epertinib (RT1978) / Shionogi, EOC Pharma, Raya Therap - LARVOL DELTA

Development of High-Throughput Quantitative Imaging Mass Spectrometry for Analysis of Drug Distribution in Tissues. (PubMed, J Mass Spectrom) - "A high-throughput quantitative MALDI-IMS methodology was developed to confirm whether epertinib is superior to lapatinib in penetrating brain metastases using intraventricular injection mouse models (IVMs) of human EGFR2 (HER2)-positive breast or T790M-EGFR-positive lung cancer cells. The quantitative MALDI-IMS results revealed that the epertinib concentrations administered to the brain sections in the lung cancer IVM were similar to those measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Quantitative MALDI-IMS, owing to its high reproducibility and throughput, is useful for selecting drug candidates in the early stages of discovery and development, enabling efficient and rapid screening of candidate compounds as well as an understanding of the mechanisms of drug efficacy, toxicity, and pharmacokinetics/pharmacodynamics."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • EGFR • HER-2

Raya Therapeutic Announces FDA and EMA Orphan Drug Designations for ALS with RT1978 (epertinib) (Firstwordpharma Press Release) - "Raya Therapeutic Inc...announces that it has received orphan drug designations (ODD) from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ALS with RT1978 (epertinib)...This molecule has completed Phase 2 clinical development in another indication and has demonstrated significant promise in multiple preclinical models in ALS, a progressive neurodegenerative disease with no known cure."

Orphan drug • Amyotrophic Lateral Sclerosis

Epertinib counteracts multidrug resistance in cancer cells by antagonizing the drug efflux function of ABCB1 and ABCG2. (PubMed, Biomed Pharmacother) - "In summary, our study demonstrates an additional pharmacological capability of epertinib against the activity of ABCB1 and ABCG2. These findings suggest that incorporating epertinib into combination therapy could be advantageous for a specific patient subset with tumors exhibiting high levels of ABCB1 or ABCG2, warranting further exploration."

Journal • Oncology • Solid Tumor • ABCB1 • ABCG2 • EGFR • HER-2

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies. (PubMed, J Mol Model) - "Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands."

Journal

A phase I/II study of epertinib plus trastuzumab with or without chemotherapy in patients with HER2-positive metastatic breast cancer. (PubMed, Breast Cancer Res) - "We observed safety, tolerability and encouraging antitumour activity of epertinib combined with trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in patients with pre-treated HER2-positive MBC, with or without brain metastases."

Clinical • Journal • P1/2 data • Brain Cancer • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor

A phase 1 study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours (ESMO-ECCO-ESTRO 2013) - Presentation time: 30 September 2013, 09:00; Abstract# 800; P1, N=33; “-222611 was generally well tolerated with two dose-limiting toxicities (rash at 1200mg; diarrhoea at 1600mg). A maximum tolerated dose was not defined. To date 17 patients (6 male; aged 32–75y) have been included in the expansion phase. Diarrhoea was the most frequent toxicity in the 50 pts, but was rarely worse than grade 1/2.”

P1 data • Oncology

Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases (SABCS 2015) - P1, N=76; "Dose reduction was required because of adverse events in 15 patients; the most frequent of which being diarrhea and elevated bilirubin. Two patients discontinued treatment due to drug- related adverse events. Of the 25 patients with HER2-positive metastatic breast cancer (MBC), 4 partial responses were observed, and prolonged stable disease (≥ 6 months) was observed in 3 additional patients."

P1 data • Breast Cancer • Oncology

Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including patients with brain metastases (ASCO 2015) - Presentation time: Saturday, May 30; 8:00 AM - 11:30 AM; Abstract #2511; P1, N=76; 2009-017817-31; "Of the 41 patients with HER2-positive cancers (26 breast, 13 esophago-gastric, 2 head & neck), 1 complete response (gastric-esophageal junction cancer) and 5 partial responses (4 breast cancer, 1 gastric cancer) were observed; all these patients had received prior HER2-directed therapy. Prolonged stable disease ( ≥ 6 months) was observed in 3 additional patients with breast cancer."

P1 data • Oncology

EOC takes on Shionogi’s HER2/EGFR TKI in Greater China (GBI Health) - "Shanghai-based EOC Pharma scored an in-license deal with Japan’s Shionogi & Co., Ltd, focused on the small-molecule tyrosine kinase inhibitor (TKI) epertinib. EOC has committed to make undisclosed upfront and milestone payments as well as royalties on future sales to Shionogi, in return gaining exclusive development, manufacturing, and marketing rights to the drug in the markets of China including Hong Kong and Macau."

Licensing / partnership

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours. (PubMed, Eur J Cancer) - "Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases."

Clinical • Journal • P1 data