Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq:
TERN), a clinical-stage biopharmaceutical company developing a
portfolio of small-molecule product candidates to address serious
diseases, including oncology, non-alcoholic steatohepatitis (NASH)
and obesity, today reported positive top-line results from the
Phase 2a DUET clinical trial of TERN-501, an orally-administered
thyroid hormone receptor-beta (THR-β) agonist, administered as a
monotherapy or in combination with TERN-101, a liver-distributed
farnesoid X receptor (FXR) agonist, for the treatment of NASH.
The DUET trial achieved its primary endpoint with the
once-daily, orally administered TERN-501 (3 mg and 6 mg)
monotherapy groups showing dose dependent and statistically
significant reductions in mean relative change from baseline in
liver fat content as assessed by magnetic resonance imaging, proton
density fat fraction (MRI-PDFF). A liver fat content reduction of
45% was observed in the TERN-501 6 mg dose group at Week 12,
compared to a 4% reduction in the placebo group (p<0.001).
Additionally, all TERN-501 monotherapy doses (1 mg, 3 mg and 6 mg)
achieved statistically higher proportions of patients with MRI-PDFF
reduction of at least 30% compared to placebo. MRI-PDFF response
rates were dose dependent with 64% of patients treated with
TERN-501 (6 mg) achieving response. A reduction in liver fat
content of at least 30% based on MRI-PDFF has been shown to have a
high correlation with improvements in NASH when confirmed by liver
biopsy.
“TERN-501 demonstrated highly encouraging efficacy results in
MRI-PDFF reductions. The high degree of liver fat content reduction
alongside the class-leading safety profile observed in the DUET
trial create the potential for TERN-501 to be the THR-β monotherapy
of choice and possibly a mainstay backbone of NASH combination
therapies,” said Erin Quirk, M.D., president and head of research
and development at Terns. “We sincerely thank all those who helped
rapidly advance the DUET trial, including our dedicated team of
investigators and clinical sites, the outstanding members of the
Terns team, and, most importantly, the patients who participated in
the trial.”
Primary and secondary TERN-501 monotherapy efficacy
results at Week 12 are summarized below.
|
PlaceboN=21 |
TERN-501 |
|
1mg |
3mg |
6mg |
At Week 12 |
N=23 |
N=19 |
N=22 |
MRI-PDFF |
|
|
|
|
Mean baseline (%) |
|
17 |
|
16.6 |
19.5 |
17.3 |
Relative change (%) from BL |
|
-4 |
|
-15 |
-27** |
-45*** |
Absolute change (%) from BL |
|
-1 |
|
-3 |
-5** |
-8*** |
Patients (%) achieving ≥30% relative reduction |
|
4% |
|
26%* |
39%** |
64%*** |
*p<0.05, **p<0.01, ***p<0.001 versus placebo
- TERN-501 (6 mg) monotherapy
demonstrated a statistically significant reduction in the secondary
endpoint of a mean change in corrected T1 (cT1), a magnetic
resonance-based imaging marker of liver fibro-inflammation
correlated with clinical outcomes in patients with liver
disease.
- TERN-501 monotherapy demonstrated
improvement or trends toward improvement in plasma lipid
parameters, such as LDL-C, HDL-C, triglycerides, and apolipoprotein
B (ApoB).
- There were dose dependent increases
in sex hormone binding globulin (SHBG), a marker of THR-β agonism
in the liver; the mean SHBG increase with TERN-501 (6 mg) exceeded
120% at Week 12 and was statistically greater than placebo
(p<0.001).
DUET TERN-501 safety findings:
- TERN-501 was generally well
tolerated, with adverse events (AEs) being generally mild and
evenly distributed across all arms, including placebo. There were
no drug-related serious adverse events (SAEs).
- Drug-related AEs of interest were
similar across all arms, including placebo, with similar rates of
GI events, including nausea, diarrhea and vomiting. No drug-related
cardiovascular AEs were observed.
- Mean change in thyroid axis
hormones, including thyroid stimulating hormone (TSH), free
triiodothyronine (fT3) and free thyroxine (fT4), and liver enzymes,
including alanine transaminase (ALT), aspartate transaminase (AST)
and gamma-glutamyltransferase (GGT), at Week 12 were similar to
placebo.
DUET TERN-501 + TERN-101 combination findings:
- The combination of TERN-501 and
TERN-101 (10 mg) resulted in modest improvements in MRI-PDFF mean
relative change (6 mg of TERN-501 combo) and >30% MRI-PDFF
responder rate (3 mg and 6 mg of TERN-501 combo) when compared to
TERN-501 monotherapy arms in Week 12. cT1 results were comparable
across mono and combo treatment arms.
- The combination of TERN-501 and TERN
101 (10 mg) did not result in LDL increases from baseline at Week
12, suggesting TERN-501 was able to reverse FXR-mediated LDL
increases.
- Overall, these results are
supportive of the ability to administer TERN-501 in combination
with FXR and potentially other therapeutics.
- There were no treatment-emergent
safety signals from the combination arms. TERN-101 safety and
tolerability findings were generally consistent with the Phase 2a
LIFT trial.
