Abstract: AMG 193 is a novel, orally bioavailable, MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor currently under investigation for the treatment of advanced solid tumors harboring methylthioadenosine phosphorylase (MTAP) deletions. MTAP deletion, which occurs in approximately 10% of all cancers, leads to the intracellular accumulation of methylthioadenosine (MTA). AMG 193 exploits this metabolic vulnerability by selectively binding to and stabilizing the PRMT5-MTA complex, thereby inducing synthetic lethality in MTAP-deleted cancer cells while sparing healthy MTAP wild-type cells. Preclinical models demonstrate robust, dose-dependent tumor growth inhibition across various MTAP-deleted xenografts without the severe hematologic toxicities characteristic of earlier, non-selective PRMT5 inhibitors. In a Phase I/Ib clinical trial (NCT05094336), AMG 193 exhibited a manageable safety profile and promising preliminary efficacy, achieving an objective response rate (ORR) of 21.4% and a disease control rate (DCR) of 54.8% at active dosage levels across multiple solid tumor types. Ongoing research is focused on evaluating AMG 193 in combination with chemotherapies, targeted therapies, and immunotherapies, as well as identifying predictive biomarkers to optimize patient selection.
1. Introduction
The continuous pursuit of novel anticancer agents that balance efficacy with tolerability has led to the identification of cancer-specific biomarkers and synthetic lethal vulnerabilities. One such prominent target is the methylthioadenosine phosphorylase (MTAP) gene, which is co-deleted with the tumor suppressor CDKN2A in approximately 10% of all human cancers[1]. Homozygous MTAP deletions (MTAP-del) are particularly prevalent in difficult-to-treat malignancies, including glioblastoma (~45%), mesothelioma (~36%), urothelial carcinoma (~26%), pancreatic cancer (~22%), and non-small cell lung cancer (NSCLC; ~15%)[1].
MTAP is the sole enzyme responsible for metabolizing methylthioadenosine (MTA) in mammalian cells. Its deficiency leads to a significant intracellular accumulation of MTA, which outcompetes S-adenosyl methionine (SAM) for binding to protein arginine methyltransferase 5 (PRMT5), partially inhibiting PRMT5 activity[1]. Early attempts to target PRMT5 utilized SAM- and substrate-competitive inhibitors that lacked tumor selectivity, resulting in narrow therapeutic windows limited by severe hematologic toxicities (e.g., anemia and thrombocytopenia)[1]. To overcome these limitations, MTA-cooperative PRMT5 inhibitors like AMG 193 were developed. AMG 193 selectively targets the PRMT5-MTA complex enriched in MTAP-del cells, offering a targeted synthetic lethality approach for advanced solid tumors while sparing healthy tissues[1].
2. Pharmacological Activity
Preclinical Activity: In preclinical studies, AMG 193 demonstrated robust, dose-dependent tumor growth inhibition across a variety of MTAP-del xenograft models, including colorectal cancer, diffuse large B-cell lymphoma, pancreatic cancer, lung cancer, melanoma, and esophageal cancer[1]. Importantly, this efficacy was achieved with prolonged drug exposure without marked toxicity, weight loss, or the significant hematologic toxicity typically observed with non-selective PRMT5 inhibitors, indicating a wide therapeutic window[1].
Clinical Efficacy: AMG 193 is currently being evaluated in a Phase I/Ib clinical trial (NCT05094336) involving patients with advanced CDKN2A-deleted and/or MTAP-del solid tumors who had received a median of two prior lines of therapy[1]. In the dose-exploration phase, 80 patients received oral AMG 193 at dosages ranging from 40 to 1,600 mg once daily or 600 mg twice daily. The maximum tolerated dose (MTD) was established at 1,200 mg once daily[1]. An efficacy analysis of 74 patients across all dose levels showed an ORR of 12.2% and a DCR of 47.3%. Notably, among 42 patients treated at active dosage levels (800 and 1,200 mg once daily, and 600 mg twice daily), the ORR improved to 21.4%, the DCR was 54.8%, and the median duration of response (DOR) was 8.3 months[1]. Objective responses were observed across eight different tumor types: NSCLC, pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma, melanoma, esophageal cancer, gallbladder cancer, renal cell carcinoma, and ovarian Sertoli-Leydig cell tumor[1].
Pharmacokinetics and Pharmacodynamics: Pharmacokinetic analyses revealed that plasma levels of AMG 193 increased proportionally with doses from 40 to 1,200 mg once daily. Pharmacodynamic modeling demonstrated a significant dose-response relationship, with near-complete elimination of symmetric dimethylarginine (SDMA)—a biomarker of PRMT5 activity—observed in posttreatment tumor samples at dosage levels of 480, 800, and 1,200 mg once daily[1].
