Phase 1 data confirm the safety of TLC-6740,
dose-dependent increases in energy expenditure, and improvements in
plasma lipids and markers of insulin resistance
Preclinical data confirm increased energy
expenditure and weight loss with TLC-6740, and the potential of
combination treatment with GLP-1 receptor agonists and the
company’s ACC2 inhibitor TLC-3595
OrsoBio, Inc., a clinical-stage biopharmaceutical company
developing treatments for obesity and obesity-associated disorders,
today announced new data for liver-targeted mitochondrial
protonophore TLC-6740 being presented at the 84th Scientific
Sessions of the American Diabetes Association being held June
21-24, 2024, in Orlando, Fla. The company will present three
abstracts sharing new data demonstrating the safety and preliminary
efficacy of its mitochondrial protonophore, TLC-6740, in healthy
humans, and preclinical data highlighting weight loss driven by
increased energy expenditure and improved glycemic control in mouse
models following monotherapy and combinations with the selective
ACC2 inhibitor, TLC-3595, and a GLP-1 receptor agonist.
“Our Phase 1 data illustrate the potential of our liver-targeted
mitochondrial protonophore, TLC-6740, to enable safe increases in
energy expenditure, metabolic benefits, and to promote weight loss
in people living with obesity,” said Rob Myers, MD, Chief Medical
Officer of OrsoBio. “In light of our new clinical and preclinical
data, we look forward to advancing TLC-6740 to treat obesity and
its comorbidities, including in combination with GLP-1 receptor
agonists.”
Increasing cellular energy expenditure by mitochondrial
uncoupling is a validated approach to weight loss. By targeting the
liver—a key organ governing whole-body energy metabolism—TLC-6740
has demonstrated substantial weight loss in rodents driven by
increased energy expenditure and fat oxidation. These new Phase 1
data confirm the safety of TLC-6740 in humans and demonstrate
clinically relevant increases in energy expenditure, utilization of
fat for energy, and multiple metabolic benefits, including
improvements in LDL cholesterol, total cholesterol, markers of
insulin resistance, and liver biochemistry. Further, data from
preclinical models of diabetes suggest that combining TLC-6740 and
drugs with complementary mechanisms, including the ACC2 inhibitor,
TLC-3595, and the GLP-1 receptor agonist, semaglutide, can have
additive benefits on insulin resistance.
“With the growing burden of obesity-related disorders, it’s
critical that new, safe, effective therapies be developed to
complement existing medications, such as GLP-1 receptor agonists,”
said Gerald Shulman, MD, PhD, MACP, MACE, FRCP, the George R.
Cowgill Professor of Medicine and Professor of Cellular and
Molecular Physiology at Yale School of Medicine, Co-Director of the
Yale Diabetes Research Center, and scientific advisor to OrsoBio.
“These human and preclinical data highlight the promise of TLC-6740
to promote healthy weight loss by driving increased energy
expenditure and fat oxidation, and directly address the root cause
of insulin resistance, which drives many of the complications of
obesity.”
ADA Presentation Details
Abstract #1186-LB: Safety, PK and preliminary efficacy
of the liver-targeted mitochondrial protonophore TLC-6740: A Phase
1 study Late-Breaking Poster Session: Saturday, June 22,
2024 (12:30 – 1:30 p.m.)
This randomized, double-blind Phase 1 trial (NCT05822544) was
designed to evaluate the safety, tolerability, PK, and
pharmacodynamics of single and multiple ascending doses of TLC-6740
(3-120 mg) in healthy subjects. OrsoBio previously presented data
from the SAD cohorts at ObesityWeek® 2023, and new data from MAD
cohorts confirmed the safety of TLC-6740 administered for 10 days.