“With no FDA approved therapies, THR-β represents a key
mechanism of action for the treatment of NASH, as it is the only
class of treatment to have demonstrated both resolution of
steatohepatitis and improvement in fibrosis in a registrational
NASH study. TERN-501's impressive efficacy within a short duration
and excellent safety profile is compelling especially with its
once-daily, oral dosing as well as its cardiovascular and GI safety
profile, the latter of which has adversely affected other NASH
modalities in development,” said Mazen Noureddin, M.D., MHSc,
Professor of Clinical Medicine, Academic Institute, Houston
Methodist, Director of Houston Research Institute, and a principal
investigator in the DUET trial. “These results add to the growing
body of evidence of the safety and efficacy profile of TERN-501 and
its promise as a therapy to treat the multiple facets of this
disease.”
Terns plans to submit data from the DUET trial for presentation
at an upcoming scientific conference.
Investor Conference Call
Terns will host an update call for investors today, August 8,
2023, beginning at 4:30 p.m. ET. The webcast of the conference call
can be accessed here. A replay of the call will also be available
on the Events page of the Investor Relations section of the Terns
website for 30 days.
About the Phase 2a DUET Trial
The Phase 2a DUET trial (NCT05415722) is a multicenter,
randomized, double-blind, placebo-controlled clinical trial in
noncirrhotic NASH, designed to evaluate efficacy and safety of
TERN-501 as a monotherapy and in combination with TERN-101. The
trial enrolled over 160 adults with body mass index (BMI) ≥ 25
kg/m2 and pre-cirrhotic NASH identified based on prior liver biopsy
and/or imaging and clinical criteria. All participants had liver
fat content measured by magnetic resonance imaging proton density
fat fraction (MRI-PDFF) of ≥10%, MRI corrected T1 (cT1) relaxation
time of ≥ 800 msec and met other inclusion and exclusion criteria.
The trial included a 12-week treatment period and a 4-week
follow-up period. The primary endpoint was the relative change from
baseline in MRI-PDFF at Week 12 for TERN-501 monotherapy compared
to placebo. Secondary endpoints included assessments of relative
change from baseline in MRI-PDFF for TERN-501+TERN-101 combination
compared to placebo and change from baseline in cT1 for TERN-501
monotherapy compared to placebo as well as for TERN-501+TERN-101
combination therapy compared to placebo.
About TERN-501
TERN-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.
Preclinical studies have demonstrated that low-doses of TERN-501
achieved complete resolution of steatosis and reductions in serum
lipids and hepatic inflammation and fibrosis. TERN-501 is 23-fold
more selective for THR-β than for THR-α activation thereby
minimizing the risk of cardiotoxicity and other off-target effects
associated with non-selective THR stimulation. TERN-501 has been
designed to be metabolically stable and has demonstrated low
pharmacokinetic variability and potential for efficacy at 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 for TERN-501 for the treatment of NASH in June
2021.
About Non-alcoholic Steatohepatitis (NASH)
NASH is a severe form of non-alcoholic fatty liver disease
(NAFLD) that affects up to 20 million people in the United States,
and up to 5% of the global population, and for which there is
currently no approved therapy in the United States or Europe. In a
study published in Hepatology in 2018, lifetime costs of treating
and managing NASH patients in the United States in 2017 were
estimated to be over $220 billion, in the absence of approved
therapies. NASH is a multifaceted disease that involves three
distinct pathogenic hepatic disease processes: accumulation of
excess fat in the liver (steatosis), inflammation and fibrosis. In
addition to these three disease processes, NASH patients often
exhibit elevated levels of glucose and atherogenic lipids, are
overweight or obese and accumulate excessive lipotoxic fat. Severe
progression of NASH can lead to cirrhosis, decompensated liver
disease and increased risk for hepatic carcinoma and liver-related
mortality.
About Terns Pharmaceuticals
Terns Pharmaceuticals, Inc. is a clinical-stage
biopharmaceutical company developing a portfolio of small-molecule
product candidates to address serious diseases, including oncology,
NASH and obesity. Terns’ pipeline includes two clinical stage
development programs including an allosteric BCR-ABL inhibitor and
a THR-β agonist (+/- an FXR agonist), and preclinical
small-molecule GLP-1 receptor agonist and GIPR modulator programs.
For more information, please visit: www.ternspharma.com.
Cautionary Note Regarding Forward-Looking
Statements
This 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 clinical trials and other development activities of
the Company and its partners; the potential indications to be
targeted by the Company with its small-molecule product candidates;
the therapeutic potential of the Company’s small-molecule product
candidates; the potential for the mechanisms of action of the
Company’s product candidates to be therapeutic targets for their
targeted indications; the potential utility and progress of the
Company’s product candidates in their targeted indications,
including the clinical utility of the data from and the endpoints
used in the Company’s clinical trials; the Company’s clinical
development plans and activities, including the results of any
interactions with regulatory authorities on its programs; the
Company’s expectations regarding the profile of its product
candidates, including efficacy, tolerability, safety, metabolic
stability and pharmacokinetic profile and potential differentiation
as compared to other products or product candidates; the Company’s
plans for and ability to continue to execute on its current
development strategy, including potential combinations involving
multiple product candidates; the impact of new legislation and
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Contacts for Terns
InvestorsMark
Vignolainvestors@ternspharma.com
MediaJenna UrbanBerry & Company Public
Relationsmedia@ternspharma.com
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