3. Molecular Mechanism of Action
AMG 193 functions as an MTA-cooperative PRMT5 inhibitor. In normal cells, PRMT5 utilizes SAM to add symmetric dimethylarginine (SDMA) to histones and target proteins involved in RNA splicing, cell cycle progression, and DNA repair[1]. In MTAP-deleted cancer cells, the inability to metabolize MTA causes intracellular MTA levels to rise significantly. This accumulated MTA binds to PRMT5, creating a high proportion of PRMT5-MTA complexes and partially inhibiting normal PRMT5 activity[1].
AMG 193 selectively binds to this PRMT5-MTA complex, further inhibiting PRMT5 activity and inducing synthetic lethality specifically in MTAP-del cells. Treatment with AMG 193 (and its representative analogue AM-9747) selectively reduces SDMA levels by 86% to 93% in MTAP-del tumors, compared to only 26% to 76% in MTAP wild-type tumors[1]. Downstream, this profound PRMT5 inhibition disrupts RNA splicing (primarily by inducing intron retention), triggers DNA damage, and alters gene expression in cell cycle and apoptosis pathways, ultimately leading to tumor cell death[1].
4. Structure-Activity Relationship (SAR)
The discovery of AMG 193 and other MTA-cooperative PRMT5 inhibitors utilized high-throughput screening for small molecules that bind selectively to PRMT5 in the presence of MTA, followed by structure-based drug design to optimize potency and selectivity[1]. X-ray crystallography of the PRMT5-binding structure of AMG 193 reveals that the compound occupies the substrate binding site of the PRMT5-MTA complex. It forms a tight van der Waals interaction with the accumulated MTA molecule while simultaneously interfering with the interaction between PRMT5 and SAM[1]. This specific structural binding mode contributes to a long dissociation half-life and confers high binding selectivity for the PRMT5-MTA complex over the PRMT5-SAM complex, which is the basis for its tumor-selective synthetic lethality[1].
5. Current Limitations
Despite its improved safety profile relative to non-selective PRMT5 inhibitors, AMG 193 is associated with treatment-related adverse events (TRAEs). In the dose-exploration phase of NCT05094336, 85% of patients experienced TRAEs, most commonly nausea (48.8%), fatigue (31.3%), and vomiting (30%)[1]. Grade ≥3 TRAEs were reported in 13.8% of patients, including fatigue (5%) and decreased lymphocyte count (3.8%). Serious TRAEs occurred in 10% of patients, leading to treatment discontinuation in 2.5% of cases[1]. However, treatment-related anemia—a major dose-limiting toxicity of earlier PRMT5 inhibitors—was observed in ≤10% of patients[1].
Another clinical limitation is the relatively long time to response. The median time to response for AMG 193 was 3.6 months at 800 mg once daily and 1.8 months at 1,200 mg once daily, suggesting that deepening tumor regression may require prolonged therapy, reminiscent of the response trajectories seen with immunotherapies[1]. Furthermore, the precise downstream pathways ultimately required for tumor cell survival following PRMT5 inhibition, as well as potential mechanisms of acquired resistance, remain incompletely understood[1].
6. Future Perspectives
The promising monotherapy activity of AMG 193 has paved the way for numerous combinatorial strategies. AMG 193 is currently being investigated in combination with standard chemotherapies (e.g., carboplatin, gemcitabine, paclitaxel, pemetrexed, and fluorouracil/oxaliplatin/leucovorin/irinotecan) in trials such as NCT06333951 and NCT06360354[1]. The combination with pemetrexed is of particular interest, as pemetrexed targets de novo purine synthesis and depletes adenine, which may synergize with MTAP deficiency[1].
Targeted therapy combinations are also advancing. AMG 193 is being evaluated alongside the KRAS G12C mutant-selective inhibitor sotorasib in PDAC and NSCLC models, as KRAS mutations frequently co-occur with MTAP deletions and do not appear to confer resistance to MTA-cooperative PRMT5 inhibition[1]. Additionally, dual targeting of the metabolic pathway using AMG 193 in combination with MAT2A inhibitors (such as IDE397) has shown synergistic preclinical activity by inducing earlier and deeper PRMT5 inhibition, a concept previously explored in clinical trial NCT05975073[1].
Finally, the discovery of predictive biomarkers will be crucial for optimizing patient selection. Potential biomarkers under investigation include the expression ratio of PRMT5 co-factors CLNS1A and RIOK1, as well as the loss of CAAP1 and AKAP17A, which may sensitize tumors to PRMT5-mediated splicing disruptions[1]. Further research into alternative modalities of MTAP deficiency (e.g., epigenetic silencing) will also help expand the patient populations that might benefit from AMG 193[1].
