Novartis' First-in-Class WRN Inhibitor HRO761 Granted IND Approval in China for MSI-H/dMMR Solid Tumors

Jan 27, 2024 09:04 CST Updated 09:04

Novartis

Drug Development and Manufacturing

▎Edited by the WuXi AppTec content team

On January 26, the official website of the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) announced,Novartis'申报的1类新药HRO761获得临床试验默示许可，拟开发治疗晚期不可切除或转移性微卫星高度不稳定型（MSI-H）Or mismatch repair-deficient solid tumors. Public information shows that HRO761 is aPotential "First-in-Class" WRN Inhibitor。Werner Syndrome RecQ Helicase (WRN) is a newly discovered "synthetic lethality" target in recent years, forMSI-HTumorHas a "synthetic lethality" effect.

Screenshot source: CDE official website

MSI-H is caused by mutations in genes responsible for repairing DNA mismatches, leading to abnormal repetitive nucleotide sequences in the DNA. MSI-H can occur in various types of cancer, including colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, and more.WRN is a multifunctional enzyme with helicase and exonuclease activities, playing an important role in various cellular processes that maintain genome stability., including DNA replication, transcription, DNA repair, and telomere maintenance, etc.

According to the previousInPublished in 2019NatureA study reported that,Researchers discovered through CRISPR screening technology that,The gene encoding WRN is crucial for the survival of tumors with MSI-H characteristics.In MSI-H tumor models, inhibition of WRN helicase activity leads to the generation of DNA double-strand breaks, triggering apoptosis. For microsatellite-stable tumors, however, inhibition of WRN activity shows no significant effect.These studies show,Therapies targeting WRN may, like PARP inhibitors, become an innovative treatment for tumors with MSI-H characteristics based on the principle of "synthetic lethality."。

HRO761 is an oral drug targeting WRN that Novartis is currently developing.According to the researchers at2023 Annual Meeting of the American Association for Cancer Research (AACR)Published onPreclinical study results,Daily oral administration of HRO761 demonstrated efficacy in both CDX and PDX models, with a 70% disease control rate across all indications.。HRO761 also induces WRN degradation in a dose-dependent manner, activates the DNA damage response, and induces p53 target genes.Combination of HRO761 with irinotecan in vitro enhances sensitivity and achieves more durable responses in MSI-H colorectal cancer cell lines. The study demonstrates that HRO761 holds promise as a new treatment for MSI-H tumors, either as monotherapy or in combination with irinotecan.

According toClinicalTrialsOfficial WebsiteInformation,Novartis is conducting activities in the United States, South Korea, Japan, and other regions.HRO761OfPhase 1First-in-human clinical study to evaluate the safety, recommended dose, and preliminary anti-tumor activity of this product as monotherapy or in combination with tislelizumab or irinotecan for microsatellite instability-high or mismatch repair-deficient tumors.

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References:

[1] Website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China. Retrieved Jan 26, 2024, from https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2] Chan et al., (2019). WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature, https://doi.org/10.1038/s41586-019-1102-x

[3]Abstract B143: HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models. Retrieved Dec 1 , 2023, from https://aacrjournals.org/mct/article/22/12_Supplement/B143/730827/Abstract-B143-HRO761-a-first-in-class-clinical

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