Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq:
TERN), a clinical-stage biopharmaceutical company developing a
portfolio of small-molecule single-agent and combination therapy
candidates for the treatment of non-alcoholic steatohepatitis
(NASH) and other chronic liver diseases, today reported positive
top-line results from a Phase 1 clinical trial of TERN-501, a
thyroid hormone receptor beta (THR-β) agonist in development for
the treatment of patients with NASH.
The Phase 1 clinical trial includes single ascending dose (SAD),
multiple ascending dose (MAD) and drug-drug interaction (DDI)
cohorts evaluating the safety, tolerability, pharmacodynamics (PDs)
and pharmacokinetics (PKs) of TERN-501. Healthy volunteers with
mildly elevated low-density lipoprotein (LDL) cholesterol were
randomized to placebo (n=2) or TERN-501 (n=6) in each cohort.
Volunteers randomized to TERN-501 received single doses of 3, 10,
30 or 60 mg of TERN-501 in the SAD portion of the study or multiple
doses of 3, 6 or 10 mg of TERN-501 once daily for 14 days in the
MAD portion of the study. In the DDI portion of the study,
volunteers received open label TERN-501 co-administered with
TERN-101, the Company’s liver-distributed farnesoid X receptor
(FXR) agonist also in development for the treatment of NASH.
TERN-501 was generally safe and well-tolerated in the SAD and
MAD cohorts with a similar incidence of adverse events (AEs) across
all TERN-501 treatment groups and placebo. All AEs were mild to
moderate with no apparent dose relationship. There were no
treatment-emergent serious AEs (SAEs) and no volunteer discontinued
TERN-501 or the study due to any AE. There were no cardiac safety
signals, no incidence of diarrhea and no differences between
TERN-501 dose groups and placebo in change from baseline in heart
rate, blood pressure or other vital signs. Thyroid function test
results were consistent with other THR-β agonists currently in
clinical development, and there were no findings of clinical hyper-
or hypo-thyroidism. There were no clinically meaningful differences
between placebo and any TERN-501 dose group in liver function
abnormalities or mean change from baseline in liver transaminases
at Day 15 in the MAD cohorts.
In the SAD and MAD cohorts, TERN-501 demonstrated a predictable
PK profile with low variability. Study drug plasma exposures were
linear and approximately dose-proportional with no overlap between
dose strengths. There was no significant accumulation of drug over
14 days of dosing. TERN-501 plasma half-life was greater than 13
hours in all single and repeat dose cohorts, supporting once-daily
dosing. The overall PK profile indicates TERN-501 is well-suited
for co-formulation with other small molecule NASH agents as an
oral, once-daily fixed dose combination.
Significant effects on sex hormone binding globulin (SHBG), a
key PD marker of THR-β engagement linked to NASH histologic
efficacy, were observed following treatment with TERN-501. As
further described in the table below, SHBG increases observed with
14 days of TERN-501 treatment were significant, dose dependent, and
have been associated with robust reductions in MRI proton density
fat fraction (MRI-PDFF) and NAFLD Activity Score in a precedent
late-stage clinical NASH trial.
In addition, significant reductions were observed in atherogenic
lipids including LDL cholesterol and apolipoprotein B (Apo-B),
comparable to or greater than those observed in Phase 1 studies of
other THR-β agonists being studied in late-stage clinical trials.
All TERN-501 dose groups demonstrated significant decreases in LDL
cholesterol compared to placebo during the dosing period. The
maximum mean LDL cholesterol decreases over the treatment period
were -22%, -28% and -27% for 3, 6 and 10 mg doses, respectively,
compared to placebo (-8%).
The PD results from these MAD cohorts are summarized below:
|
TERN-501 MAD (QD)Mean % Change from Baseline to Day 15 |
|
Placebo (N=6) |
3 mg (N=6) |
6 mg (N=6) |
10 mg (N=6) |
Sex Hormone Binding Globulin (%) |
-12% |
55% |
134%* |
166%* |
Low Density Lipoprotein - cholesterol (%) |
-4% |
-17% |
-19% |
-21%* |
Triglycerides (%) |
-16% |
-22% |
-21% |
-36% |
Apolipoprotein-B (%) |
-6% |
-18%* |
-23%* |
-28%* |
Note: Day 15 represents 24 hours following the last dose of
TERN-501* p-value vs. placebo: <0.05
In the SAD cohorts, single doses of TERN-501 up to 60 mg
resulted in significant and dose-dependent reductions in Apo-B and
LDL cholesterol and significant increases in SHBG relative to
placebo. Additional data from the SAD cohorts will be presented at
AASLD The Liver Meeting® Digital Experience in November 2021.
In the DDI cohort, the combination of TERN-101 and TERN-501 was
well tolerated. Preliminary PK results support the
co-administration of TERN-101 and TERN-501 in NASH patients, with
no apparent need for dose adjustment.
“The TERN-501 proof of concept data are highly encouraging and
indicate potent liver target engagement and the potential for broad
benefits in NASH patients. We are particularly pleased to see high
TERN-501 exposures at lower doses than initially projected
accompanied by marked dose-dependent increases in SHBG and
decreases in LDL cholesterol. These results, along with the
predicted non-variable PK of TERN-501 as well as its low potential
for drug-drug interactions, may offer an advantage within the THR-β
agonist class,” said Erin Quirk, M.D., president, chief medical
officer and head of R&D at Terns. “Taken together with its
significant changes in PD markers and positive Phase 1 safety
profile observed in the trial, we believe TERN-501 is strongly
positioned to be a promising therapeutic candidate for NASH and is
well suited for co-formulation and combination therapy development.
