Tenaya Therapeutics Announces Publication of Preclinical HDAC6 Inhibitor Data for Heart Failure with Preserved Ejection Fraction in Nature Communications
February 26 2024 - 8:30AM
Tenaya Therapeutics, Inc. (NASDAQ: TNYA), a clinical-stage
biotechnology company with a mission to discover, develop and
deliver potentially curative therapies that address the underlying
causes of heart disease, today announced the publication of
preclinical research related to Tenaya’s small molecule inhibitors
of histone deacetylase 6 (HDAC6), including TN-301, in the February
26, 2024, issue of Nature Communications. The article, titled
“Targeting HDAC6 to Treat Heart Failure with Preserved Ejection
Fraction in Mice,” details the potential of inhibiting HDAC6 for
the treatment of Heart failure with preserved ejection fraction
(HFpEF), a form of heart failure that effects more than three
million people in the U.S. alone1.
The extensive body of preclinical research described in Nature
Communications showed that inhibition of HDAC6:
- Successfully addressed many of the biologic hallmarks of HFpEF,
with direct effects on the heart such as diastolic relaxation and
systemic benefits including normalization of metabolic and
inflammatory factors, in a preclinical murine model that replicates
the HFpEF disease state.
- Achieved comparable or superior efficacy and was shown to have
a distinctive multi-modal mechanism of action versus empagliflozin,
a sodium-glucose cotransporter-2 (SGLT2) inhibitor approved by the
U.S. Food and Drug Administration as a treatment for HFpEF.
- Showed additive benefits when combined with empagliflozin
compared to either agent alone, indicating the potential for the
use of a small molecule HDAC6 inhibitor alone or as a combination
therapy for the treatment of HFpEF.
“With a combination of direct and systemic benefits on disease
pathophysiology, HDAC6 inhibition shows significant potential for
the treatment of HFpEF, one of the largest unmet needs in heart
disease treatment,” said Tim Hoey, Ph.D., Chief Scientific Officer
of Tenaya. “Our extensive preclinical package, detailed in the
current publication in Nature Communications, along with the
encouraging data from our TN-301 Phase 1 study, provide strong
rationale for Tenaya’s HDAC6 inhibitor program as a promising
therapeutic strategy for HFpEF patients.”
Last year, Tenaya completed a Phase 1 clinical trial in which
TN-301 achieved encouraging safety, target engagement and
pharmacokinetic results across a wide range of doses tested in
healthy participants2.
Tenaya’s highly selective small molecule inhibitors of the
enzyme HDAC6 were discovered using the company’s modality-agnostic
target discovery and validation capabilities. Unlike other members
of the HDAC family, HDAC6 is localized to the cell cytoplasm where
it coordinates cellular processes through interactions with
multiple substrates, including tubulin, and tubulin acetylation was
identified as a reliable plasma biomarker of HDAC6 target
engagement.
Having previously reported on the cardioprotective qualities of
HDAC6 inhibition in a model of genetic cardiomyopathy3, researchers
set out to assess the potential of HDAC6 inhibition in HFpEF using
multiple models of HFpEF, including a proprietary high fat diet
(HFD) and moderate transverse aortic constriction (mTAC) murine
model that replicated the metabolic and mechanical stress seen in
patients with HFpEF. For preclinical studies, Tenaya researchers
used TYA-018, an HDAC6 inhibitor structurally and functionally
similar to the company’s clinical candidate, TN-301.
Key Findings
- Treatment with TYA-018 as a single agent resulted in direct
effects on the heart (reversal of diastolic and mitochondrial
dysfunction, decreased hypertrophy, reduced fibroblast activation
and enhanced energetics), and systemic benefits (improved exercise
performance and glucose tolerance and reduced markers of
inflammation).
- TYA-018 showed comparable benefit to empagliflozin in the
murine HFpEF model.
- Gene expression analysis provided insights on TYA-018’s
distinct mechanism of action. HDAC6 inhibition was shown to restore
hypertrophy, fibrosis and mitochondrial energy production. TYA-018
demonstrated greater impact on markers of oxidative stress,
inflammation and metabolism as compared to SGLT2 inhibition.
- The combination of TYA-018 and empagliflozin resulted in
additive benefits, exceeding the efficacy observed with either
agent alone with measurements of cardiac function nearing that of
healthy controls.
- The selective effects of HDAC6 inhibition were reaffirmed
through genetic deletion studies, in which treatment of Hdac6
knockout mice did not display any of the beneficial effects that
wild-type HFpEF mice did following treatment.
About HFpEF and TN-301Heart failure with
preserved ejection fraction (HFpEF) is a common, debilitating
syndrome characterized by a stiffening of the heart muscle
resulting in an inability for the left ventricle to relax properly
during normal heart rhythm, referred to as diastolic dysfunction.
