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Predix Pharmaceuticals Initiates Phase I Clinical Trial of 5-HT2B Receptor Antagonist for Pulmonary Hypertension
Woburn, MA and Ramat Gan, Israel, May 3, 2005 – Predix Pharmaceuticals, a drug discovery and development company, today announced the initiation of Phase I first in human studies with PRX-08066, its highly selective, proprietary 5-HT2B receptor antagonist for the treatment of pulmonary hypertension (PH) and hypoxia-induced PH syndromes caused by chronic obstructive pulmonary disease and mountain sickness. This drug candidate is the third compound Predix has discovered and advanced into clinical development in less than three years.
As a selective 5-HT2B antagonist, PRX-008066 has the potential to act both as a vasodilator of pulmonary but not systemic blood vessels, and as a disease-modifying agent to slow the progression of the disease. The primary objectives of the Phase I study are to evaluate the safety and tolerability of the compound and to obtain pharmacokinetic data in humans.
"There currently exists a significant market need for additional PH therapies that can be used alone or in combination which do not reduce patients’ systemic blood pressure, are not associated with liver toxicity issues, and which can slow disease progression," said Silvia Noiman, Ph.D., founder, senior vice president of pipeline management and general manager in Israel for Predix. "To address this need, Predix Pharmaceuticals has moved rapidly from biological proof of concept, which demonstrated the activation of 5-HT2B receptors as a limiting step in the development of PH, to the initiation of Phase I trials."
Christine H. Wang, vice president of drug development operations, added, "Predix is able to move rapidly from discovery to clinical development because of our dedication to operational excellence and commitment to teamwork. Our organization is empowered to make decisions and take rapid action to ensure the highest levels of quality throughout our drug discovery and clinical development efforts. Our program teams never lose sight of our ultimate goal: to develop safe and effective drugs that will benefit patients."
About Pulmonary Hypertension
Pulmonary hypertension (PH) is a progressive, debilitating and often fatal disease that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. PH is estimated to affect 100,000 people worldwide. Current treatments include systemically administered intravenous and subcutaneous prostacyclin analogs and orally active endothelin receptor antagonists, which mainly cause pulmonary arterial dilation to relieve symptoms. There is only one approved orally active agent for PH available for patients, a non-specific endothelin A and B receptor antagonist which requires liver toxicity monitoring. Recent industry research estimates the global market for PH to be under-penetrated, and is expected to grow from approximately $600 million in 2004 to over $1 billion in 2007.
The Role of 5-HT2B Receptor Antagonists
5-HT2B receptor antagonists have the potential to be selective for diseased pulmonary vasculature (i.e., vessels affected by hypoxic conditions) compared to normal pulmonary and systemic vessels. Due to this selectivity, 5-HT2B antagonists offer a possible therapeutic advantage over the available agents for the treatment of pulmonary hypertension.
About Predix
Predix is a privately held, clinical stage drug development company that uses a proprietary discovery and lead optimization system to develop drugs for G-protein coupled receptor (GPCR) and ion channel targets. Over the past two and a half years, the company has discovered several novel drug candidates, three of which are now in human clinical trials. Predix has completed three Phase I trials and initiated a Phase II trial with PRX-00023, a 5-HT1A receptor agonist for anxiety and depression, as well as initiated Phase I trials with PRX-03140, a 5-HT4 receptor agonist for Alzheimer’s disease and cognitive impairment, and a Phase I trial with PRX-08066, a novel 5-HT2B antagonist for pulmonary hypertension and other hypoxia-associated diseases. For more information on Predix, please visit www.predixpharm.com.
Letairis
Generic Name: ambrisentan
Date of Approval: June 15, 2007
Company: Gilead Sciences, Inc.
Treatment for: Pulmonary Arterial Hypertension
FDA Approves Letairis
The U.S. Food and Drug Administration (FDA) has granted approval of Letairis (ambrisentan) tablets for the once-daily treatment of pulmonary arterial hypertension.
Letairis is an endothelin receptor antagonist (ERA) indicated for the once-daily treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO Functional Class II or III symptoms to improve exercise capacity and delay clinical worsening.
Letairis Clinical Trials
In two randomized, double-blind, 12-week, placebo-controlled Phase III clinical trials (ARIES-1 and ARIES-2) involving a total of 393 patients, treatment with Letairis resulted in a significant improvement in six-minute walk distance. An increase in walk distance was observed after four weeks of treatment with each dose regimen of Letairis, with a dose-response observed after 12 weeks of treatment. In ARIES-1, placebo-adjusted mean and median changes from baseline of 31 meters and 27 meters (p=0.008), respectively, were observed for the 5 mg dose. Placebo-adjusted mean and median changes from baseline of 51 meters and 39 meters (p less than 0.001), respectively, were observed for the 10 mg dose. In ARIES-2, placebo-adjusted mean and median changes from baseline of 59 meters and 45 meters (p less than 0.001), respectively, were observed for the 5 mg dose.
