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Tranzyme has discovered several first-in-class drugs to treat
gastrointestinal (GI) and metabolic diseases. Tranzyme’s lead
drugs are directed at modulating the ghrelin and motilin
receptors. These receptors are known to regulate
gastrointestinal motility, appetite and energy balance. The
Company’s lead product candidate, TZP-101, is an intravenous
ghrelin agonist with potent prokinetic properties. It is
currently in Phase IIb clinical trials for two distinct
indications: post-operative ileus and severe gastroparesis.
Tranzyme is also developing an oral ghrelin agonist, TZP-102, to
treat mild-to-moderate (chronic) gastroparesis and other functional
GI disorders. In addition to the ghrelin agonists, Tranzyme is
developing a motilin antagonist, TZP-201, for the treatment of
various forms of moderate-to-severe diarrhea, and a ghrelin
antagonist, TZP-301, for the treatment of obesity and metabolic
syndrome.
| Post-Operative Ileus (POI) |
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Post-operative ileus (POI) is the impairment of gastrointestinal
motility that routinely occurs after major abdominal surgery.
POI contributes significantly to post-operative morbidity,
prolonged hospitalization and increased health care costs. The
pathophysiology of POI is multifactorial, and its duration
correlates with the degree of surgical trauma. Morbidity related
to POI includes increased post-operative pain, increased nausea
and vomiting, delayed resumption of food intake, poor wound
healing, delayed post-operative mobilization, and increased risk
of other post-operative complications (e.g., pneumonia and
pulmonary embolism). POI is reportedly the most common cause of
delayed hospital discharge after abdominal surgery. In the
United States alone, it is estimated that 2.4 million patients
undergo open abdominal surgeries each year with a concomitant
high risk for POI. No treatments for POI have been approved by
the US Food and Drug Administration.
TZP-101 for POI
Tranzyme is developing TZP-101, a potent ghrelin agonist, for
the treatment of POI. In preclinical studies, TZP-101 has
demonstrated the ability to rapidly restore gastrointestinal
function impaired by surgery, opioids and high caloric meals. In
both single-dose and multi-dose Phase I human studies, TZP-101
has been demonstrated to be safe and well-tolerated in healthy
subjects.
A Phase IIb trial of TZP-101 for POI is now underway. This
multicenter, randomized, double-blind, placebo-controlled,
dose-ranging study will assess the efficacy and safety of
TZP-101 when administered as a 30-minute i.v.
infusion to patients undergoing major open abdominal
surgery. Tranzyme expects to have data available from this trial
in the first quarter of 2008.
| Gastroparesis |
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Gastroparesis is paralysis of the gastrointestinal tract
characterized by delayed gastric emptying in the absence of a
mechanical cause of obstruction. Disease severity ranges from
mild to moderate to severe. Symptoms include post-prandial
fullness, bloating, nausea, vomiting, and upper abdominal pain.
The most common etiologies of gastroparesis are diabetes (an
estimated 30% of gastroparesis patients), unknown etiology
(36%), and post-surgical causes (13%). The prevalence of
gastroparesis in the United States and globally is not known
precisely, but reports suggest that incidence of gastroparesis
is increasing with the growing worldwide incidence of diabetes
and obesity. Gastroparesis is a major complication of diabetes.
Studies indicate that approximately 25% of Type 1 diabetes
patients and 5% of Type 2 diabetes patients suffer from
gastroparesis – an estimated 13 million diabetic gastroparesis
patients worldwide, and 2 million in the US, according to the
World Health Organization (WHO).
Patients with mild gastroparesis are generally able to maintain
their weight and nutrition on a regular diet, and in most cases
symptoms can be easily controlled. In moderate cases, however,
patients may experience only partial symptomatic control through
diet and lifestyle modifications, and use of daily medications.
Hospital admissions can occur in mild-to-moderate cases,
although infrequently.
Severe gastroparesis, or gastroparesis with gastric failure, is
characterized by refractory symptoms that are not controlled
despite medical therapy. Patients suffering from severe
gastroparesis are often unable to maintain nutrition, or
medication via oral delivery. Because of their unremitting
symptoms, they may be dependent on gastric suctioning and
enteral/parenteral nutrition. Frequent physician visits,
emergency room visits, or hospitalizations often result from the
difficulties of managing and treating the disorder. In 2005,
there were approximately 150,000 hospitalizations in the United
States where gastroparesis was the primary or secondary
diagnosis.
No efficacious therapy for gastroparesis is available. Most
current drug treatments are only moderately effective at best,
and may cause neurological side effects. Metoclopramide, the
only drug approved by the FDA for gastroparesis, is associated
with unwanted adverse events that include extrapyramidal
reactions and tardive dyskinesia.
TZP-101 for severe gastroparesis
Tranzyme is developing TZP-101 (i.v.) for severe forms of
gastroparesis. In July 2007, TZP-101 received the FDA’s Fast
Track Designation for this indication. The Fast Track program
mandates the FDA to facilitate development and expedite review
of a drug intended to treat a serious or life-threatening
condition that demonstrates the potential to address an unmet
medical need.
Support for the fast track designation was based upon positive
data from Tranzyme’s Phase IIa clinical study of TZP-101 in
diabetic patients with severe gastroparesis, and from
preclinical studies demonstrating that TZP-101 has the potential
to address this unmet medical need. In the double-blind,
randomized, four-way crossover Phase IIa study, TZP-101
significantly accelerated gastric emptying and reduced the
symptoms of gastroparesis.
