In the Pipeline
The following table summarizes the development status of AMITIZA® and our key product candidates. We currently hold all of the commercialization rights to the prostone compounds in our product pipeline, other than for commercialization fo AMITIZA in the United States and Canada, which is covered by our collaboration and license agreement with Takeda.
To learn more about a particular indication, please click on its name in the table below.
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| Product Candidate | |
Target Indication | Development Phase | Next Milestone | ||||
| AMITIZA® (lubiprostone) | |
Chronic idiopathic constipation (adult) | Marketed in the U.S. | |||||
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Marketing Authorization Application submitted in nine European countries | Regulatory action by the European countries | ||||||
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| Phase IIb dose-ranging study in Japan ongoing | Phase III program in Japan | |||||||
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Chronic idiopathic constipation in pediatric patients |
Phase IV pediatric ongoing | |||||||
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| Renal impairment | Phase IV trial completed | |||||||
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| Hepatic impairment | Phase IV trial ongoing | |||||||
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| Irritable bowel syndrome with constipation | Approved for Marketing in the U.S. | Product Launch Scheduled During DDW; Full Scale Launch Scheduled before end of 2nd quarter 2008. | ||||||
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Opioid-induced bowel dysfunction | Phase III pivotal trials ongoing | Filing of NDA or supplemental NDA with FDA | |||||
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| Product Candidate | |
Target Indication | Development Phase | Next Milestone | ||||
| Cobiprostone | |
Gastrointestinal |
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Non-steroidal anti-
inflammatory drug (NSAID) induced ulcers |
Phase II trial ongoing | Phase II dose-ranging trial planned to commence in 2009 | |||||
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Cystic fibrosis gastrointestinal disorder (oral formulation) |
Phase II trial completed | Phase II dose-ranging trial planned to commence in 2009 | |||||
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| Liver |
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| Portal hypertension | Phase II proof-of-concept study planned to commence in 2008 | Phase II dose-ranging trial planned to commence in 2009 | ||||||
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| Non-alcoholic fatty liver disease | Phase II trial completed | Pending availability of new diagnostic tool | ||||||
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| Pulmonary |
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| Cystic fibrosis - respiratory symptoms (inhaled formulation) | Preclinical | Finalize inhaled formulation | ||||||
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| Chronic obstructive pulmonary disease | Preclinical | Finalize inhaled formulation | ||||||
| Product Candidate | |
Target Indication | Development Phase | Next Milestone | ||||
| SPI-017 | |
Peripheral arterial and vascular disease | Preclinical | Phase I trials of intravenous formulation planned to commence in 2008* | ||||
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Stroke | Preclinical | Phase I trials of intravenous formulation planned to commence in 2008* | |||||
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| Alzheimer's disease | Preclinical | Phase I trials of oral formulation planned to commence in 2009* | ||||||
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* Results from Phase I trials of both intravenous and oral formulations may be useful in development of any of these indications.
Additionally, we have recently initiated pharmacologic studies on six additional preclinical prostone compounds, including two combination candidates, as we focus on development and commercialization of therapies for age-related diseases.
Chronic Idiopathic Constipation
Constipation is characterized by infrequent and difficult passage of stool and becomes chronic when a patient suffers specified symptoms for the last 3 months with symptom onset at least 6 months prior to diagnosis. Chronic constipation is idiopathic if it is not caused by other diseases or by use of medications. Symptoms of chronic idiopathic constipation include straining, hard stools, bloating and abdominal pain or discomfort. Factors contributing to the development of chronic idiopathic constipation include a diet low in soluble and insoluble fiber, inadequate exercise, bowel disorders and poor abdominal pressure and muscular weakness.
Studies published in The American Journal of Gastroenterology estimate that approximately 42 million people in the United States suffer from constipation. Based on these studies, we estimate that approximately 12 million people can be characterized as suffering from chronic idiopathic constipation. In an additional study published in The American Journal of Gastroenterology, 91% of physicians expressed a desire for better treatment options for constipation.
As published in the Journal of Pediatric Gastroenterology and Nutrition and the American Family Physician, constipation in children, while in a small number of cases may be due to organic causes, is most commonly due to a functional cause manifested as chronic idiopathic constipation, functional fecal retention, and/or fecal incontinence, and is responsible for 3-5% of pediatric outpatient visits and 25% of pediatric gastroenterology consultations. Constipation in children has similar characteristics to that of constipation in adults in that symptoms include infrequent bowel movements, hard stools, and painful passage of stools. Children may also experience fecal retention due to withholding.
