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CLINICAL PROGRAMS
Obesity is a
complex multifactorial chronic disorder characterized by the
accumulation of adipose tissue. Obesity and overweight are
associated with an increased risk of developing co-morbid conditions
including hypertension, dyslipidemia, type 2 diabetes, coronary
artery disease, stroke, osteoarthritis, sleep apnea, respiratory
diseases, and malignancies of the breast, endometrium, prostate and
colon. Increased consumption of energy-dense, nutrient-poor foods
combined with lower levels of physical activity has led to a
worldwide epidemic of obesity. The World Health Organization (WHO)
estimates that at least 300 million people worldwide are obese.
Obesity is defined by a body mass index (BMI) of ≥ 30 kg/m2. The
prevalence of overweight is substantially more common and is defined
as a BMI of 25 to 29.9 kg/m2.
The treatment of
obesity depends upon the clinical assessment of an affected
individual taking into account the presence of co-morbid conditions
and patient motivation to lose weight. Dietary, behavioral and
lifestyle modifications are generally recommended to facilitate
weight loss. In many cases the addition of a pharmacological agent
is required to induce weight loss. Six agents are currently approved
by the FDA for the treatment of obesity. Although these drugs are
generally well tolerated, their efficacy is modest. Because of the
rising incidence and health burden of obesity, more effective
therapies for weight loss are urgently needed.
THR-4109 is
composed of two drugs from different classes that have been approved
for other indications. The two drugs have well-understood
side-effect profiles and have proven to be safe in clinical use. The
clinical use of combination therapy with drugs from the two classes
is common in certain patient populations, and appears to be safe and
well tolerated. Initial results from a physician-initiated study
indicate that the combination therapy may have a significant effect
on weight loss. In a small uncontrolled study of nine obese and
overweight subjects, the experimental treatment resulted in an
average 11% loss of body weight over 7½ months of follow-up.
In August 2007 Theracos initiated a
Phase II clinical trial to study
the safety and effect of THR-4109 on weight loss in obese subjects
over a 24-week treatment period. The multinational trial is a randomized,
double-blind, placebo-controlled study with a planned enrollment of 220
subjects at up to 20 investigational sites in Europe.
DIABETES - THR-0921
In 2002,
approximately 5-6% of the U.S. population was afflicted with type 2
diabetes. Worldwide over 150 million people have the disease, and
this number is projected to reach 300 million by 2025. Type 2
diabetes is a chronic metabolic disorder characterized by increased
serum glucose (hyperglycemia) due to impaired insulin action and
insufficient insulin secretion to overcome the pathological
resistance to insulin. Many type 2 diabetics also have abnormally
elevated blood lipid concentrations (dyslipidemia). Currently five
classes of oral anti-hyperglycemia drugs are available. These
include sulfonylureas, biguanides, glucosidase inhibitors,
thiazolidinediones (TZDs), and meglitinides. Often, patients take
two or more of these drugs in combination, and even then, their
glucose concentrations and blood lipids may be poorly controlled or
they may suffer from dangerous adverse effects such as hypoglycemia
and agent specific toxicities (e.g. lactic acidosis, hepatic
toxicity).
TZD drugs are
agonists of the peroxisome proliferator activated receptor-gamma (PPAR-γ).
PPARs are ligand-activated nuclear transcription factors that exist
in three isoforms: alpha (PPAR-α), gamma (PPAR-γ) and delta (PPAR-δ).
PPAR-γ is highly expressed in adipose tissue, whereas PPAR-α is
expressed in liver, skeletal tissue and macrophages. Despite their
similar mechanisms of action, the TZDs that have been approved for
marketing in the United States have distinguishable pharmacological
profiles, leading to variations in safety and efficacy. The
differences in the actions of the existing TZDs has suggested that
new drugs in this class might be developed that have lower liability
for the known adverse effects associated with the existing marketed
compounds.
THR-0921 is a TZD
analog of an earlier drug candidate that had been developed from a
natural product source. THR-0921 is a prototype of a new class of
unconventional TZDs, which have glucose-lowering activity in vivo
that greatly exceeds the activity predicted by in vitro measures of
PPAR agonism. In vitro, THR-0921 is a weak PPAR agonist, and is less
adipogenic than the marketed TZD rosiglitazone. In rodent models of
type 2 diabetes, THR-0921 showed strong antihyperglycemic activity,
exhibiting equipotency at blood glucose lowering with marketed TZDs.
In vivo studies have demonstrated that THR-0921 also lowers
triglyceride levels in diabetic animals. A Phase I/II clinical trial
of THR-0921 has been completed and showed that the drug was safe and
well tolerated in normal subjects and patients with type 2 diabetes.
Based upon the preclinical data and early clinical data obtained to
date, Theracos believes that THR-0921 has the potential to offer a
significant improvement over earlier TZD compounds with respect to
potential side effects.
PRECLINICAL
PROGRAMS
THR-4218
Oral anti-obesity
agent.
In the course of
the conduct of preclinical studies to support THR-4109, Theracos has
identified additional compounds with a novel mechanism of action and
unusually potent activity. These compounds appear to act through a
central satiety circuit that is poorly understood at present.
THR-4218 appears to have no major toxicological liabilities or side
effects in preclinical studies.
THR-5XXX
Oral anti-diabetic
agent.
In partnership with
Egret Pharma Shanghai Ltd and BioFocus DPI,
Inc., Theracos has created highly active compounds with excellent
metabolic stability and a favorable toxicity profile.
THR-090717
Orally available
TNF-alpha inhibitor.
THR-090717
has good in vivo potency and a high NOAEL in rodents.
THR-0940
Oral anti-diabetic
agent.
THR-0940 is
an insulin sensitizer with a different profile from THR-0921.
THR-0100
Oral anti-diabetic
agent.
THR-0100 is
an orally-active, glucose-lowering principle from the bitter melon
Momordica charantia that has an undefined mechanism of
action. The glucose-lowering activity is robust and the compound, a
linear peptide, has an excellent preclinical safety profile.
Clinical studies carried out on unfractionated Momordica
extracts have demonstrated a statistically significant reduction in
blood glucose following an oral glucose tolerance test in newly
diagnosed type 2 diabetics.
Welihinda J, et al. Effect of Momordica charantia on the glucose
tolerance in maturity onset diabetes. J Ethnopharmacol
1986;17:277-82.
THR-3608
Third generation
antidepressant.
THR-3608 is a
combination medication based on augmentation of existing therapeutic
pathways with novel anti-depressant actions. THR-3608 is expected to
be dosed as a fixed formulation consisting of one novel and one
existing agent.
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