Product Development Pipeline

Tranzyme has discovered first-in-class drugs to treat both acute care (hospital-based) and chronic indications with significant unmet medical need. Tranzyme's drug candidates are directed at modulating the ghrelin and motilin receptors. These receptors are known to regulate gastrointestinal (GI) motility, appetite and energy balance. The Company's lead product, TZP-101, is an intravenous ghrelin agonist with potent prokinetic properties. TZP-101 is being evaluated for acute gastric motility disorders such as postoperative ileus (POI) and acute, severe gastroparesis, and is poised to enter Phase 3 clinical trials for both indications in the near term. Tranzyme is also developing an oral ghrelin agonist, TZP-102, for the treatment of chronic gastrointestinal disorders; TZP-102 is currently being evaluated in a multinational Phase 2 study. 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.

TZP-101: GI Prokinetic in Acute Care (Hospital-Based) Setting

Postoperative Ileus (POI)

Postoperative ileus is a transient impairment of gastrointestinal motility following abdominal or other surgery and is often protracted and exacerbated by multiple factors including the use of opioids for pain management. Symptoms of POI can include abdominal pain and distention, nausea and vomiting, and inability to pass stools and tolerate a solid diet. Delays in resuming a normal diet may lead to poor healing and increased risk of infection through a cascade of events, and patients are at greater risk for pulmonary complications since POI may result in reduced patient mobility. POI is associated with an increased length of hospital stay and is the most common cause of delayed hospital discharge after abdominal surgery. In the United States alone, over 1 million patients undergo open abdominal surgery each year and are at high risk for POI. No unrestricted treatments for POI have been approved by the US Food and Drug Administration to date.

TZP-101, Tranzyme's intravenous ghrelin agonist, is a product developed from the Company's internal drug discovery efforts and is being evaluated clinically for the treatment of postoperative ileus (POI).

A multinational, double-blind, placebo-controlled Phase 2b clinical trial for POI has been successfully completed. The study was designed to assess the time to recovery of gastrointestinal (GI) function as defined by the time to first bowel movement (the study's primary endpoint). Study results demonstrated that TZP-101 was both safe and highly effective in reducing the duration of ileus following surgery in patients undergoing open bowel resection. In fact, for the primary endpoint, TZP-101 was superior to placebo at all doses tested, with the two most effective doses, showing a statistically significant difference.

Statistical significance was also achieved in the most effective doses in another important secondary endpoint, time to recovery of GI function as defined by the later of the first bowel movement and first solid food intake.

A multinational Phase 3 trial of TZP-101 for POI will begin in the near term.

Acute Severe Gastroparesis

In addition to POI, this intravenous ghrelin agonist, TZP-101, is being evaluated clinically for the treatment of severe gastroparesis in acute care settings. Severe gastroparesis, or gastroparesis with gastric failure, is characterized by symptoms that are not controlled despite medical therapy. Patients suffering from severe gastroparesis are often unable to maintain nutrition, or tolerate 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 acute escalation of symptoms and the difficulties of managing and treating the disorder. In 2006, there were over 180,000 hospitalizations in the United States where gastroparesis was the primary or secondary discharge diagnosis.

No efficacious therapy for gastroparesis is available. Most current drug treatments are moderately effective at best, and may cause neurologic side effects. Metoclopramide, the only drug approved by the FDA for gastroparesis, is associated with side effects that include extrapyramidal reactions and tardive dyskinesia, resulting in an FDA-mandated black box warning due to these safety concerns.

The safety and pharmacokinetic profiles of TZP-101 have been extensively characterized in healthy subjects across multiple dose levels, and the prokinetic properties of the compound have been well established in various animal models, with or without concomitant opioids. In a double-blind, randomized, four-way crossover Phase 2a study, TZP-101 significantly accelerated gastric emptying and reduced the symptoms of gastroparesis.

In a multinational, double-blind, placebo-controlled Phase 2b study, TZP-101 demonstrated symptom improvement in as little as 4 days, and at the end of dosing, showed statistically significant symptom improvement with its best dose over placebo for vomiting, loss of appetite, nausea and postprandial fullness. In addition, TZP-101 had a sustained effect on vomiting for 30 days and a reduction in hospitalizations due to gastroparesis during a 30-day follow-up period.

A multinational Phase 3 trial of TZP-101 for gastroparesis in acute settings will begin in the near term.

Gastric Stasis and Feed Intolerance in the Critical Care Setting

The well-established safety and prokinetic properties of TZP-101 make this product an ideal candidate to be studied for the treatment of gastric stasis and feed intolerance in the critical care setting. Because TZP-101 is administered intravenously, it could be an important therapeutic option for patients in the critical care setting who are suffering from gastrointestinal dysmotility but cannot take medication orally due to vomiting, sedation, breathing tubes, etc. Gastrointestinal dysmotility is a major complication in critically ill patients often manifesting as gastric stasis (delayed gastric emptying) when the propulsive activities of the stomach and GI tract are compromised and food remains in the stomach. This can result in a patient’s inability to tolerate the delivery (feed intolerance) of gastric enteral nutrition, considered a best practice in critical care patients. In the US alone, feed intolerance affects more than half of the 5.5 million critical care patients admitted annually, occurring most frequently in patients with multiple trauma, burns, and severe sepsis. Feed intolerant patients are at increased risk for aspiration and the development of other sequelae including GI bleeding, sepsis, ventilator-associated pneumonia and multi-organ failure, all of which contribute to prolonged stay in the critical care unit (CCU) and increases in morbidity and mortality.

Prokinetic agents are considered first-line therapy for gastric stasis and feed intolerance; however, currently available prokinetic drugs have major limitations including limited efficacy, side effects and drug interactions.