Irritable Bowel Syndrome with Constipation
Irritable bowel syndrome is a disorder of the intestines with symptoms that include severe cramping, pain, bloating and extreme changes of bowel habits, such as diarrhea or constipation. Patients diagnosed with irritable bowel syndrome are commonly classified as having one of three forms: irritable bowel syndrome with constipation, irritable bowel syndrome with diarrhea, or mixed-pattern irritable bowel syndrome alternating between constipation and diarrhea. Currently, irritable bowel syndrome in all its forms is considered to be one of the most common gastrointestinal disorders
According to the American College of Gastroenterology, irritable bowel syndrome affects approximately 58 million people in the United States, and irritable bowel syndrome with constipation accounts for approximately one-third of these cases.
Opioid-induced bowel dysfunction comprises a variety of gastrointestinal side effects stemming from the use of narcotic medications such as morphine and codeine, which are referred to as opioids. Physicians prescribe opioids for patients with advanced medical illnesses, such as cancer and AIDS, patients undergoing surgery and patients who experience chronic pain. Despite their pain-relieving effectiveness, opioids are known to produce gastrointestinal effects that lead to constipation, including inhibition of large intestine motility, decreased gastric emptying and hard stools.
According to the American Pain Foundation, over 50 million Americans suffer from chronic pain, and nearly 25 million Americans experience acute pain each year due to injuries or surgery. Opioid pain relievers are widely prescribed for these patients, many of whom also develop opioid-induced constipation
Lubiprostone Effects in Patients with Hepatic Impairment
Millions of people in the U.S. are affected by liver disease or related illnesses that result in hepatic impairment. The liver is involved in the clearance of many drugs and drug metabolites through a variety of metabolic and excretion pathways. Hepatic impairment alters these pathways, which may lead to increases and/or accumulation of drug levels in the body. Current literature indicates that liver dysfunction, by altering the absorption and disposition of drugs, may also change their efficacy and safety profile compared with non-impaired patients. Clinical studies in patients with hepatic impairment provide important information that can help guide initial dosing and dosage adjustment in patients with impaired liver function.
Lubiprostone Effects in Patients with Renal Impairment
Impaired kidney function, or renal impairment, is a widespread condition in which the kidneys steadily lose their ability to clear waste from the bloodstream. The most obvious type of change arising from renal impairment is a decrease in renal excretion and/or metabolism of a drug and/or its metabolites. Renal impairment is also associated with changes in drug absorption, plasma protein binding, drug distribution, as well as metabolism of drugs by the liver. All of these changes can result in altered drug efficacy and safety, even when the kidneys are not the primary route of drug elimination. Therefore, clinical studies in patients with renal impairment provide important information that can be used to help guide initial dosing and dosage adjustment in patients with impaired renal function.
Non-Steroidal Anti-Inflammatory Drug-Induced Ulcers
NSAIDs, such as aspirin and ibuprofen, are among the most commonly prescribed drugs worldwide. They are used to treat common medical conditions, such as arthritis, headaches and fever. In addition, with the recent withdrawal from the marketplace of the COX-2 inhibitors Vioxx® (rofecoxib) and Bextra® (valdecoxib), which were widely prescribed for arthritis patients, an increased number of these patients are returning to NSAID therapy. However, gastrointestinal symptoms, such as gastric, or stomach, ulcers and bleeding, are major limiting side effects of long-term NSAID use.
According to a study published in Postgraduate Medicine, approximately 13 million patients in the United States are regular users of NSAIDs. According to the American Chronic Pain Association, as many as 20% of patients who take NSAIDs daily may develop gastric ulcers. We believe that many patients treated with NSAIDs are not prescribed preventative treatment for gastric ulcers due to a combination of high cost, side effects and lack of a well established standard of care.
Portal hypertension is the build-up of pressure in the portal vein connecting the intestines and the liver and is caused by a narrowing of the blood vessel as a result of liver cirrhosis. Increased pressure in the portal vein can lead to the development of large, swollen veins in the esophagus, stomach and rectum which, if ruptured, can result in potentially life-threatening blood loss. According to a physician survey conducted by MEDACorp, an independent strategic consulting firm focused on the health care sector approximately 4.0 million Americans suffer from liver cirrhosis, with approximately 1.5 million of those individuals also diagnosed with portal hypertension.
