Kymera Therapeutics Announces Publication of Phase 1 Trial Results for KT-474 (SAR444656), a First-in-Class IRAK4 Degrader, in Nature Medicine
14 November 2023 - 3:00AM
Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage
biopharmaceutical company advancing a new class of small molecule
medicines using targeted protein degradation (TPD), today announced
that results from the positive Phase 1 clinical trial from its lead
program, KT-474 (SAR444656), a potent, highly selective, orally
bioavailable IRAK4 degrader, were published in Nature Medicine. The
results showed a reduction of disease-relevant inflammatory
biomarkers in the blood and skin of HS and AD patients associated
with improvement in skin lesions and symptoms. The full manuscript,
“IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis:
a phase 1 trial,” was published online on November 13, 2023, on the
Nature Medicine website.
The data reported in the publication show that KT-474
administered to HS and AD patients had safety, pharmacokinetics and
pharmacodynamics similar to healthy volunteers (HVs), achieved
robust IRAK4 degradation in blood and skin lesions associated with
a systemic anti-inflammatory effect, and showed activity in HS and
AD. The Company previously reported Phase 1 results in December
2022 and at the European Academy of Dermatology and Venereology
Symposium in May 2023. The publication also highlights preclinical
data on KT-474, including the first publication of the compound’s
chemical structure.
“The Phase 1 results published in Nature Medicine highlight the
transformative potential of IRAK4 degradation in TLR/IL-1R-driven,
high unmet need inflammatory diseases, with KT-474 demonstrating a
favorable safety profile, broad anti-inflammatory effect including
downregulation of disease-relevant gene transcripts in skin
lesions, and promising impact on skin lesions and symptoms in HS
and AD patients after only 28 days of dosing,” said Jared Gollob,
M.D., Chief Medical Officer, Kymera Therapeutics. “These positive
data show TPD’s unique ability to unlock this critical pathway, and
we look forward to sharing additional updates as our partner Sanofi
advances the Phase 2 clinical trials of KT-474 in HS and AD.”
Highlights from the Nature Medicine
Publication
KT-474 (SAR444656) was studied in a Phase 1 randomized,
placebo-controlled, single and multiple ascending dose trial to
assess safety, pharmacokinetics, pharmacodynamics and clinical
activity (NCT04772885). 105 healthy volunteers (HVs) were enrolled
in the placebo-controlled single and multiple ascending dose
escalation cohorts (SAD and MAD) and 21 HS and AD patients were
enrolled into an open-label patient cohort. KT-474 was administered
as a single dose and then daily for 14 days in the fasted state in
HVs followed by dosing for 28 days in the fed state in patients
with HS or AD. Degradation of IRAK4 was observed in HV blood, with
mean reductions after a single dose of ≥93% at 600–1600 mg and
after 14 daily doses of ≥95% at 50–200 mg. In patients treated with
75 mg of KT-474, similar IRAK4 degradation was achieved in blood,
and IRAK4 was normalized in skin lesions where it was overexpressed
relative to HVs. Reduction of disease-relevant inflammatory
biomarkers was demonstrated in the blood and skin of HS and AD
patients associated with improvement in skin lesions and symptoms.
KT-474 was well-tolerated with no drug-related infections. These
results from the first published clinical trial using a
heterobifunctional degrader provide initial proof of concept for
KT-474 in HS and AD to be further confirmed in placebo-controlled
Phase 2 trials.
About KT-474 (SAR444656)KT-474 (SAR444656) is a
first-in-class IRAK4 degrader in development for the treatment of
immune-inflammatory diseases with significant patient need, such as
hidradenitis suppurativa (HS), atopic dermatitis (AD), and
potentially others. IRAK4 is a key protein of the myddosome complex
that mediates signaling through IL-1 and toll-like receptors, which
play a crucial role in initiating the immune response against
invading pathogens. IRAK4 is a scaffolding kinase that acts at the
interface of the innate and adaptive immune responses with a
variety of functions depending on its kinase activity and
scaffolding function. Eliminating IRAK4 completely through
degradation impacts both the kinase and scaffolding functions,
therefore having the potential to achieve a broad, well-tolerated,
anti-inflammatory effect providing a novel therapeutic approach for
a variety of immune-inflammatory diseases. Sanofi, which is
collaborating with Kymera on the development of KT-474 (SAR444656)
outside of the oncology and immuno-oncology fields, is conducting
Phase 2 clinical trials of KT-474 in both HS and AD.
More information on the Phase 2 studies in HS (NCT06028230) and
AD (NCT06058156) can be found at www.clinicaltrials.gov.
About Kymera TherapeuticsKymera 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 programs designed to 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
therapeutic candidates designed to address the most promising
targets and provide patients with more effective
treatments. Kymera’s initial programs target IRAK4 and STAT3
within the IL-1R/TLR or JAK/STAT pathways, and the MDM2
oncoprotein, providing the opportunity to treat patients with a
broad range of immune-inflammatory diseases, hematologic
malignancies, and solid tumors.
Founded in 2016, Kymera is headquartered in Watertown, Mass.
Kymera has been named a “Fierce 15” company by Fierce Biotech and
has been recognized by both the Boston Globe and the Boston
Business Journal as one of Boston’s top workplaces. For more
information about our people, science and pipeline, please visit
www.kymeratx.com or follow us on X (previously Twitter) or
LinkedIn.
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