On October 27, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported the first data from the single agent dose-escalation arm of the Phase 1 study of AG-270 in methylthioadenosine phosphorylase (MTAP)-deleted tumors at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Agios Pharmaceuticals, OCT 27, 2019, View Source [SID1234548673]). AG-270 is an investigational, first-in-class methionine adenosyltransferase 2A (MAT2A) inhibitor.
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"The single agent arm of the Phase 1 trial for AG-270 provides the first data from a clinical study of a MAT2A inhibitor," said Rebecca Heist, M.D., Massachusetts General Hospital and an investigator in the study. "These data demonstrate that AG-270 induces reductions in the biomarkers of MAT2A inhibition, notably plasma concentrations of S-adenosylmethionine (SAM) and tumor levels of symmetrically demethylated arginine (SDMA), at well tolerated doses. These findings will help guide the dosing and schedule for the next phase of development of AG-270 in combination with taxanes."
"Inhibition of MAT2A is a unique approach to cancer treatment, based on discoveries made by Agios scientists looking for differences in metabolism between cancer cells and normal cells," said Chris Bowden, M.D., chief medical officer at Agios. "This early clinical work with AG-270 confirms that it has the desired pharmacologic effects when given as single agent, and, supported by strong pre-clinical work and rationale, we are now enrolling patients in two combination arms in homogenous patient populations to better understand AG-270’s clinical profile when combined with taxane-based regimens for non-small cell lung and pancreatic cancer. These arms will be instrumental in gathering sufficient data to determine the next steps in clinical development."
AG-270 Phase 1 Study
The Phase 1 study of AG-270 in MTAP-deleted tumors began with a single agent dose-escalation arm to establish the maximum tolerated dose of AG-270. Secondary objectives were to characterize AG-270’s safety, tolerability, pharmacokinetics and pharmacodynamics as a monotherapy. Two additional Phase 1 arms were recently initiated to explore AG-270 in combination with taxanes in second-line non-small cell lung cancer and first or second-line pancreatic cancer.
As of the August 16, 2019 data cutoff date, 39 patients had been treated in the single agent dose-escalation arm with oral AG-270 either once or twice daily, at total daily doses ranging from 50 mg to 400 mg. The study enrolled patients with a wide range of advanced and treatment-refractory solid tumors, including bile duct cancer (18%), pancreatic cancer (18%), mesothelioma (10%) and non-small cell lung cancer (10%). Nearly half of the patients enrolled had received three or more prior lines of therapy. Thirty-six patients discontinued AG-270, primarily due to disease progression.
Pharmacokinetic and Pharmacodynamic Results
Mean exposure increased in an approximately dose-proportional manner between 50 mg and 200 mg once daily.
Mean exposure was lower at 400 mg once daily than 200 mg once daily; due to this observation, a dose of 200 mg twice daily was evaluated, which increased steady-state area under the plasma concentration-time curve (AUC) by 1.9-fold relative to a dose of 200 mg once daily.
Plasma SAM concentration decreased by 65-74% across doses of 50-200 mg once daily and 200 mg twice daily.
Analysis of nine paired tumor biopsies by IHC showed decreases in levels of SDMA residues, consistent with inhibition of the methyltransferase PRMT5, downstream of MAT2A inhibition.
Safety and Efficacy Results
The most common treatment-related adverse events Grade 3 or above were reversible increases in bilirubin (10%) due to AG-270’s known ability to inhibit UGT1A1, and reversible decreases in the platelet count (8%).
Three patients (treated at 100 mg once daily, 150 mg once daily and 200 mg twice daily) developed a generalized erythematous rash. One case resolved less than 1 week after AG-270 interruption and two cases were successfully re-challenged at a lower dose.
For patients treated in the 200 mg twice daily cohort, two of six experienced reversible acute liver injury, manifested as asymptomatic Grade 3 and 4 increases in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Outpatient treatment with oral steroids led to complete resolution. Two of six patients experienced Grade 3 and 4 thrombocytopenia.
The maximum tolerated dose was determined to be 200 mg once daily.
In this group of patients with treatment-refractory malignancies, one confirmed partial response was observed in a patient with a high-grade neuroendocrine carcinoma of the lung treated with 200 mg of AG-270 once daily. Two additional patients experienced prolonged stable disease for >6 months.
Next Steps for AG-270 Clinical Development
Patients are currently enrolling in the two combination arms of the Phase 1 study.
One arm will test AG-270 in combination with docetaxel in up to 40 patients with MTAP-deleted non-small cell lung cancer who have had no more than two prior lines of cytotoxic therapy.
The second arm will test AG-270 in combination with nab-paclitaxel and gemcitabine in up to 45 patients with MTAP-deleted pancreatic ductal adenocarcinoma who have had no more than one prior line of cytotoxic therapy.
The goal of these arms is to further characterize the safety, tolerability, PK and PD, and to detect preliminary evidence of anti-tumor activity for the combinations.
Targeting MAT2A in Cancers with MTAP Deletion
Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. MTAP deletion almost always coincides with the loss of cyclin-dependent kinase inhibitor 2A (CDKN2A), a well known negative prognostic factor in cancer. Deletion of MTAP results in the accumulation of the enzyme’s substrate, methylthioadenosine (MTA). Increased concentrations of MTA partially inhibit the activity of protein arginine methyltransferase 5 (PRMT5), while other methyltransferases are relatively unaffected. Further reduction of PRMT5 activity can be achieved through modest reductions in the concentration of its normal substrate, the methyl donor S-adenosylmethionine (SAM). Inhibition of PRMT5 activity results in a reduction in symmetrically demethylated arginine residues (SDMAs) on target proteins, many of which are involved in mRNA splicing. AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis.
Investor Event and Webcast Information
Agios will host an investor event today at 6:30 p.m. ET in Boston to review the AG-270 Phase 1 dose-escalation data and pre-clinical research. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.