TZP-102: Oral GI Prokinetic Applications

Chronic Gastroparesis

Gastroparesis, a chronic and often progressive disorder, is an impairment or paralysis of upper gastrointestinal tract function characterized by delayed gastric emptying in the absence of mechanical obstruction. Symptoms of gastroparesis include post-prandial fullness, early satiety, abdominal pain, nausea, vomiting, and weight loss. Disease severity ranges from mild to severe. Gastroparesis is a major complication of diabetes leading to metabolic imbalance when liquid and food intake and absorption of oral medications are impaired. Improved glucose control in patients with diabetes may be achieved by better regulation of gastric emptying as well. Debilitating chronic symptoms impact quality of life including physical functioning, pain, vitality, social functioning and increase the risk of chronic malnutrition, dehydration and weight loss.

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 (2 million in the US) according to the World Health Organization (WHO). Gastroparesis may also result from abdominal surgery, other medical conditions such as autoimmune diseases or be idiopathic in nature. Current medications for the treatment of gastroparesis are only moderately effective and many are associated with neurologic side effects. It is estimated that over 5 million patients suffer from gastroparesis in the United States.

Patients with mild to moderate gastroparesis may generally be able to control their symptoms through diet and lifestyle modifications, and use of daily medications, while patients with more progressive disease may realize partial or no symptom control. For the most severe forms of gastroparesis, symptoms may cycle in a pattern of flare-ups that may necessitate hospital admission.

Tranzyme is developing TZP-102, an orally administered ghrelin agonist for the management of chronic gastroparesis requiring long-term medication for symptom management, and to reduce/avoid severe exacerbations of symptoms where acute care and/or hospital admission becomes necessary.

In studies, TZP-102 has demonstrated strong prokinetic properties. Excellent animal efficacy and preclinical safety have been established. TZP-102 has also been shown to be safe and well-tolerated in healthy volunteers.

A multinational Phase 2 trial of TZP-102 for chronic gastroparesis in diabetic patients is ongoing.

Other Clinical Applications for Prokinetic Agents

Prokinetic agents play a valuable role in the management of gastrointestinal symptoms that present across a spectrum of medical conditions including gastroesophageal reflux disease (GERD), functional dyspepsia, opioid bowel dysfunction (OBD), and cancer-chemotherapy associated dyspepsia syndrome. Studies have also demonstrated that gastric motility dysfunction can occur following pancreatic surgery and organ transplant, in patients with chronic liver disease, chronic renal diseases, and cystic fibrosis, among a host of other medical conditions.

In the Western population, GERD is considered the most common digestive disease affecting between 10-20% of the population. Proton-pump inhibitors (PPIs), which are considered first-line therapy for the treatment of GERD, fail in up to one-third of PPI users. Prokinetic agents are considered a valuable tool in the treatment of GERD. The withdrawal from the market of prokinetic agents cisapride (Propulsid™) and tegaserod (Zelnorm™), both 5HT4 receptor blockers, due to serious cardiac adverse events however have left practitioners with few treatment options.

TZP-201

Chemotherapy-Induced Diarrhea (CID)

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 gastrointestinal tract. Certain chemotherapeutic agents such as irinotecan and 5-fluorouracil are associated with rates of chemotherapy-induced diarrhea (CID) as high as 80%. Diarrhea is also known to occur with methotrexate, taxanes, monoclonal antibodies and abdominal or pelvic radiotherapy. It is estimated that as many as 50% of patients who endure this side effect experience severe diarrhea which can require chemotherapy dose reductions, changes in chemotherapy regimen or discontinuation of chemotherapy, all of which can negatively impact treatment outcomes. Mild to moderate CID is customarily managed through diet and with anti-diarrheal agents, however, limited effective treatment options exist for severe CID. CID also leads to increased mortality, risk of infectious complications and increased morbidity.

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 (CID), 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 gastrointestinal (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 reduce the incidence of diarrhea upon repeat treatment with the chemotherapeutic agent.

Tranzyme expects to file an IND for TZP-201 in the next several months.

TZP-301

Obesity & Metabolic Syndrome

Obesity and metabolic syndrome are considered major global public health crises and their prevalence continues to rise. Both conditions are significant causes of morbidity and mortality. Obesity is associated with about 112,000 excess deaths per year in the US population relative to healthy weight individuals.

According to the WHO, as of 2005 there were approximately 1.6 billion overweight adults globally, of whom at least 300 million were clinically obese. Approximately two-thirds of US adults, nearly 167 million, are overweight or obese.

Metabolic syndrome is a collection of metabolic and cardiovascular risk factors, (e.g., abdominal obesity, elevated blood pressure, dyslipidemia, impaired fasting glucose), which identify persons at high risk for developing cardiovascular disease and/or Type 2 diabetes. The more risk factors a person has, the greater their chances of developing heart disease, diabetes, or a stroke. In general, a person with metabolic syndrome is twice as likely to develop heart disease and five times as likely to develop diabetes as someone without metabolic syndrome. 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 with an additional 30% of obese adults at risk for developing it.

Tranzyme is developing TZP-301, a ghrelin antagonist for the treatment of obesity and metabolic syndrome.

Ghrelin is a gut hormone involved in the control of the body's energy expenditure — it has been shown to stimulate appetite, cause weight gain, and impact fat synthesis in rodent models. Rodents where 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 regulating feeding. Considering the significant effects of ghrelin on feeding and weight gain, a small molecule ghrelin antagonist could 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. Tranzyme anticipates identifying a TZP-301 anti-obesity IND candidate in the near future.