AMG 193

Overview

AMG 193 (also reported as AM‑9747) is an oral, methylthioadenosine (MTA)–cooperative PRMT5 inhibitor being developed for cancers harboring homozygous MTAP deletion, a lesion present in roughly 10–15% of solid tumors. A first‑in‑human phase 1 study has reported preliminary antitumor activity with a manageable safety profile and no clinically significant myelosuppression observed. (aacrjournals.org)

Mechanism of action

• Target: PRMT5 (protein arginine methyltransferase 5). MTAP loss leads to intratumoral accumulation of MTA, which partially inhibits PRMT5 and creates a selective vulnerability. AMG 193 exploits this by preferentially binding and inhibiting PRMT5 in the presence of MTA (the PRMT5–MTA complex), aiming to spare MTAP–wild‑type tissues. Preclinical work shows potent, lineage‑agnostic activity in MTAP‑deleted models, induction of DNA damage and G2/M arrest, and synergy with chemotherapies and KRAS G12C inhibition. (aacrjournals.org)

• Preclinical pharmacology: In MTAP‑deleted xenografts (e.g., BxPC‑3 pancreatic, U87MG glioma), AMG 193 produced robust tumor growth inhibition; discovery work also reports brain penetration. (pubs.acs.org)

Efficacy

• Phase 1 dose‑exploration (Annals of Oncology, published December 2024): Among efficacy‑assessable patients treated at active/tolerable doses (800 mg QD, 1200 mg QD, or 600 mg BID; n=42), the objective response rate (ORR) was 21.4% (95% CI 10.3–36.8). Confirmed responses occurred across eight tumor types, including squamous and non‑squamous NSCLC, pancreatic adenocarcinoma, and biliary tract cancer. Molecular responses (ctDNA clearance) were also observed in some patients. (pubmed.ncbi.nlm.nih.gov)

• Conference updates: Early dose‑escalation results from the ongoing first‑in‑human study were first presented at the AACR‑NCI‑EORTC Molecular Targets meeting (October 2023), reporting preliminary antitumor activity in biomarker‑selected solid tumors with MTAP loss. (aacr.org)

Note: As of October 2025, randomized data are not yet available; multiple phase 1b master protocols are exploring AMG 193 alone and in combinations (e.g., with platinum doublets, pembrolizumab, pemetrexed, or sotorasib) in MTAP‑deleted thoracic and gastrointestinal malignancies. (cdek.pharmacy.purdue.edu)

Safety

• Across 80 patients in dose exploration (40–1600 mg QD or 600 mg BID), the most common treatment‑related adverse events (TRAEs) were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose‑limiting toxicities at doses ≥240 mg included nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose (MTD) was 1200 mg QD. Notably, “no clinically significant myelosuppression” was reported. (pubmed.ncbi.nlm.nih.gov)

Dosing explored to date

• Oral dosing in continuous 28‑day cycles; exposures increased approximately dose‑proportionally from 40 mg to 1200 mg. Pharmacodynamic tumor biopsies showed complete intratumoral PRMT5 inhibition at doses ≥480 mg. (pubmed.ncbi.nlm.nih.gov)

Ongoing clinical development

• First‑in‑human phase 1/1b/2 trial of AMG 193 monotherapy and in combination with docetaxel (NCT05094336) remains active. Additional phase 1b “MTAPESTRY” master protocols are enrolling MTAP‑deleted thoracic tumors (NCT06333951) and MTAP‑deleted gastrointestinal/biliary/pancreatic cancers with various combinations. (fdaaa.trialstracker.net)

Further reading

• First‑in‑human phase 1 dose‑exploration results (Annals of Oncology, 2024): https://pubmed.ncbi.nlm.nih.gov/39293516/ (pubmed.ncbi.nlm.nih.gov)
• Mechanistic and translational study (Cancer Discovery, 2025): https://aacrjournals.org/cancerdiscovery/article/15/1/139/750846/AMG-193-a-Clinical-Stage-MTA-Cooperative-PRMT5 (aacrjournals.org)
• Medicinal chemistry/discovery report (J. Med. Chem., 2025): https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c03121 (pubs.acs.org)
• Trial design abstract (ASCO 2022): https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.TPS3167 (ascopubs.org)
• AACR‑NCI‑EORTC 2023 initial clinical results news/abstract: https://www.aacr.org/about-the-aacr/newsroom/news-releases/new-investigational-targeted-therapy-shows-early-promise-in-patients-with-solid-tumors/ and https://aacrjournals.org/mct/article/22/12_Supplement/PR006/730845/Abstract-PR006-Initial-results-from-first-in-human (aacr.org)

Clinical trial entries: - NCT05094336 (monotherapy ± docetaxel): overview and status. (fdaaa.trialstracker.net)
- NCT06333951 (thoracic tumors, combinations), NCT06360354/MTAPESTRY 103 (GI/biliary/pancreatic, combinations). (cdek.pharmacy.purdue.edu)

Notes: All figures above reflect publications and conference disclosures available through October 7, 2025.

Last updated: Oct 2025