There are several cellular processes thought to underly the
pathophysiology of HFpEF including increases in fibrosis and
inflammation and defects in metabolism. Although HFpEF accounts for
approximately 50 percent of all heart failure hospitalizations in
the U.S.4, there are few proven treatment options.
TN-301 is Tenaya’s highly specific potential first-in-class
small molecule histone deacetylase (HDAC) 6 inhibitor, initially
being developed for the treatment of HFpEF. TN-301 has a
multi-modal mechanism of action that includes modifying
cytoskeletal and other proteins to coordinate cellular processes.
In preclinical studies, TN-301 has been shown to reverse many of
the signs and symptoms of HFpEF, with evidence of improved cardiac
function and improved glucose tolerance and reduced inflammation
and fibrosis. Tenaya has completed a dose escalating Phase 1
clinical trial of TN-301 in healthy participants. TN-301 was well
tolerated across a broad dose range with dose-proportional
pharmacokinetics supportive of once-daily dosing and target
engagement observed.
About Tenaya TherapeuticsTenaya Therapeutics is
a clinical-stage biotechnology company committed to a bold mission:
to discover, develop and deliver potentially curative therapies
that address the underlying drivers of heart disease. Leveraging
its integrated and interrelated Gene Therapy, Cellular Regeneration
and Precision Medicine platforms and proprietary core capabilities,
the company is advancing a pipeline of novel therapies with diverse
treatment modalities for rare genetic cardiovascular disorders and
more prevalent heart conditions. Tenaya’s most advanced candidates
include TN-201, a gene therapy for MYBPC3-associated
hypertrophic cardiomyopathy (HCM), TN-401, a gene therapy
for PKP2-associated arrhythmogenic right ventricular
cardiomyopathy (ARVC), and TN-301, a small molecule HDAC6 inhibitor
being initially developed for heart failure with preserved ejection
fraction (HFpEF). Tenaya also has multiple early-stage programs
progressing through preclinical development. For more information,
visit www.tenayatherapeutics.com.
1. Tsao, et al, Circulation 20232. Bexon, et al, HFSA 20233.
Yang, et al, Sci Trans Med 20224. Shah, et al, JACC 2017
Forward Looking Statements
This press release contains forward-looking statements as that
term is defined in Section 27A of the Securities Act of 1933 and
Section 21E of the Securities Exchange Act of 1934. Statements in
this press release that are not purely historical are
forward-looking statements. Words such as “potential,” “promising,”
and similar expressions are intended to identify forward-looking
statements. Such forward-looking statements include, among other
things, the clinical, therapeutic and commercial potential of
TN-301 both alone and/or in combination with an emerging standard
of care as a treatment for HFpEF. The forward-looking statements
contained herein are based upon Tenaya’s current expectations and
involve assumptions that may never materialize or may prove to be
incorrect. These forward-looking statements are neither promises
nor guarantees and are subject to a variety of risks and
uncertainties, including but not limited to: the potential failure
of TN-301 to demonstrate safety and/or efficacy in clinical
testing; unexpected concerns that may arise as a result of the
occurrence of adverse safety events or additional data analyses of
clinical trials evaluating TN-301, both alone or in combination
with other therapies; the timing, scope and likelihood of
regulatory filings and approvals for TN-301; risks associated with
the process of discovering, developing and commercializing drugs
that are safe and effective for use as human therapeutics and
operating as an early stage company; Tenaya’s ability to develop,
initiate or complete preclinical studies and clinical trials, and
obtain approvals, for any of its product candidates; Tenaya’s
continuing compliance with applicable legal and regulatory
requirements; Tenaya’s ability to raise any additional funding it
will need to continue to pursue its business and product
development plans; Tenaya’s reliance on third parties; Tenaya’s
manufacturing, commercialization and marketing capabilities and
strategy; the loss of key scientific or management personnel;
competition in the industry in which Tenaya operates; Tenaya’s
ability to obtain and maintain intellectual property protection for
its product candidates; general economic and market conditions; and
other risks. Information regarding the foregoing and additional
risks may be found in the section entitled “Risk Factors” in
documents that Tenaya files from time to time with the Securities
and Exchange Commission. These forward-looking statements are made
as of the date of this press release, and Tenaya assumes no
obligation to update or revise any forward-looking statements,
whether as a result of new information, future events or otherwise,
except as required by law.
Contacts
Michelle CorralVice President, Investor Relations and Corporate
CommunicationsTenaya TherapeuticsIR@TenayaThera.com
InvestorsAnneMarie FieldsStern
IRAnneMarie.Fields@SternIR.com
MediaWendy RyanTen Bridge
Communicationswendy@tenbridgecommunications.com
Tenaya Therapeutics (NASDAQ:TNYA)
Historical Stock Chart
From Apr 2024 to May 2024
Tenaya Therapeutics (NASDAQ:TNYA)
Historical Stock Chart
From May 2023 to May 2024