Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage
biopharmaceutical company advancing targeted protein degradation to
deliver novel small molecule protein degrader medicines, today
presented new preclinical results demonstrating that STAT3
degradation alleviates Th17 inflammation and is active in a
preclinical animal model of CNS inflammation, and that IRAK4
degradation blocks multiple innate immune signaling pathways across
different immune cell types in a manner superior to kinase
inhibitors. Data will be shared in two separate posters at the
American Association of Immunologists (AAI) Annual Meeting 2022,
taking place from May 6 - 10, 2022 in Portland, Oregon.
“Collectively, the findings demonstrate the advantage of using
degraders to effectively drug signaling nodes driving inflammation
as well as the translation of in vitro activity to in vivo proof of
concept in animal models of autoimmune disease,” said Anthony
Slavin, Vice President, Immunology. “The impact of STAT3
degradation on immune and stromal cell activation and Th17
inflammation leading to potent effects in a mouse model of multiple
sclerosis, as well as the broad effect of IRAK4 degradation on
TLR-mediated signaling and cytokine induction and its superiority
to kinase inhibition, underscore the clinical potential of these
degraders in the treatment of inflammatory and autoimmune
disorders.”
STAT3 is a transcriptional regulator that has been linked to
numerous cancers as well as multiple autoimmune and fibrotic
diseases. Heterobifunctional degraders have emerged as a novel
therapeutic modality with great potential to drug historically
“undruggable” protein targets like STAT3. Kymera has previously
shown its selective STAT3 degraders can suppress the growth of
tumors in preclinical models of lymphoma and solid tumors. Findings
presented at AAI reveal for the first time the activity of Kymera’s
STAT3 degraders against Th17 inflammation, including in vivo proof
of concept in a clinically relevant mouse experimental autoimmune
encephalitis (EAE) model of multiple sclerosis. Degradation of
STAT3 inhibited Th17 development and cytokine release, which in
turn blocked disease induction and also mitigated ongoing disease
in the EAE model.
IRAK4 is known to play a significant role in inflammation
mediated by the activation of toll-like receptors (TLRs) and IL-1
receptors (IL-1Rs). While TLR and IL-1R signaling via IRAK4 is
involved in immune surveillance, abnormal activation of these
pathways is the underlying cause of multiple inflammatory and
autoimmune diseases, including atopic dermatitis (AD), hidradenitis
suppurativa (HS) and rheumatoid arthritis (RA). The function of
IRAK4 is dependent both on its kinase and scaffolding activity;
therefore, targeting both functions with a degrader has the
greatest potential to inhibit IL-1R/TLR pathway activation. Data to
be shared in a second poster showed that potent and selective IRAK4
degraders effectively block TLR-mediated NF-kB and MAP kinase
signaling and cytokine induction across multiple different immune
cell subsets, including monocytes and B cells, with activity that
was superior to IRAK4 kinase inhibitors.
“We are excited to expand the study of our STAT3 degraders from
oncology into inflammation and autoimmune indications, where our
findings with respect to impact on Th17 development and activation
and Th17-mediated diseases open up multiple development
opportunities for this novel approach to drugging the JAK-STAT
pathway” said Nello Mainolfi, PhD, Co-Founder, President and CEO,
Kymera Therapeutics. “The data showing both the mechanistic as well
as functional differentiation of IRAK4 degraders compared to small
molecule kinase inhibitors further demonstrate the degrader
advantage not only for undruggable targets like STAT3, but also for
targets like IRAK4 where the full impact of targeting can only be
realized by addressing both the scaffolding and catalytic functions
of the protein.”
Posters at AAI Annual
Meeting:
- Title: STAT3 degraders inhibit
cellular activation, cytokine production, and Th17 development,
resulting in profound inhibition of autoimmunity in the MOG-EAE
model of CNS inflammation
- Abstract Number: 2297
- Session Day/Time: Saturday, May 7; 2:30-3:45 p.m. PT
- Location: Oregon Convention Center, Portland, OR
- Presenter: Jeffrey Sullivan,
Research Associate I, Immunology, Kymera Therapeutics
- Additional Research Highlights:
- STAT3 degradation showed broad and
potent activity in-vitro against TLR receptor and cytokine-induced
activation of immune and stromal cells.
- STAT3 degradation in CD4+ helper T
cells potently inhibited Th17 development, decreasing IL-17, IL-22,
IL-8/CXCL8, and TNFa production, with concomitant increase in Treg
numbers, that was superior to JAK1/2 kinase inhibition.
- STAT3 degradation was subsequently
evaluated in-vivo in a murine EAE model of multiple sclerosis, with
dose-dependent decrease of incidence, disease onset and
histopathology observed in comparison to a S1P1 inverse agonist or
steroid treatment.
- Title: Selective IRAK4 degradation, not kinase inhibition,
blocks TLR-activated NF-Κβ and p38 signaling leading to broad
cytokine inhibition
- Abstract Number: 2188
- Session Day/Time: Sunday, May 8; 2:30-3:45 p.m. PT
- Location: Oregon Convention Center, Portland, OR
- Presenter: Virginia Massa, Research
Associate II, Immunology, Kymera Therapeutics
- Additional Research Highlights:
- IRAK4 degradation, but not kinase inhibition, inhibited NF-Κβ
p65 activation and phosphorylation of p38 pathway members by TLR
agonists in monocytes and B cells.
- Peripheral blood mononuclear cells (PBMCs) pretreated with an
IRAK4 degrader and then stimulated with the TLR7/8 agonist, R848,
exhibited significantly broader inhibition of cytokines (IL-6,
TNF⍺, IL-8 and IL-1β) compared to those pretreated with a selective
IRAK4 kinase inhibitor.
- An IRAK4 degrader inhibited B cell IL-6 production induced by
the TLR9 agonist CpG, whereas an IRAK4 kinase inhibitor did
not.
- A sustained effect of the IRAK4 degrader on both target
pharmacodynamics and cytokine inhibition was observed, unlike IRAK4
kinase inhibition.
Kymera is collaborating with Sanofi on the development of
degrader candidates targeting IRAK4, including KT-474 (SAR444656),
outside of the oncology and immuno-oncology fields.
About Kymera TherapeuticsKymera 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 IRAK4 and STAT3 degrader programs; 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-Q for the period ended March 31,
2022, filed on May 3, 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:Todd Cooper Senior Vice
President, Corporate Affairs media@kymeratx.com857-285-5300
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