mefuparib (CVL218) / Convalife - LARVOL DELTA

Understanding the Ocular Accumulation of Mefuparib and its N-dealkylation metabolite: Pharmacokinetics, Melanin Affinity, and Cellular Disposition. (PubMed, Exp Eye Res) - "Its melanin binding parameter Bmax (451±3.15 nmol/mg) was significantly higher than that of M8 (120±6.43 nmol/mg). In conclusion, the high uptake, low release and strong melanin binding capacity of mefuparib jointly lead to its intraocular accumulation, providing data support for the subsequent optimization of compound structure to reduce ocular accumulation or offering new directions for the development of new ocular treatments."

Journal • PK/PD data • Oncology • 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

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) (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