A severe gastroparesis Phase IIb trial of TZP-101 has been
initiated. This multicenter, randomized, double-blind,
placebo-controlled, dose-ranging study will assess the efficacy
and safety of TZP-101 when administered as a 30-minute i.v.
infusion to patients with severe gastroparesis. Tranzyme expects
to have data available from this trial in the first quarter of
2008.
TZP-102 for mild-to-moderate gastroparesis
Tranzyme is developing TZP-102, an orally available ghrelin
agonist for mild-to-moderate gastroparesis. The chronic nature
of gastroparesis (and gastroparesis stemming from other
etiologies) requires long-term oral medication. TZP-102 is
being developed to meet this need.
Tranzyme expects to file an IND for TZP-102 by December, 2007.
|
Moderate-to-Severe Diarrhea |
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Diarrhea is a serious side-effect
experienced by many cancer patients undergoing chemotherapy.
Chemotherapy agents have a broad spectrum of cell-killing
activity and often adversely affect the growth of normal cells
in the GI tract. Common chemotherapeutics such as irinotecan,
5-fluorouracil, oxaliplatin, capecitabine, and methotrexate
result in chemotherapy-induced diarrhea in 50-80% of patients.
TZP-201 for chemotherapy-induced diarrhea
TZP-201 is a potent motilin antagonist
being developed by Tranzyme for the treatment of various forms
of moderate-to-severe diarrhea. Promising applications for
TZP-201 include chemotherapy-induced diarrhea, diarrhea
associated with infection, and diarrhea associated with
irritable bowel syndrome.
Motilin is a gut hormone that mediates
digestive system motility by controlling the phasic contraction
of Migrating Motor Complexes (MMCs) throughout the GI tract.
High motilin levels have been shown to provoke upper gut
hypermotility, which can result in diarrhea.
TZP-201 has demonstrated excellent in
vitro and in vivo efficacy, exceptional selectivity
for the motilin receptor, significant reduction in pre- and
post-prandial MMC patterns in dog models with dose-dependent
activity in vivo at a dose as low as 0.1 mg/kg. TZP-201
has also proven to be efficacious in a dog model of
chemotherapy-induced diarrhea. It reduced the incidence of
diarrhea in dogs treated with irinotecan more effectively than
either of two current treatments, octreotide and loperamide.
TZP-201 also appeared to protect the GI tract, and reduced the
incidence of diarrhea upon repeat treatment with the
chemotherapeutic agent.
Tranzyme expects to file an IND for TZP-201 by the third quarter
of 2008.
|
Obesity & Metabolic Syndrome |
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Obesity and metabolic syndrome are considered to be major public
health crises in the US and globally. Both conditions are
significant causes of morbidity and mortality.
An expert panel convened by the National Institutes of Health
has defined overweight as a body mass index (BMI) of 25 to 29.9
kg/m˛, and obesity as a BMI of 30 kg/m˛ or greater.
According to the WHO, as of 2005 there were approximately 1.6
billion overweight adults globally, of whom at least 300 million
are clinically obese. Approximately two-thirds of US adults –
nearly 167 million - are overweight or obese. Nearly one-third
(31.4%) are obese, according to the National Institute of
Diabetes and Digestive and Kidney Diseases. The prevalence of
overweight and obesity in US adults has steadily increased over
the years among both genders, all ages, all racial and ethnic
groups, all educational levels, and all smoking levels.
Most studies show an increase in mortality rates associated with
obesity. Individuals who are obese have a 10-50% increased risk
of death from all causes, compared with healthy weight
individuals. Most of the increased risk is due to cardiovascular
causes. Obesity is associated with about 112,000 excess deaths
per year in the U.S. population relative to healthy weight
individuals.
Metabolic syndrome is a collection of unhealthy body measurements and abnormal
laboratory test results, which identify persons at
high risk for developing cardiovascular disease
and/or Type 2 diabetes. Aggressive lifestyle modification and
possible use of medications to treat the conditions
that make up metabolic syndrome may reduce a person's
chances of developing heart disease or stroke.
According to the Centers for Disease Control and Prevention, an
estimated 47 million Americans – nearly one-fourth of US adults
– have metabolic syndrome.
TZP-301 for obesity & metabolic syndrome
Tranzyme is developing TZP-301, a ghrelin antagonist for the
treatment of obesity and the metabolic syndrome.
Ghrelin is a gut hormone involved in the control of the body’s
energy expenditure — it stimulates appetite, weight gain, and
fat synthesis in rodent models. Transgenic rats in which the
ghrelin receptor has been knocked out have exhibited reduced
feeding, diminished fat deposition and decreased weight. By
measuring ghrelin levels in humans, researchers have shown that
ghrelin increases after fasting and decreases after a meal,
consistent with its role in stimulating feeding. Considering the
significant effects of ghrelin on feeding and weight gain, a
small molecule ghrelin antagonist would produce an effect of
food satiation.
A safe and effective ghrelin antagonist is considered to be a
leading approach to treating obesity. Building on Tranzyme’s
success and expertise in developing small molecule agonists of
the ghrelin receptor, ghrelin antagonists are a natural fit for
Tranzyme’s chemistry.
Tranzyme has identified ghrelin antagonist lead molecules with
potent binding and functional activity. Still in the lead
optimization stage, Tranzyme anticipates identifying a TZP-301
anti-obesity IND candidate by mid-2008.
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