Treatment with Letairis also significantly delayed time to clinical worsening of PAH. Clinical worsening was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape (progressive disease).
The long-term follow-up of the patients who were treated with Letairis in the two pivotal studies and the open-label extension (n=383) shows that 95 percent were still alive at one year and 94 percent were still receiving Letairis monotherapy. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis.
In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5 or 10 mg once daily and 132 patients received placebo. The most common adverse events that occurred at a higher frequency among Letairis-treated patients compared to placebo in the ARIES-1 and ARIES-2 studies included (placebo-adjusted frequency): peripheral edema (6 percent), nasal congestion (4 percent), sinusitis (3 percent), flushing (3 percent) and palpitations (3 percent). Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.
In addition to data from Phase III clinical trials, the Letairis approval is also supported by data from an uncontrolled, open-label study of 36 patients who had previously discontinued endothelin receptor antagonists (bosentan, an investigational drug, or both) due to aminotransferase elevations greater than three times the upper limit of normal(ULN). With a median follow-up period of 13 months and with 50 percent of patients increasing the dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. The most common adverse events observed were peripheral edema, headache, dyspnea and flushing. The study suggests that Letairis may be an option for patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.
About the Letairis Education and Access Program (LEAP)
Because of the risks of liver injury and birth defects, Letairis is available only through a special restricted distribution program called the Letairis Education and Access Program (LEAP) by calling 1-866-664-LEAP (1-866-664-5327). Only prescribers and pharmacies registered with LEAP are able to prescribe and distribute Letairis. In addition, Letairis may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.
WARNING: POTENTIAL LIVER INJURY
Letairis can cause elevation of liver aminotransferases (ALT and AST) to at least three times the upper limit of normal (ULN). Letairis treatment was associated with aminotransferase elevations greater than three times ULN in 0.8 percent of patients in 12-week trials and 2.8 percent of patients including long-term open-label trials out to one year. One case of aminotransferase elevations greater than three times ULN has been accompanied by bilirubin elevations greater than two times ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly.
Elevations in aminotransferases require close attention. Letairis should generally be avoided in patients with elevated aminotransferases greater than three times ULN at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin greater than two times ULN, treatment should be stopped. There is no experience with the re-introduction of Letairis in these circumstances.
CONTRAINDICATION: PREGNANCY
Letairis is very likely to produce serious birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals. Pregnancy must therefore be excluded before the initiation of treatment with Letairis and prevented thereafter by the use of at least two reliable methods of contraception unless the patient is unable to become pregnant. In women who can become pregnant, pregnancy tests should be obtained monthly.
Important Safety Information
The most common adverse events that occurred at a higher frequency among Letairis-treated patients compared to placebo included (placebo-adjusted frequency): peripheral edema (6 percent), nasal congestion (4 percent), sinusitis (3 percent), flushing (3 percent), palpitations (3 percent), nasal pharyngitis (2 percent), abdominal pain (2 percent), constipation (2 percent), dyspnea (1 percent) and headache (1 percent).
Elevations of liver aminotransferases have been reported with Letairis and serious liver injury has been reported with related drugs. Patients should be monitored monthly for liver aminotransferases and treatment with Letairis should be discontinued if greater than five times the upper limit of normal or if signs or symptoms of liver dysfunction are observed.
Letairis is not recommended in patients with moderate to severe hepatic impairment. For women of childbearing potential, Letairis treatment should only be initiated after a negative pregnancy test and only in those using at least two reliable methods of contraception.
Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases were observed within the first few weeks of treatment with Letairis, and stabilized thereafter.
Peripheral edema is a known class effect of endothelin receptor antagonists and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg of Letairis compared to placebo. Most edema was mild to moderate in severity. Peripheral edema was similar in younger patients (age less than 65 years) receiving Letairis (14 percent; 29/205) or placebo (13 percent; 13/104), and was greater in elderly patients (age greater than or equal to 65 years) receiving Letairis (29 percent; 16/56) compared to placebo (4 percent, 1/28). The results of such subgroup analyses must be interpreted cautiously.
Caution should be used when Letairis is co-administered with cyclosporine A, as it may cause increased exposure to Letairis.
Caution should be used when Letairis is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) or CYP2C19-inhibitors (e.g., omeprazole).
No clinically relevant interactions of Letairis with warfarin or sildenafil have been observed.
About Letairis
Letairis (ambrisentan) is an endothelin receptor antagonist that is selective for the endothelin type-A (ET(A)) receptor. Activation of the ET(A) receptor by endothelin, a small peptide hormone, leads to vasoconstriction (narrowing of blood vessels) and cell proliferation. The clinical impact of high selectivity for ET(A) is not known. PAH is associated with elevated endothelin blood levels.
About Pulmonary Arterial Hypertension
PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.
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