mefuparib (CVL218) / Convalife - LARVOL DELTA

Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance. (PubMed, Eur J Med Chem) - "In this study, we report the development of a novel PARP1/c-Met dual inhibitor derived from the benzofuran-7-carboxamide moiety of the PARP1 inhibitor Mefuparib. Compared with compound 16 obtained in the previous study, compound S12 was identified as a highly potent dual inhibitor with lower molecule weight and better solubility, demonstrating robust inhibitory activity against both PARP1 (IC50 = 21.8 nM) and c-Met (IC50 = 30.2 nM). Importantly, S12 exhibited remarkable anti-tumor efficacy in the HCT116OR xenograft models, suggesting that targeting both PARP1 and c-Met represents an effective therapeutic strategy to overcome PARP1 inhibitor resistance mediated by c-Met amplification."

Journal • Preclinical • Oncology • MET

Phase I Clinical Trial of CVL218, a Novel PARP1/2 Inhibitor, in Patients with Advanced Solid Tumors. (PubMed, MedComm (2020)) - "CVL218 was generally well tolerated and safe. It showed potential antitumor activity in patients treated with the recommended dose."

Journal • P1 data • Oncology • Renal Disease • Solid Tumor

A phase Ib/II study of PARPi Mefuparib Hydrochloride (CVL218) in combination with PD-1 inhibitor plus chemotherapy in metastatic or recurrent triple-negative breast cancer (TNBC) (AACR 2025) - P1/2 | "500mg BID CVL218 was administered orally in combination with toripalimab 240 mg on Day 1 of every 21-day cycle and paclitaxel nanoparticle albumin-bound 125 mg/m2 on Day 1 of every 21-day cycle. CVL218 combined with PD-1 antibody and chemotherapy appears to be well tolerated and has good preliminary efficacy in TNBC patients."

Combination therapy • IO biomarker • Metastases • P1/2 data • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1

A phase Ib/II study of PARPi Mefuparib Hydrochloride (CVL218) in combination with PD-1 inhibitor plus chemotherapy in metastatic or recurrent triple-negative breast cancer (TNBC) (SABCS 2024) - "TORCHLIGHT trial is a randomized, double-blinded, phase 3 study assesses the efficacy and safety of toripalimab (programmed cell death-1 inhibitor) combined with nab-paclitaxel (nab-P) as a first-line treatment for patients diagnosed with metastatic or recurrent TNBC...Phase III OlympiAD study has established the efficacy of Poly ADP-ribose polymerase inhibitors (PARPi) olaparib in patients with germline BRCA gene mutation (gBRCAm) and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer... Mefuparib Hydrochloride(CVL218) combined with PD-1 and chemotherapy appears to be well tolerated and has preliminary efficacy in TNBC patients. In this phase II study, stratified analyses will be conducted for PD-L1 expression and HRD status. In patients with BRCA 1 and /or BRAC 2 mutation TNBC, this CVL218 combination therapy is expected to further break through the clinical treatment effect."

Combination therapy • IO biomarker • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • HER-2 • HRD • PD-L1 • PGR

Utility of quantitative whole-body autoradiography (QWBA) and oxidative combustion (OC) analysis in the assessment of tissue distribution of [14C]Mefuparib (CVL218) in SD and LE rats. (PubMed, PLoS One) - "Both the OC and QWBA methods revealed that [14C]CVL218 could be widely distributed in the tissues of rats. The OC had a lower limit of quantification while QWBA provided a more comprehensive analysis of [14C]CVL218 distribution. More safety was associated with using LE rat data to estimate the dosimetry of [14C]CVL218 for the whole-body, for human radiolabeled mass balance studies."

Journal • Preclinical

The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity. (PubMed, Structure) - "Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Orphan Designation: treatment of pancreatic cancer (FDA) - Date Designated: 08/23/2024

Orphan drug • Pancreatic Cancer

PARP Inhibitor CVL218 in Combination Therapy for Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=96 | Not yet recruiting | Sponsor: Fujian Cancer Hospital

Combination therapy • Metastases • New P1/2 trial • Breast Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • CHEK2 • PD-L1