Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage
biopharmaceutical company advancing targeted protein degradation to
deliver novel small molecule protein degrader medicines, today
presented preclinical data from its 4th development program, a
novel MDM2 degrader, at the American Association for Cancer
Research (AACR) Annual Meeting 2022, taking place from April 8 -
13, 2022 in New Orleans, Louisiana.
The murine double minute 2 (MDM2) oncoprotein is the E3 ligase
that ubiquitinates and degrades the p53 tumor suppressor. While
reversible small molecule inhibitors (SMIs) of the MDM2/p53
interaction have been developed to stabilize and upregulate p53
expression in order to induce cancer cell death in wild-type p53
tumors, they induce a feedback loop that upregulates MDM2 protein
levels and thereby reduce p53 stabilization – limiting their
biological activity and clinical application. Kymera is developing
KT-253, an MDM2 protein degrader whose unique mechanism of action
overcomes the MDM2-p53 autoregulatory feedback loop, allowing for a
rapid apoptotic response and potentially superior efficacy and
safety compared to SMIs.
The results showed that KT-253 inhibited tumor cell growth in
the picomolar range and was >200-fold more potent than
clinically active MDM2 SMIs across a panel of solid and
hematological tumor cell lines. Short term (as brief as three to
four hours) exposures of KT-253 in a p53 wild-type acute
lymphoblastic leukemia (ALL) cell line more potently stabilized p53
compared to SMIs, leading to robust apoptosis that was not observed
with SMIs.
In addition, a single low dose of KT-253 resulted in sustained
tumor regression in a mouse xenograft model of ALL, correlating
strongly with induction of pro-apoptotic p53 target genes.
Administration of KT-253 every 3 weeks at exposures well-tolerated
in NHP also achieved sustained tumor regression in a mouse
xenograft AML model where SMIs only resulted in partial tumor
growth inhibition.
“We are encouraged to see a clear biologic and therapeutic
advantage over SMIs in preliminary studies of our novel MDM2
degrader,” said Juliet Williams, Senior Vice President and Head of
Biology, Kymera Therapeutics. “KT-253 has demonstrated extremely
potent in vitro cell killing and in vivo antitumor activity with
intermittent dosing that is superior to existing SMIs and indicates
the potential for improved efficacy and safety with the degrader
approach in p53 wild-type tumors.”
KT-253 has broad franchise opportunities in p53 wild-type
tumors, which comprise over 50% of all liquid and solid
malignancies.
“Within the broad development landscape of p53 wild-type tumors,
Kymera is focused on a biomarker selection strategy for identifying
those tumor types where MDM2 degradation will elicit a rapid
apoptotic response, which will enhance the therapeutic index,” said
Nello Mainolfi, Ph.D., Co-Founder, President and CEO, Kymera
Therapeutics. “We are excited to progress this compelling compound
further into clinical trials in an anticipated broad set of
indications in both liquid and solid tumors, and we anticipate
filing an IND in 2022.”
Additional Research Highlights:
- MDM2 levels were maintained at
undetectable levels with KT-253 while an SMI showed increased MDM2
protein expression at four hours post exposure.
- A single 1 mg/kg dose of KT-253 in
RS4;11 ALL xenograft animal models led to tumor regression showing
rapid increase in key apoptotic biomarkers such as p53, p21, and
PUMA as early as 3 hours post dose.
- KT-253 also showed sustained tumor
regression in MV-4-11 AML xenograft animal model and led to a rapid
increase in GDF15, p21, and PUMA as early as 3 hours post
dose.
Presentation at AACR Annual
Meeting:
- Title: KT-253, a highly potent and selective heterobifunctional
MDM2 degrader for the treatment of wild-type p53 tumors with
superior potency and differentiated biological activity compared to
small molecule inhibitors (SMI)
- Abstract Number: 3934 / 8
- Session Time: 9:00 AM – 12:30 PM CDT, April 13, 2022
- Location: Section 22
- Presenter: Yogesh Chutake, Principal Scientist, Oncology,
Biology, Kymera Therapeutics
About MDM2 Degrader Program, KT-253
KT-253 is a potent and selective degrader of MDM2 with potential
to be a best-in-class p53 stabilizer. Degradation of MDM2 has
blocks the feedback loop which up-regulates MDM2 production and in
doing so more effectively drives tumor cells to rapid apoptosis. As
wild-type p53 is present in more than 50% of tumors, KT-253
represents another program with broad franchise potential in liquid
and solid tumors. Kymera is focused on indications with specific
sensitivity to this mechanism of action, such as AML, lymphomas,
uveal melanoma, and others through a focused biomarker strategy.
