S095033 / Servier - LARVOL DELTA

MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial (Nat Commun, Nature) - P1 | N=123 | NCT03435250 | Sponsor: Institut de Recherches Internationales Servier | "Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile."

P1 data • Cholangiocarcinoma • Mesothelioma • Non Small Cell Lung Cancer • Pancreatic Cancer

MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial (Nat Commun, Nature) - P1 | N=123 | NCT03435250 | Sponsor: Institut de Recherches Internationales Servier | "Forty patients were treated with AG-270/S095033. Plasma concentrations of AG-270/S095033 increased with dose. Maximal reductions in plasma SAM concentrations ranged from 54% to 70%. Analysis of paired tumor biopsies showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues. Reversible increases in liver function tests, thrombocytopenia, anemia and fatigue were common treatment-related toxicities. Two partial responses were observed; five additional patients achieved radiographically confirmed stable disease for ≥16 weeks. AG-270/S095033 has a manageable safety profile."

P1 data • Cholangiocarcinoma • Mesothelioma • Non Small Cell Lung Cancer • Pancreatic Cancer

Exploring the Clinical Translation of Synthetic Lethality, PRMT5 Inhibitors in MTAP-Deleted Cancers: A Scoping Review (ISPOR-EU 2024) - P1/2 | "Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models...Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours. There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination."

Clinical • Review • Synthetic lethality • Oncology • Solid Tumor • BRCA • MTAP

SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors. (PubMed, MedComm (2020)) - "Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors."

Combination therapy • Journal • Oncology • FANCA • MAT2A • MTAP

The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity. (PubMed, Biochem Biophys Res Commun) - "Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC...More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MAT2A • METTL3 • MTAP

Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors. (PubMed, ACS Med Chem Lett) - "The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270."

Journal • Oncology • MAT2A • MTAP

Single Cell Multi-Omic Analysis of Neoplastic Plasma Cells across the Disease Spectrum Identifies Novel Pathobiologic Mediators and Potential Therapeutic Targets in Multiple Myeloma (MM) (ASH 2023) - "Notably, MAD2L1 inhibition with M2I1, and MAT2A targeting with the allosteric inhibitor AG-270, both produced a dose- and time-dependent inhibition in cell proliferation and reduction in myeloma cell line viability... Our combined single-cell transcriptomics and VDJ sequencing allowed a greater understanding of heterogeneity among neoplastic PCs compared to each patient's own polyclonal PCs. These analyses can identify putative novel mediators of disease pathobiology that impact prognosis, and that can serve as potential new therapeutic targets using either novel agents, or drug repurposed from other therapeutic areas, setting the stage for their translation to the clinic."

IO biomarker • Omic analysis • Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • Plasmacytoma • CD27 • DKK1 • HGF • LDHA • MAD2L1 • MAT2A

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. (PubMed, J Biol Chem) - "Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP cancers, especially the remaining 98% of CRCs without the MTAP genotype."

Journal • Preclinical • Synthetic lethality • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MAT2A • MDM4 • MTAP

Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov) - P1 | N=123 | Terminated | Sponsor: Institut de Recherches Internationales Servier | Completed ➔ Terminated; Strategic reasons

Metastases • Trial termination • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • MTAP

Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov) - P1 | N=123 | Completed | Sponsor: Institut de Recherches Internationales Servier | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • MTAP

Discovery of novel, potent and orally available MAT2A inhibitors (AACR 2023) - "We describe here potent and orally bioavailable MAT2A inhibitors (“Euregen MAT2Ais”) with superior potency and selectivity compared to AG-270...Furthermore, Euregen MAT2Ais revealed excellent oral bioavailability and PK properties in pre-clinical species. We are optimizing multiple MAT2A inhibitors that exhibit activity across a wide range of cancers with MTAP-deletion."

Oncology • CDKN2A • MAT2A • MTAP

Combination therapeutic strategy with type I PRMT inhibition in cancer treatment (AACR 2023) - "We validated the synergistic effects and mechanisms of combined treatment with a type I PRMT inhibitor and a PRMT5 inhibitor (JNJ-64619178, GSK3326595/EPZ015938 or an in-house PRMT5i) using cell-based assays and in vivo studies...In vitro and in vivo studies revealed that inhibitors of type I PRMT and MAT2A (AG-270) dosing combination indeed exhibited stronger anti-cancer activity than mono-treatment...In vivo, the combination of type I PRMT inhibitor with different FLT3 inhibitors (Gilteritinib, Midostaurin, or CTS2016) led to deeper antitumor responses in a variety of FLT3-ITD AML models. Taken together, these findings support the co-administration of type I PRMT inhibitor with various therapies including epigenetic reprogramming, cancer metabolism modulation, or targeted therapies for receptor tyrosine kinases, which could benefit cancer patients as a promising therapeutic strategy."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • FLT3 • MAT2A • PRMT1 • PRMT5

Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability. (PubMed, J Med Chem) - "More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model."

