The detailed pharmacological and mechanistic
characterization of MRTX1719 demonstrates that blocking PRMT5-MTA
complex is a rational and differentiated approach to treat cancers
harboring MTAP deletion
Partial responses observed in patients with advanced
cancer along with a well-tolerated safety profile demonstrate
MRTX1719 may represent a potential new therapeutic strategy for the
treatment of multiple cancer types that have strong unmet medical
need
SAN
DIEGO, Aug. 9, 2023 /PRNewswire/ -- Mirati
Therapeutics, Inc.® (NASDAQ: MRTX), a
commercial stage biotechnology company, announced today 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. 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.
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.1 MTAP 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.
About Mirati Therapeutics, Inc.®
Mirati Therapeutics, Inc. is a commercial stage biotechnology
company whose mission is to discover, design and deliver
breakthrough therapies to transform the lives of patients with
cancer and their loved ones. The company is relentlessly focused on
bringing forward therapies that address areas of high unmet need,
including lung cancer, and advancing a pipeline of novel
therapeutics targeting the genetic and immunological drivers of
cancer. Unified for patients, Mirati's vision is to unlock the
science behind the promise of a life beyond cancer.
For more information about Mirati, visit us
at Mirati.com or follow us
on Twitter, LinkedIn and Facebook.
Forward Looking Statements
This press release includes forward-looking statements regarding
Mirati's business, financial guidance and the therapeutic and
commercial potential of KRAZATI® (adagrasib), MRTX1719
(MTA-cooperative PRMT5 inhibitor), MRTX0902 (SOS1 inhibitor), and
MRTX1133 (selective KRASG12D inhibitor), Mirati's technologies and
Mirati's other products in development. Any statement describing
Mirati's goals, expectations, intentions or beliefs, financial or
other projections, is a forward-looking statement and should be
considered an at-risk statement. Such statements are subject to
certain risks and uncertainties, including those related to the
impact COVID-19 could have on our business, and including those
inherent in the process of discovering, developing and
commercializing medicines that are safe and effective for use as
human therapeutics, and in the endeavor of building a business
around such medicines.
Mirati's forward-looking statements also involve assumptions
that, if they never materialize or prove correct, could cause its
results to differ materially from those expressed or implied by
such forward-looking statements. Although Mirati's forward-looking
statements reflect the good faith judgment of its management, these
statements are based only on facts and factors currently known by
Mirati. As a result, you are cautioned not to rely on these
forward-looking statements. These and other risks concerning
Mirati's programs are described in additional detail in Mirati's
annual report on Form 10-K, and most recent Form 10-Q, which are on
file with the Securities and Exchange Commission and available at
the SEC's Internet site (https://www.sec.gov/). These
forward-looking statements are made as of the date of this press
release, and Mirati assumes no obligation to update the
forward-looking statements, or to update the reasons why actual
results could differ from those projected in the forward-looking
statements, except as required by law.
Mirati Contacts
Investor Relations: ir@mirati.com
Media Relations: media@mirati.com
References
- Smith C.R., Aranda R, Bobinski T.P., Briere D.M., Burns
A.C., et al. Fragment-Based Discovery of MRTX1719, a Synthetic
Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of
MTAP-Deleted Cancers. J Med Chem. 2022 Jan 18. doi:
10.1021/acs.jmedchem.1c01900. Online ahead of print.
- Han G, Yang G, Hao D, et al. 9p21 loss confers a cold tumor
immune microenvironment and primary resistance to immune checkpoint
therapy. Nat Commun. 2021 Sep
23;12(1):5606. doi: 10.1038/s41467-021-25894-9.
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SOURCE Mirati Therapeutics, Inc.