Agios Presents Data from Single Agent Dose-Escalation Arm of Phase 1 Study of AG-270, a MAT2A Inhibitor, in Patients with MTA...
28 October 2019 - 2:50AM
Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of
cellular metabolism to treat cancer and rare genetic diseases,
today presented 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-NCI-EORTC International Conference on Molecular Targets and
Cancer Therapeutics. AG-270 is an investigational, first-in-class
methionine adenosyltransferase 2A (MAT2A) inhibitor.
“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 StudyThe 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
DevelopmentPatients 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
DeletionHomozygous 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 InformationAgios
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.
About AgiosAgios is focused on discovering and
developing novel investigational medicines to treat cancer and rare
genetic diseases through scientific leadership in the field of
cellular metabolism and adjacent areas of biology. In addition to
an active research and discovery pipeline across both therapeutic
areas, Agios has two approved oncology precision medicines and
multiple first-in-class investigational therapies in clinical
and/or preclinical development. All Agios programs focus on
genetically identified patient populations, leveraging our
knowledge of metabolism, biology and genomics. For more
information, please visit the company's website at
www.agios.com.
About Agios/Celgene CollaborationAG-270 is part
of our 2016 global research collaboration agreement with Celgene
Corporation focused on metabolic immuno-oncology. Celgene has the
option to participate in a worldwide 50/50 cost and profit share
with Agios, under which Agios is eligible for up to $169 million in
clinical and regulatory milestone payments for the program.
Cautionary Note Regarding Forward-Looking
Statements This press release contains forward-looking
statements within the meaning of The Private Securities Litigation
Reform Act of 1995. Such forward-looking statements include those
regarding: the potential benefits of AG-270; Agios’ plans for the
further clinical development of AG-270 and Agios’ strategic plans
and prospects. The words “anticipate,” “believe,” “estimate,”
“expect,” “intend,” “may,” “plan,” “predict,” “project,” “would,”
“could,” “potential,” “possible,” “hope” and similar expressions
are intended to identify forward-looking statements, although not
all forward-looking statements contain these identifying words.
Such statements are subject to numerous important factors, risks
and uncertainties that may cause actual events or results to differ
materially from Agios' current expectations and beliefs. For
example, there can be no guarantee that any product candidate Agios
is developing will successfully commence or complete necessary
preclinical and clinical development phases; that positive safety
and efficacy findings observed in early stage clinical trials will
be replicated in later stage trials; or that development of any of
Agios' product candidates will successfully continue. There can be
no guarantee that any positive developments in Agios' business will
result in stock price appreciation. Management's expectations and,
therefore, any forward-looking statements in this press release
could also be affected by risks and uncertainties relating to a
number of other important factors, including: Agios' results of
clinical trials and preclinical studies, including subsequent
analysis of existing data and new data received from ongoing and
future studies; the content and timing of decisions made by the
U.S. FDA and other regulatory authorities,
investigational review boards at clinical trial sites and
publication review bodies; Agios' ability to obtain and maintain
requisite regulatory approvals and to enroll patients in its
planned clinical trials; unplanned cash requirements and
expenditures; competitive factors; Agios' ability to obtain,
maintain and enforce patent and other intellectual property
protection for any product candidates it is developing; Agios'
ability to maintain key collaborations; and general economic and
market conditions. These and other risks are described in greater
detail under the caption “Risk Factors” included in Agios’ public
filings with the Securities and Exchange Commission. Any
forward-looking statements contained in this press release speak
only as of the date hereof, and Agios expressly disclaims any
obligation to update any forward-looking statements, whether as a
result of new information, future events or otherwise.
Investor & Media Contact: Holly Manning,
617-844-6630 Associate Director, Investor Relations
Holly.Manning@agios.com
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