Journal • Preclinical • Colon Cancer • Gastrointestinal Cancer • Oncology • MAT2A • MTAP

A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion (AACR-NCI-EORTC 2019) - P1; "Conclusion AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models."

Clinical • P1 data

A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion (AACR-NCI-EORTC 2019) - P1; "Conclusion AG-270 causes reductions in plasma [SAM] and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models."

Clinical • P1 data

Mitotic defects induced by MAT2A inhibitors guides translational drug combination strategies with AG-270 and taxanes (AACR-NCI-EORTC 2019) - P1; "Furthermore, we demonstrated substantially advantageous combination benefits between AG-270 and anti-mitotic taxanes in in vitro cell lines and in in vivo patient-derived xenograft models of non-small cell lung, pancreatic and esophageal cancers. These findings uncover relevant combination strategies targeting MTAP-deleted malignancies, and provide preclinical mechanistic proof-of-concept to explore such combinations in the clinical setting."

[VIRTUAL] The MAT2A inhibitor, AG-270, combines with both taxanes and gemcitabine to yield enhanced anti-tumor activity in patient-derived xenograft models (AACR-II 2020) - P1 | "Some of the best performing enhancers from this screen included paclitaxel (and docetaxel, using orthogonal screens) and gemcitabine. Taken together, these data suggest AG-270 complements the known mechanism of action of taxanes and gemcitabine, and leads to enhanced DNA damage and inhibition of cellular proliferation. This work has helped identify a therapeutic strategy of combining AG-270 with taxanes and gemcitabine, which is currently being explored in an ongoing phase 1 clinical trial (NCT03435250).Page 1 of 1"

Brain Cancer • Glioblastoma • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Thoracic Cancer

Targeting MAT2A in CDKN2A/MTAP-deleted cancers (AACR 2019) - P1; "AG-270 is the first MAT2A inhibitor to enter clinical development and is under investigation in a Phase I trial that is currently enrolling patients with MTAP-deleted solid tumors (NCT03435250). Our findings suggest clinically-applicable combination strategies which may further enhance the efficacy of AG-270 in malignancies with this genetic lesion."

MTAP inhibitor MTDIA expands anti-cancer efficacy of MAT2a inhibitors to MTAP+/+ cancers and inhibits PRMT5 (ACS-Sp 2023) - "We propose using MTAP inhibitor methylthio-DADMe-Immucillin A (MTDIA), transition state analogue developed by Schramm laboratory in combination with MAT2a inhibitor AG-270 will phenocopy the therapeutic effects seen with AG-270 in MTAP-/- cancers...The data suggest that MTDIA will expand the anti-cancer efficacy of MAT2a inhibitors through specific inhibition of PRMT5 and may extend therapeutic potential to the other 85% of MTAP+ cancers. Experiments on gene expression alterations, proteomic quantification of global and specific methylation changes, and safety and efficacy in animal models are underway."

Clinical • Metabolic Disorders • Oncology • CDKN2A • CDKN2B • MAT2A • MTAP • PRMT5

S095033 in Combination With Paclitaxel as 2nd- or 3rd-line Treatment in Participants With Advanced or Metastatic ESCC (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Institut de Recherches Internationales Servier | N=105 ➔ 0 | Initiation date: Aug 2022 ➔ May 2025 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Dec 2025 ➔ Jun 2026

Combination therapy • Enrollment change • Trial initiation date • Trial primary completion date • Trial withdrawal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • MTAP • PD-L1

"Select projects targeting synthetic lethality TNG908 MRTX1719 SKL27969 AMG 193 AG-270 IDE397 JNJ-64619178 PRT543 PRT811 RP-6306 GSK3326595 GSK3368715 PF-06939999 JBI-778 TNG462 ISM020 AGX323 AT101/ AT201 @JacobPlieth @evaluatepharma https://t.co/74gBPzNLcn https://t.co/5Um0uV9GAB" (@BRAINCURES)

Synthetic lethality

Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov) - P1 | N=123 | Active, not recruiting | Sponsor: Institut de Recherches Internationales Servier | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Lung Cancer • Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDKN2A • MTAP

Targeting the methionine-methionine adenosyl transferase 2A-S-adenosyl methionine axis for cancer therapy. (PubMed, Curr Opin Oncol) - "The methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy."

Journal • Oncology • MAT2A • MTAP

Discovery of SCR-7952, a novel, potent and high selective MAT2A inhibitor shows robust anti-tumor activities and better safety profile (AACR 2022) - "In contrast, AG-270 at 200mpk resulted in significant increase of bilirubin. In conclusion, the above data demonstrate that SCR-7952 is a more potent and higher selective MAT2A, and will be filed IND in 2022."

Clinical • Oncology • CDKN2A • MAT2A • MTAP

Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads. (PubMed, J Med Chem) - "Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS)."

Journal • Oncology • MAT2A • MTAP