inhibitor and ATG-008 (onatasertib), an mTORC1/2 inhibitor, and one Phase I dose escalation program for our ERK1/2 inhibitor'..."

Clinical data • P1 data • Oncology

Synergistic effects of the combination of Kras (G12C) with SHP2, ERK 1/2, mTORC1/2 or XPO1 inhibition for the treatment of Kras (G12C) mutated cancer (AACR 2022) - "This study tested the antitumor effects induced by the combination of ATG-012, a KRAS G12C inhibitor, with SHP2 inhibitor (ET0038), ERK 1/2 kinase inhibitor (ATG-017), mTORC1/2 kinase inhibitor (ATG-008) or XPO1 inhibitor (selinexor), in preclinical tumor models. The in vivo combinations of the drugs were tested in NCI-H358 (non-small cell lung cancer) and Mia-Paca-2 (pancreatic cancer) CDX mouse model. Strong in vivo synergism has been observed for the combination of a Kras (G12C) inhibitor (ATG-012) with a SHP2 inhibitor, ERK 1/2 inhibitor, mTORC1/2 inhibitor or XPO1 inhibitor, suggesting promising clinical therapeutic strategies for cancer patients carrying the KRAS G12C mutation."

IO biomarker • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Antengene Announces Publication of Five Posters at the 2022 American Association for Cancer Research (AACR) Annual Meeting (PRNewswire) - "Antengene Corporation Limited...announced the publication of five posters that will be presented during the upcoming 2022 American Association for Cancer Research Annual Meeting (AACR 2022)....While ATG-012 monotherapy induced dose-dependent tumor growth inhibition at day 27,...the authors also found strong in vivo synergism in 2-agent combinations. In particular, ATG-012 and clinical stage ERK inhibitor (ATG-017) demonstrate strong in vitro and in vivo synergism, suggesting potential clinical application which may overcome the rapid resistance of KRAS inhibitors."

Preclinical • Oncology

Antengene Announces Clinical Collaboration with Bristol Myers Squibb to Evaluate ATG-017 in Combination with Opdivo (nivolumab) in Advanced Solid Tumors (PRNewswire) - "Antengene Corporation Limited...announced today a clinical trial collaboration to evaluate the safety, pharmacokinetics and preliminary efficacy of ATG-017 in combination with Bristol Myers Squibb's PD-1 checkpoint inhibitor, Opdivo (nivolumab). The open-label Phase 1/2 trial will evaluate the investigational combination as a potential treatment option for patients with advanced solid tumors....'We are excited to enter this clinical collaboration with Bristol Myers Squibb and look forward to initiating enrollment in this exciting combination regimen in the first half of 2022'."

Enrollment status • Licensing / partnership • New P1/2 trial • Oncology • Solid Tumor

Synergistic effect of the combination of ATG-017, an ERK1/2 inhibitor, and immune checkpoint inhibitor in preclinical cancer models (SITC 2021) - "Anti-PDL1 antibody (atezolizumab), the combination of ATG-012 or ATG-017 and atezolizumab, and the triple combination of atezolizumab, ATG-012 and ATG-017 were tested in a PD(L)1 blockade insensitive syngeneic lung cancer model,LL/2. More data from LL/2 and A20 model are being generated. Conclusions Synergism has been observed for the combination of checkpoint inhibition and ERK1/2 inhibition in vivo, suggesting promising therapeutic strategies for cancer patients that warrants further clinical investigation."

Checkpoint inhibition • IO biomarker • Preclinical • Hematological Malignancies • Lung Cancer • Lymphoma • Oncology • Solid Tumor • BRAF • CD8 • KRAS • PTPRC

Antengene Presents Compelling Preclinical Data on Two Programs at the Society for Immunotherapy of Cancer (SITC) Annual Meeting on November 12, 2021 (PRNewswire) - "Antengene presented data on an in vivo study that evaluated ATG-017 in combination with an anti-PD-L1 monoclonal antibody (atezolizumab), in an aggressive, immune checkpoint inhibitor resistant mouse cancer model. Data in the poster showed that the combination enhanced the antitumor efficacy as well as increasing the percentage of infiltrating CD8+ T cells, NK cells, CD8:CD4 ratio and M1:M2 macrophage ratio in the tumor microenvironment, rendering a 'cold' tumor 'hot'."

Preclinical • Oncology

ERASER: Safety and Preliminary Efficacy of ATG-017 Monotherapy in Advanced Solid Tumors and Hematological Malignancies (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: Antengene Therapeutics Limited; Trial completion date: Feb 2022 ➔ Aug 2023; Trial primary completion date: Jul 2021 ➔ May 2023

Clinical • Monotherapy • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

"#Antengene to Present Data of Its #PDL1 #41BB #BispecificAntibody #ATG101 and #ERK1 #ERK2 #Inhibitor #ATG017 at #SITC21 https://t.co/ihtsmDsdpp" (@1stOncology)

Oncology • MAPK1

Lipopolysaccharide-induced inflammation in human peritoneal mesothelial cells is controlled by ERK1/2-CDK5-PPARγ axis. (PubMed, Ann Transl Med) - "Knockdown of CDK5 using its siRNA caused similar changes as AZD0364, minus ERK1/2 inactivation. Our results suggested that LPS-induced inflammation in human peritoneal mesothelial cells can be partly suppressed by inhibiting the ERK1/2/CDK5/PPARγ axis."

Journal • Immunology • Inflammation • IL12A • IL1B • IL6 • PPARG