On August 9, 2023 Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial stage biotechnology company, reported Cancer Discovery published preclinical and initial clinical data from a first-in-human Phase 1/2 clinical trial of MRTX1719, a PRMT5 / methylthioadenosine (MTA)-cooperative inhibitor evaluated in methylthioadenosine phosphorylase (MTAP) deleted cancers (Press release, Mirati, AUG 9, 2023, View Source [SID1234634100]). These results provide preclinical and early clinical proof-of-concept for this differentiated approach and demonstrate that MRTX1719 may represent a promising targeted therapy for the ~10% of cancer patients with this biomarker. The publication can be found here.

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In preclinical studies, MRTX1719 was demonstrated to be a potent, selective inhibitor of the PRMT5/MTA complex. This compound exploits the elevated MTA levels present in MTAP-deleted cancers and turns this altered metabolic state into a therapeutic vulnerability to selectively kill MTAP deleted cancer cells while sparing normal cells. Preclinical results showed marked anti-tumor activity of MRTX1719, including regression, across lung, pancreatic, mesothelioma, and other solid tumor models.

As of June 13, 2023, there were 18 patients with solid tumors harboring MTAP deletions in the Phase 1/2 trial of MRTX1719 that were evaluable for clinical response at dose levels of 100mg QD or greater. Initial dose level started at 50mg administered once-daily orally over 21-day cycles followed by 100% dose escalations for subsequent dose levels. Six individual case narratives were selected for inclusion in the Cancer Discovery publication:

There were six confirmed objective responses observed in the Phase 1 study including one patient who achieved a response which subsequently confirmed post-data cutoff
MRTX1719 achieved apparent complete PRMT5 inhibition in MTAP deleted tumor cells at a dose of 200 mg QD as evidenced by pretreatment and on-treatment tumor biopsies of the PRMT5 biochemical biomarker symmetric dimethyl arginine (SDMA)
It was notable that four patients were on therapy for multiple cycles before experiencing an initial objective response, with their tumors continuing to decrease in size over the course of treatment.
These findings suggest that tumor response may continue to deepen over time indicating the importance of evaluating tumor response kinetics and response rates across a broader patient population with longer follow up.
MRTX1719 was well-tolerated with no dose limiting toxicities observed at dose levels up to 400mg QD. None of the patients treated with MRTX1719 experienced dose-limiting adverse events associated with first generation PRMT5 inhibitors such as thrombocytopenia, anemia or neutropenia.
"Many cancers with a prevalence of MTAP deletion have few treatment options so it is encouraging to see these initial responses in the clinic. These data, including the favorable safety profile, demonstrate the development of a possible therapeutic approach for a significant population of patients with MTAP-deleted cancers in need of new treatment options," said Jordi Rodon Ahnert, MD, PhD, The University of Texas MD Anderson Cancer Center. "It will be important for next-generation sequencing tests to expand their panel of targets to include for markers of PRMT5 inhibition."

"The targeting strategy of MRTX1719 is differentiated from first generation PRMT5 inhibitors and has so far shown to be well tolerated in this patient population with dire unmet need," said James Christensen, Ph.D., chief scientific officer, Mirati Therapeutics, Inc. "We are pleased that Cancer Discovery recognized the importance and potential impact of this early data from MRTX1719, and we look forward to pursuing continued development of MRTX1719 for the benefit of patients living with cancer."

About MRTX1719 (MTA-cooperative PRMT5 inhibitor)

MRTX1719, discovered at Mirati, is an orally bioavailable, methylthioadenosine (MTA)-cooperative PRMT5 inhibitor that exhibits synthetic lethality in MTAP-deleted cancers. MTAP deletion leads to MTA accumulation in cancer cells and MRTX1719 is designed to selectively bind the PRMT5-MTA complex ultimately inhibiting PRMT5 function in MTAP-deleted cancer cells while sparing healthy non-tumor cells.1MTAP deletions occur in around 10% of all cancers2, including a high percentage of pancreatic cancer, non-small cell lung cancer, and mesothelioma which are associated with a poor prognosis, representing a significant unmet medical need. The PRMT5-MTA complex creates a novel drug target for the treatment of MTAP-deleted cancers. Targeting this complex involves a new and potentially improved therapeutic approach. MRTX1719 is being evaluated as monotherapy and in combination with other therapeutic options to treat patients with advanced, unresectable or metastatic solid tumor malignancy with homozygous deletion of the MTAP gene.

For more information visit Mirati.com/science.