All TLC-6740-related adverse events were mild, and there were no
drug-related discontinuations, lab abnormalities, or temperature
increases. The PK profile of TLC-6740 includes a prolonged
half-life (18 to 33 hours), supporting once-daily, oral dosing. In
addition, indirect calorimetry demonstrated significant,
dose-dependent increases in resting energy expenditure and
reductions in respiratory quotient (RQ), indicating a preference
for oxidation of fat for energy, with TLC-6740 treatment. Finally,
TLC-6740 caused dose-dependent improvements in serum total and LDL
cholesterol, markers of insulin resistance, and liver
biochemistry.
Abstract #899-P: Combinations of the mitochondrial
protonophore TLC-6740 and/or the ACC2 inhibitor TLC-3595 provide
additive glycemic benefits to semaglutide (SEMA) in db/db mice
Poster Session: Sunday, June 23, 2024 (12:30 – 1:30
p.m.)
This preclinical study assessed the effects of TLC-6740,
TLC-3595, and semaglutide in the db/db mouse model of diabetes.
Mice were treated with these compounds as monotherapy, or a
combination of either two or three of these agents, and fasting
blood glucose (FBG), HbA1c, and glucose during an oral glucose
tolerance test were measured. All groups saw reductions in FBG and
HbA1c; the greatest reductions were observed in groups treated with
combination therapy. Both TLC-6740 and TLC-3595 improved glycemic
parameters as monotherapy and had additive benefits when combined
with each other and semaglutide. These data provide evidence to
support the continued evaluation of TLC-6740 and TLC-3595 as
monotherapy and in combination with GLP-1 receptor agonists as
potential treatments for type 2 diabetes.
Abstract #1637-P: TLC-6740, a liver-targeted
mitochondrial protonophore, increases energy expenditure and lipid
utilization in obese mice Poster Session: Monday, June
24, 2024 (12:30 – 1:30 p.m.)
This preclinical study evaluated mechanisms of weight loss with
TLC-6740 treatment in diet-induced obese (DIO) mice. Body weight
and energy (food) intake were monitored, and energy expenditure was
measured by indirect calorimetry. The data showed that TLC-6740
increased energy expenditure by ~20%, without altering food intake,
thereby inducing a negative energy balance, and causing weight
loss. In addition, TLC-6740 decreased RQ, indicating increased fat
oxidation, consistent with data observed in the Phase 1 human
study, and supporting continued development of TLC-6740 for the
treatment of obesity.
About TLC-6740
TLC-6740 is a novel, oral, liver-targeted mitochondrial
protonophore in development for the treatment of obesity and
obesity-associated diseases, including diabetes and MASH. Based on
active hepatic uptake and mitochondrial protonophore activity,
TLC-6740 increases energy expenditure in hepatocytes, and is
expected to have broad, systemic metabolic and cardiovascular
benefits, including weight loss, and improved insulin sensitivity,
MASH, and dyslipidemia. TLC-6740 is currently being evaluated in a
12-week, Phase 1b clinical trial in patients living with obesity
(NCT05822544).
About TLC-3595 and ACC2 Inhibition
TLC-3595 is a novel and selective ACC2 inhibitor designed to
treat type 2 diabetes by increasing fatty acid oxidation (FAO),
reducing ectopic lipid accumulation, and improving insulin
sensitivity in skeletal muscle and liver. The compound may also
have potential as a treatment for other conditions characterized by
impaired FAO, including cirrhosis with myosteatosis-associated
sarcopenia and MASH. TLC-3595 is currently being evaluated in a
12-week, Phase 2a clinical trial in patients with insulin
resistance and type 2 diabetes (NCT05665751).
About OrsoBio, Inc.
OrsoBio, Inc. is a privately held, clinical-stage
biopharmaceutical company dedicated to developing therapies to
treat obesity and obesity-associated disorders, including type 2
diabetes, MASH, and severe dyslipidemias. OrsoBio currently has
four programs in clinical and preclinical development with
first-in-class compounds that address central pathways in energy
metabolism. For more information, please visit www.orsobio.com.
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