AstraZeneca's Novel PRMT5 Inhibitor AZD3470 Granted Clinical Approval in China for MTAP-Deficient Solid Tumors

Jan 25, 2024 17:35 CST Updated 17:35

AstraZeneca

Biopharmaceutical Manufacturer

▎Edited by the WuXi AppTec content team

Today (January 25), the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China announced that AstraZeneca's Class 1 new drug, AZD3470 film-coated tablets, has been approved for clinical trials, intended for development to treatMTAPDeficient Advanced/Metastatic Solid Tumors. Public data shows that this is a specific targetedMethylthioadenosine（MTA) andProtein Arginine Methyltransferase 5（PRMT5) Complex of the New GenerationPRMT5 InhibitorPRMT5 inhibitors are an emerging class of anti-cancer drugs and one of the next promising "synthetic lethality" therapies following PARP inhibitors.

Screenshot source: CDE official website

"Synthetic Lethality"It refers to the phenomenon where the simultaneous inhibition of two non-lethal genes leads to cell death. By leveraging this mechanism to identify specific mutations in tumors and then finding their "synthetic lethal partner," there is hope to specifically kill cancer cells. Public data shows that PARP inhibitors are the first drugs to successfully utilize the concept of "synthetic lethality" in clinical applications.

PRMT5 is a protease that adds methylated modifications to the arginine of histones and other proteins. Studies have shown that PRMT5 is overexpressed in a variety of cancers, including bladder cancer, triple-negative breast cancer, as well as lymphoma and myeloid blood cancers.PRMT5 has also been found to form "synthetic lethal" partnerships with mutations in multiple genes, including methylthioadenosine phosphorylase (MTAP) and the metabolic enzyme methionine adenosyltransferase 2α (MAT2A).。

Public information shows that the first generation of PRMT5 inhibitors designed based on SAM and/or substrates have high toxicity and a narrow safety window. Therefore, the industry is developing a new generation of PRMT5 inhibitors, aiming to selectively inhibit MTAP-deficient cells without affecting normal cells, thereby improving the safety of the drug.

AZD3470 is a new generation PRMT5 inhibitor developed by AstraZeneca.。According toClinicalTrials Official WebsiteInformation: AstraZeneca is conducting two Phase 1/2 clinical trials to evaluate AZD3470 as a monotherapy and in combination with other anticancer drugs for hematologic malignancies andMTAPSafety, Tolerability, and Preliminary Efficacy in Subjects with Advanced/Metastatic Solid Tumors.

Notably, AstraZeneca has also developed another PRMT5/MTA complex inhibitor.AZ-PRMT5i-1, The drug is currently in the preclinical research stage.

References:

[1] Official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China. Retrieved Jan 25, 2024, fromhttps://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2] A Study of AZD3470, a PRMT5 Inhibitor, in Patients With MTAP Deficient Advanced/Metastatic Solid Tumours (PRIMROSE). Retrieved Jan 25 , 2024, from https://classic.clinicaltrials.gov/ct2/show/NCT06130553?term=AZD3470&draw=2&rank=1

[3] AZD3470 as Monotherapy and in Combination With Anticancer Agents in Participants With Relapsed/Refractory Haematologic Malignancies. (PRIMAVERA). Retrieved Jan 25 , 2024, from https://classic.clinicaltrials.gov/ct2/show/NCT06137144?term=AZD3470&draw=2&rank=2

[4] Abstract 6272: AZ-PRMT5i-1: A potent MTAP-selective PRMT5 inhibitor with pharmacodynamic and monotherapy anti-tumor activity in MTAP-deleted tumours. Retrieved Apr 4 , 2023, from https://aacrjournals.org/cancerres/article/83/7_Supplement/6272/721055/Abstract-6272-AZ-PRMT5i-1-A-potent-MTAP-selective

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