We are excited to move forward with our plan to initiate the first
NASH trial of TERN-101, our FXR agonist, in combination with
TERN-501, our THR-β agonist, in the first half of 2022.”
About TERN-501TERN-501 is a thyroid hormone
receptor beta (THR-β) agonist with high metabolic stability,
enhanced liver distribution and greater selectivity for THR-β
compared to other THR-β agonists in development. Agonism of THR-β
increases fatty acid metabolism via mitochondrial oxidation and
affects cholesterol synthesis and metabolism. As a result, THR-β
stimulation has the ability to reduce hepatic steatosis and improve
serum lipid parameters including LDL cholesterol and triglycerides.
In vivo NASH studies in a rodent model have demonstrated that
low-doses of TERN-501 achieved complete resolution of steatosis and
reductions in serum lipids, hepatic inflammation and fibrosis.
TERN-501 has high liver distribution and is 23-fold more selective
for THR-β than for THR-α activation in a cell free assay, thereby
minimizing the risk of cardiotoxicity and other off-target effects
associated with non-selective THR stimulation. Finally, TERN-501
has been designed to be metabolically stable and is therefore
expected to have little pharmacokinetic variability and a low
clinical dose, making it an attractive candidate for use in
fixed-dose combinations for NASH treatment. Terns received Fast
Track designation from the U.S. Food and Drug Administration (FDA)
for TERN-501 for the treatment of NASH in June 2021.
About Terns PharmaceuticalsTerns
Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company
developing a portfolio of small-molecule single-agent and
combination therapy candidates for the treatment of non-alcoholic
steatohepatitis, or NASH, and other chronic liver diseases. Terns’
pipeline includes three clinical stage development programs
including an FXR agonist, a VAP-1 inhibitor and a THR-β agonist,
and a preclinical GLP-1 receptor agonist program. Terns is focused
on developing combination therapies based on clinically validated
and complementary mechanisms of action to address the multiple
hepatic disease processes of NASH in order to drive meaningful
clinical benefits for patients. For more information, please visit:
www.ternspharma.com.
Cautionary Note Regarding Forward-Looking
StatementsThis press release contains forward-looking
statements about Terns Pharmaceuticals, Inc. (the “Company,” “we,”
“us,” or “our”) within the meaning of the federal securities laws,
including those related to the Company’s expectations of timing and
potential results of the Company’s clinical trials and other
development activities, including in relation to the therapeutic
potential of TERN-501; the potential for thyroid hormone receptor
beta (THR-β) to be a therapeutic target for NASH; the potential
utility and progress of the Company’s product candidates in NASH,
including the clinical utility of the data from and the endpoints
used in the Phase 1 trial; the Company’s clinical development plans
and activities, including the development plans for TERN-501 in
combination with TERN-101 and potentially other product candidates;
the Company’s expectations regarding the profile of its product
candidates, including tolerability, safety, metabolic stability and
pharmacokinetic profile; and the Company’s ability to continue to
execute on its clinical strategy and plans. All statements other
than statements of historical facts contained in this press
release, including statements regarding the Company’s strategy,
future financial condition, future operations, projected costs,
prospects, plans, objectives of management and expected market
growth, are forward-looking statements. In some cases, you can
identify forward-looking statements by terminology such as “aim,”
“anticipate,” “assume,” “believe,” “contemplate,” “continue,”
“could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,”
“may,” “objective,” “plan,” “positioned,” “potential,” “predict,”
“seek,” “should,” “target,” “will,” “would” and other similar
expressions that are predictions of or indicate future events and
future trends, or the negative of these terms or other comparable
terminology. The Company has based these forward-looking statements
largely on its current expectations, estimates, forecasts and
projections about future events and financial trends that it
believes may affect its financial condition, results of operations,
business strategy and financial needs. In light of the significant
uncertainties in these forward-looking statements, you should not
rely upon forward-looking statements as predictions of future
events. These statements are subject to risks and uncertainties
that could cause the actual results and the implementation of the
Company’s plans to vary materially, including the risks associated
with the initiation, cost, timing, progress and results of the
Company’s current and future research and development activities
and preclinical studies and clinical trials. In particular, the
impact of the COVID-19 pandemic on the Company’s ability to
progress with its research, development, manufacturing and
regulatory efforts, including the Company’s clinical trials for its
product candidates, will depend on future developments that are
highly uncertain and cannot be predicted with confidence at this
time, such as the ultimate duration of the pandemic, travel
restrictions, quarantines, social distancing and business closure
requirements in the United States and in other countries, and the
effectiveness of actions taken globally to contain and treat the
disease. These risks are not exhaustive. For a detailed discussion
of the risk factors that could affect the Company’s actual results,
please refer to the risk factors identified in the Company’s SEC
reports, including but not limited to its Annual Report on Form
10-K for the year ended December 31, 2020 and its Quarterly Reports
on Form 10-Q for the periods ended March 31, 2021 and June 30,
2021. Except as required by law, the Company undertakes no
obligation to update publicly any forward-looking statements for
any reason.
Contacts for Terns
InvestorsJustin Nginvestors@ternspharma.com
MediaJenna UrbanBerry & Company Public
Relationsmedia@ternspharma.com
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