Tenaya Therapeutics Presents Encouraging New Clinical and Preclinical Data from HDAC6 Inhibitor Program TN-301 for the Potential Treatment of Heart Failure with Preserved Ejection Fraction at the 2023 HFSA Annual Scientific Meeting
October 09 2023 - 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 released new data for TN-301 at the
2023 Heart Failure Society of America (HFSA) Annual Scientific
Meeting. TN-301 is Tenaya’s highly selective small molecule
inhibitor of histone deacetylase 6 (HDAC6) being developed for the
potential treatment of heart failure with preserved ejection
fraction (HFpEF).
"TN-301 continues to generate promising early data as a
differentiated candidate for the treatment of HFpEF, a form of
heart failure with few treatment options and unacceptably low
survival rates. The first-in-human data from our Phase 1 study of
TN-301 demonstrated safety and tolerability in healthy participants
with dose-proportional pharmacokinetics and robust target
engagement,” said Whit Tingley, M.D., Tenaya’s Chief Medical
Officer. “The attractive therapeutic profile seen in our Phase 1
trial of healthy participants and the additive benefits observed
preclinically of HDAC6 inhibition in combination with empagliflozin
support the potential for TN-301 to be utilized as a single agent
or in combination with an emerging standard of care. Taken
together, these data support continued development of TN-301 as a
potential treatment to address the many HFpEF patients underserved
by today’s treatment options.”
Phase 1 Results Demonstrate Safety, Target Engagement
and Suitability for Once-Daily DosingResults from the
Phase 1 clinical trial of TN-301 were presented in an ePoster,
Phase 1 Clinical Trial Of TN-301, A Highly Selective HDAC6
Inhibitor with Potential in HFpEF, Shows Target Engagement (#417).
Tenaya initiated the randomized, double-blind, placebo-controlled
Phase 1 clinical trial in September 2022 to assess the safety and
tolerability of escalating, oral doses of TN-301, as well as
pharmacokinetics (PK) and pharmacodynamics (PD) measures. The Phase
1 trial enrolled a total of 72 healthy adult participants in two
stages. In Stage 1, participants received single ascending doses
(SAD) of either TN-301 at doses ranging from 1mg – 700mg or
placebo. Tubulin acetylation was previously established as a
relevant PD marker of HDAC6 inhibition in preclinical studies and
utilized in the Phase 1 clinical trial to confirm target
engagement. Upon achieving evidence of target engagement at single
doses of 5mg, participants were enrolled in Stage 2 and received
multiple ascending doses (MAD) of TN-301 at once daily doses of
25mg, 100mg and 300mg for 14 days.
Key Findings:
- TN-301 was generally well tolerated across the broad range of
doses studied, with no dose-limiting toxicities or serious adverse
events observed. The most common adverse events observed were
related to gastrointestinal disturbances. These occurred with
similar frequency among those who received placebo or TN-301 and
did not increase with TN-301 dose. All participants completed the
study.
- PK results showed overall dose proportionality in both the SAD
and MAD stages of the study with a half-life supportive of
once-daily dosing.
- Robust HDAC6 inhibition was observed and increasing doses and
exposures with TN-301 correlated with increasing PD effects. Plasma
exposure and target engagement observed in this healthy participant
study met or exceeded those required for maximal efficacy in
preclinical studies.
- There were no changes in histone acetylation with TN-301,
underscoring the selectivity of TN-301 for HDAC6 and potentially
reducing the risk of off target effects observed with less
selective HDAC6 inhibitors or pan-HDAC inhibition.
- Future studies of TN-301 in HFpEF patients may evaluate a range
of doses starting at approximately 25 mg and higher.
Additive Benefit Observed with Combination of Tenaya’s
HDAC6 inhibitor with Approved SGLT2 inhibitor in HFpEF
ModelThe ePoster titled, Co-Administration of Inhibitors
of HDAC6 and SGLT2 in Murine HFpEF Models Results in Additive
Improvements in Cardiac Structural and Functional Measures (#104),
describes an effort by Tenaya researchers to examine the effect of
combining TYA-018 (an HDAC6 inhibitor structurally and functionally
similar to TN-301) with empagliflozin (a sodium-glucose
cotransporter-2 (SGLT2) inhibitor) which is approved for the
treatment of HFpEF) in the company’s proprietary HFpEF mouse model.
This study compared healthy controls with those treated with
TYA-018 and empagliflozin administered alone or in combination vs.
untreated HFpEF mice.
Key findings:
- Evidence of additive benefits at or nearing that of healthy
controls were observed in all treatment groups at eight weeks, but
more substantially with combination treatment, across multiple
measures of diastolic function (E/e’, E/A, end diastolic pressure)
without negative consequences to ejection fraction.
- At a gene level, an extensive reversal of disease toward
healthy controls was observed in TYA-018 and combination groups,
but less so in the empagliflozin group. A gene set enrichment
analysis of pathway and functional level HFpEF changes provided
insights on the distinct impact of HDAC6 inhibition on disease
pathophysiology compared to SGLT2 inhibition, with TYA-018
demonstrating a greater impact on improving metabolism, oxidative
stress and inflammation.
About HFpEF and TN-301 HFpEF is 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
failures, there are few proven treatment options.
TN-301 is Tenaya’s highly specific first-in-class small molecule
histone deacetylase (HDAC) 6 inhibitor, initially being developed
for the potential 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.
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.
Forward Looking StatementsThis 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
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; 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.
ContactMichelle CorralVP, Corporate
Communications and Investor RelationsIR@tenayathera.com
InvestorsJulie SeidelStern Investor
RelationsJulie.seidel@SternIR.com
MediaWendy RyanTen Bridge
Communicationswendy@tenbridgecommunications.com
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