Amgen Announces First-in-Human Phase 1 Clinical Results of AMG 193, a Novel MTA-Cooperative PRMT5 Inhibitor, in MTAP-Deficient Solid Tumors

▎WuXi

Edited by the Kant Content Team

Today, at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Symposium held by the American Association for Cancer Research (AACR), Phase 1 trial results of Amgen's investigational Protein Arginine Methyltransferase 5 (PRMT5) inhibitor AMG193 were presented for the treatment of multiple solid tumors in patients with Methylthioadenosine Phosphorylase (MTAP) deficiency. According to the American Association for Cancer Research website, the trial results showed that AMG 193 is safe and exhibits preliminary anti-tumor activity.

PRMT5 is a synthetic lethal target for MTAP mutations.MTAP gene deletion occurs in approximately 10% of cancers, including pancreatic cancer, lung cancer, and bladder cancer., These patients have abnormally elevated levels of methylthioadenosine (MTA), which inhibits the activity of PRMT5. PRMT5 is an enzyme involved in essential cellular functions, and the elevation of MTA makes tumor cells more sensitive to additional PRMT5 inhibition. However, since the first-generation PRMT5 inhibitors are not tumor-specific, they exhibit high toxicity.

AMG 193 is a second-generation PRMT5 inhibitor that cooperates with MTA., which can inhibit the function of PRMT5 in MTAP-deficient cells while preserving its function in healthy cells, thereby selectively killing tumor cells.

This trial is the first-in-human Phase 1 clinical trial of AMG 193, enrolling 47 patients with MTAP-deleted solid tumors, including 10 pancreatic ductal adenocarcinoma, 6 non-small cell lung cancer, 5 cholangiocarcinoma, 3 mesothelioma, and 23 other cancer types. Study participants were assigned to seven dose-escalation cohorts to determine the recommended Phase 2 dose.

The analysis shows,AMG193 is safe and does not cause bone marrow toxicity., which is a common issue with the first generation of PRMT5 inhibitors.

Image Source: 123RF

In addition,Among the 31 patients who received at least one scan after the start of treatment, five patients with different tumor types showed partial response (PR, 16%), 14 patients had stable disease (SD), and 12 patients experienced disease progression.Notably, the PR exhibited by the patient was durable and still ongoing at the time of data analysis, with the patient having received treatment for 140-275 days. Additionally, the tumors of nine patients with SD showed some degree of shrinkage, although these effects were not sufficient to be considered as PR.

PRMT5 is an emerging target for cancer treatment. Recently acquired by Bristol Myers Squibb.AcquisitionMirati Therapeutics also has an investigational MTA-cooperative PRMT5 inhibitor, MRTX1719. The Phase 2 clinical trial of MRTX1719 is expected to commence in the first half of 2024.