Non-Alcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease is characterized by elevations of specific liver enzymes in the absence of excessive alcohol intake or other chronic liver diseases. Although all levels of non-alcoholic fatty liver disease lead to fat accumulation in the liver, the more advanced versions of this disease, known as Type 3 and Type 4 non-alcoholic fatty liver disease, also involve fibrosis and greatly increase the risk of progressive liver disease, cirrhosis and liver-related death. There is currently no treatment available for non-alcoholic fatty liver disease and the market size is unknown. According to the National Institute of Diabetes and Digestive and Kidney Diseases, a division of the National Institutes of Health, approximately 10% to 20% of Americans are affected by fat in the liver, and this condition is becoming more common, possibly due to the greater number of Americans with obesity.
Cystic fibrosis is a congenital disease that usually develops during childhood. The gene product responsible for cystic fibrosis is a protein called the cystic fibrosis transmembrane conductance regulator, or CFTR. CFTR is found in cells lining the internal surfaces of the lungs, salivary glands, pancreas, sweat glands, intestine and reproductive organs and acts as a channel transporting chloride ions out of the cell. Cystic fibrosis is caused by a defect in the CFTR protein, which prevents the transport of chloride ions between cells, causing the body to develop thick, sticky mucus in the lungs, pancreas and liver. Although development of pulmonary infection and chronic obstructive pulmonary disease (COPD) are the primary causes of morbidity and mortality in CF patients, the development of liver disease and other GI effects has become an increasing risk as the life expectancy of CF patients is extended by improvements in available therapeutic treatments for the disease. According to the Cystic Fibrosis Foundation, cystic fibrosis currently affects approximately 30,000 people in the United States and is usually diagnosed in infants and children.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is characterized by the progressive development of airflow limitation in the lungs that is not fully reversible and encompasses chronic bronchitis and emphysema. According to the National Heart, Lung and Blood Institute, or the NHLBI, a division of the National Institutes of Health, approximately 12 million adults 25 years of age or older in the United States are diagnosed with chronic obstructive pulmonary disease. The NHLBI further estimates that approximately 24 million adults in the United States have evidence of impaired lung function, indicating in their view that this disease is underdiagnosed.
Peripheral Arterial and Vascular Disease
Peripheral arterial disease, which also is sometimes referred to as peripheral vascular disease, is a chronic condition that results from narrowing of the vessels that supply blood to the stomach, kidneys, arms, legs and feet. Peripheral arterial disease is caused by the build-up of fatty deposits, or plaque, in the inner walls of the arteries as a result of a vascular condition known as atherosclerosis. This build-up of plaque restricts the flow of blood throughout the body, particularly in the arms and legs, and can lead to painful cramping and fatigue after exercise. The American Heart Association estimates that peripheral arterial disease affects as many as 8 million to 12 million people in the United States.
Alzheimer's disease is a chronic debilitating disease, with patients suffering from a progressive dementia over a number of years, ultimately resulting in severe incapacitation and a shortened lifespan. According to the Alzheimer's Association, there are approximately 4.5 million Alzheimer's disease patients in the United States.
Products and Product Candidates
AMITIZA® (Lubiprostone)
We are developing AMITIZA for the treatment of multiple constipation-related gastrointestinal disorders. AMITIZA functions as a selective activator of the ClC-2 chloride channel through which negatively charged chloride ions flow out of the cells lining the small intestine and into the intestinal cavity. As these negatively charged chloride ions enter the intestine, positively charged sodium ions move through spaces between the cells into the intestine to balance the negative charge of the chloride ions. As these sodium ions move into the intestine, water is also allowed to pass into the intestine through these spaces between the cells. We believe that this movement of water into the small intestine promotes increased fluid content, which in turn softens the stool and facilitates its movement, or motility, through the intestine.
Cobiprostone
We are developing the prostone compound Cobiprostone for oral administration to treat various gastrointestinal and liver disorders, including NSAID-induced ulcers, non-alcoholic fatty liver disease and portal hypertension. We also plan to develop an inhaled formulation of Cobiprostone for the treatment of respiratory disorders, such as cystic fibrosis and chronic obstructive pulmonary disease. We believe that Cobiprostone, like AMITIZA, is an activator of the chloride ion channel ClC-2, which is known to be present in gastrointestinal, liver and lung cells.
SPI-017
We are conducting preclinical development of SPI-017 for the treatment of peripheral arterial and vascular disease and central nervous system disorders. Initially, we are working on the development of an intravenous formulation of SPI-017 for the treatment of peripheral arterial disease. We also are developing an oral formulation of SPI-017 for the treatment of Alzheimer's disease.