Kymera expects to file an IND for KT-253 in 2022.
About Kymera Therapeutics
Kymera Therapeutics (Nasdaq: KYMR) is a biopharmaceutical
company pioneering the field of targeted protein degradation, a
transformative approach to address disease targets and pathways
inaccessible with conventional therapeutics. Kymera’s Pegasus
platform is a powerful drug discovery engine, advancing novel small
molecule therapies that harness the body’s innate protein recycling
machinery to degrade dysregulated, disease-causing proteins. With a
focus on undrugged nodes in validated pathways, Kymera is advancing
a pipeline of novel therapeutics designed to address the most
intractable pathways and provide new treatments for patients.
Kymera’s initial programs target IRAK4, IRAKIMiD, and STAT3 within
the IL-1R/TLR or JAK/STAT pathways, providing the opportunity to
treat patients with a broad range of immune-inflammatory diseases,
hematologic malignancies, and solid tumors. For more information,
visit www.kymeratx.com.
Founded in 2016, Kymera is headquartered in Watertown, Mass.
Kymera has been named a “Fierce 15” biotechnology company by Fierce
Biotech and has been recognized by the Boston Business Journal as
one of Boston’s “Best Places to Work.” For more information about
our people, science, and pipeline, please visit www.kymeratx.com or
follow us on Twitter or LinkedIn.
Cautionary Note Regarding Forward-Looking
StatementsThis press release contains forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995, as amended, including, without limitation,
implied and express statements regarding its: strategy, business
plans and objectives for the MDM2 degrader program; and plans and
timelines for the clinical development of Kymera Therapeutics'
product candidates, including the therapeutic potential and
clinical benefits thereof. The words "may," “might,” "will,"
"could," "would," "should," "expect," "plan," "anticipate,"
"intend," "believe," “expect,” "estimate," “seek,” "predict,"
“future,” "project," "potential," "continue," "target" and similar
words or expressions are intended to identify forward-looking
statements, although not all forward-looking statements contain
these identifying words. Any forward-looking statements in this
press release are based on management's current expectations and
beliefs and are subject to a number of risks, uncertainties and
important factors that may cause actual events or results to differ
materially from those expressed or implied by any forward-looking
statements contained in this press release, including, without
limitation, risks associated with: the impact of COVID-19 on
countries or regions in which we have operations or do business, as
well as on the timing and anticipated results of our current
preclinical studies and future clinical trials, strategy and future
operations; the delay of any current preclinical studies or future
clinical trials or the development of Kymera
Therapeutics' drug candidates; the risk that the results
of current preclinical studies may not be predictive of future
results in connection with future clinical trials; Kymera
Therapeutics' ability to successfully demonstrate the safety and
efficacy of its drug candidates; the timing and outcome of the
Company’s planned interactions with regulatory authorities; and
obtaining, maintaining and protecting its intellectual
property. These and other risks and uncertainties are
described in greater detail in the section entitled "Risk Factors"
in the Quarterly Report on Form 10-K for the period ended December
31, 2021, filed on February 24, 2022, as well as discussions of
potential risks, uncertainties, and other important factors in
Kymera Therapeutics' subsequent filings with the Securities and
Exchange Commission. In addition, any forward-looking statements
represent Kymera Therapeutics' views only as of today and should
not be relied upon as representing its views as of any subsequent
date. Kymera Therapeutics explicitly disclaims any obligation to
update any forward-looking statements. No representations or
warranties (expressed or implied) are made about the accuracy of
any such forward-looking statements.
Investor Contact:Bruce Jacobs Chief Financial
Officer investors@kymeratx.com857-285-5300
Chris BrinzeyManaging Director,
Westwickechris.brinzey@westwicke.com339-970-2843
Media Contact:Tyler GagnonDirector, Corporate
Communicationstgagnon@kymeratx.com508-904-9446
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