Tracleer and PPH News International Approvals: Ceplene, Reducol, Remodulin Yael Waknine
March 14, 2005 — The European Commission has approved orphan drug status for histamine dihydrochloride, allowing its use in the European Union for the treatment of acute myeloid leukemia, and an expanded indication for a phytosterol product, allowing its use in seven major food groups to aid in the reduction of low-density lipoprotein cholesterol. The French regulatory authority, Agence Française de Sécurité Sanitaire des Produits de Santé, has approved treprostinil sodium subcutaneous injection for the treatment of pulmonary hypertension in patients with heart failure. Orphan Drug Histamine Dihydrochloride (Ceplene) for AML Approved in EU On March 9, the European Commission granted orphan drug status for histamine dihydrochloride (Ceplene, made by Maxim Pharmaceuticals, Inc.), allowing its use in the European Union (EU) for the treatment of acute myeloid leukemia (AML). The approval was based on the results of a phase 3 study showing that histamine dihydrochloride significantly improved leukemia-free survival compared with standard of care (no treatment) in patients having first or subsequent remissions of AML (P = .00964). Histamine dihydrochloride is designed to protect immune system cells that are required for an effective response to cancer (natural killer, cytotoxic T, and natural-killer/T cells) from the suppressive effects of oxygen free radicals released by phagocytes (oxidative stress). Histamine dihydrochloride was previously granted orphan drug status for this indication by the U.S. FDA. Cholesterol-Reducing Food Ingredient (Reducol) Approved in EU for Use in 7 Food Groups On March 2, the European Commission approved an expanded indication for a blend of plant-derived phytosterols and phytostanols (Reducol, made by Forbes Medi-Tech Inc.) in the European Union (EU), allowing its inclusion in seven major food groups as an aid to a low-fat diet and exercise in the reduction of low-density lipoprotein (LDL) cholesterol levels. Approved food groups include margarine, fermented milk products, soy drinks, low-fat cheese products, yogurt products, spicy sauces, and salad dressings. A daily dose of 1.8-g/day of the product (1.5 g/70 kg of body weight) is recommended. The ingredients (beta-sitosterol, campesterol, sitostanol, and campestanol) are derived from coniferous tree oils and serve to block intestinal absorption of cholesterol. They are poorly absorbed and excreted via the feces. According to a company news release, positive results of more than 100 clinical studies support the efficacy of phytosterols in lowering LDL cholesterol levels. The product is not genotoxic and demonstrates no reproductive or developmental toxicity; no adverse events have been associated with its use. The product was previously approved in the EU for use in milk-based products. It has been generally recognizes as safe by the U.S. FDA. Further, the U.S. National Cholesterol Education Program recommended consumption of 2 g per day of phytosterols as part of the updated "clinical primary prevention" guidelines for coronary heart disease in May 2001. Subcutaneous Treprostinil (Remodulin) Approved in France for Pulmonary Hypertension On March 8, the French regulatory authority (Agence Française de Sécurité Sanitaire des Produits de Santé) approved treprostinil sodium injection (Remodulin, made by United Therapeutics Corp.) for subcutaneous administration in the treatment of primary pulmonary arterial hypertension (PAH) in patients with left ventricular dysfunction (New York Heart Association [NYHA] class III symptoms). The mutual recognition procedure allowing its use in other member states of the European Union will be initiated in May. According to a company news release, the approval letter did not request any additional clinical trials regarding subcutaneous delivery of treprostinil. Treprostinil sodium is approved by the U.S. FDA for intravenous and subcutaneous administration in the treatment of PAH in patients with NYHA class II to IV symptoms to diminish the symptoms associated with exercise. It is also approved for use in Canada, Israel, Switzerland, and Australia. Reviewed by Gary D. Vogin, MD
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Pulmonary Arterial Hypertension
What Is Pulmonary Arterial Hypertension?
Pulmonary (PULL-mun-ary) arterial hypertension (PAH) is continuous high blood pressure in the pulmonary artery. The average blood pressure in a normal pulmonary artery is about 14 mmHg when the person is resting. In PAH, the average is usually greater than 25 mmHg.
PAH is a serious condition for which there are treatments but no cure. Treatment benefits many patients.
The pulmonary arteries are the blood vessels that carry oxygen-poor blood from the right ventricle (VEN-trih-kul) in the heart to the small arteries in the lungs. In PAH, three types of changes may occur in the pulmonary arteries:
The muscles within the walls of the arteries may tighten up. This makes the inside of the arteries narrower.
The walls of the pulmonary arteries may thicken as the amount of muscle increases in some arteries. Scar tissue may form in the walls of arteries. As the walls thicken and scar, the arteries become increasingly narrow.
Tiny blood clots may form within the smaller arteries, causing blockages.
There is less room for the blood to flow through these narrower arteries. The arteries may also stiffen. Over time, some of the arteries may become completely blocked.
The narrowing of the pulmonary arteries causes the right side of heart to work harder to pump blood through the lungs. Over time, the heart muscle weakens and loses its ability to pump enough blood for the body's needs. This is called right heart failure. Heart failure is the most common cause of death in people with PAH.
There are two types of PAH:
Primary pulmonary arterial hypertension (PPAH) is inherited or occurs for no known reason.
Secondary pulmonary arterial hypertension (SPAH) either is caused by or occurs because of another condition. The conditions include chronic heart or lung disease, blood clots in the lungs, or a disease like scleroderma (skler-o-DER-ma).
About 300 new cases of PPAH are diagnosed in the United States each year. SPAH is much more common.
Doctors have learned a lot about PAH in recent years. More treatments are now available. Researchers are also studying several promising new treatments that may prolong lives as well as improve the quality of life for people living with PAH.
Sitaxsentan Tops Bosentan as Pulmonary Hypertension Treatment: Presented at ATS
By Jill Stein
SAN DIEGO, C.A. -- June 2, 2006 -- The investigational oral, once-daily selective endothelin A receptor antagonist sitaxsentan appears to outperform bosentan on several important measures in patients with pulmonary arterial hypertension, according to a study presented here at the International Conference of the American Thoracic Society (ATS).
Bosentan is presently the most widely used treatment for treatment of pulmonary hypertension but is limited by twice-daily dosing, and has an 11% rate of elevated liver function tests (LFTs), according to its label. The rate of elevated LFTs with sitaxsentan appears to be significantly lower (3%) in clinical studies to date.
Robert Naeije, MD, professor, pulmonary medicine division, Erasmus University Hospital, Brussels, Belgium, presented interim results from the Sitaxsentan to Relieve ImpaireD Exercise (STRIDE)-2X trial, which is an ongoing, prospective, 1-year, open-label extension study of the STRIDE-2 trial.
STRIDE-2 was an 18-week, multicenter, randomized study that evaluated sitaxsentan 50 mg or 100 mg, placebo, open-label (6-minute walk distance [6MWD] and functional class [FC] rater blind), and standard-dose bosentan.
Patients who responded to full-dose sitaxsentan or bosentan in STRIDE-2 were enrolled in the extension trial STRIDE-2X, Dr. Naeije said in a presentation on May 23rd. Overall, 92 patients received sitaxsentan 100 mg for a mean of 44 weeks, and 84 patients received open-label bosentan at the standard dose for a mean of 37 weeks.
Results showed that functional class and the 6-minute walking test improved with both sitaxsentan and bosentan and did not differ significantly between treatments.
Time to clinical worsening was improved to a greater extent with sitaxsentan than with bosentan.
Rates of premature withdrawal from treatment due to adverse effects were 15% and 30%, respectively.
Elevated LFTs were observed in 6% of the sitaxsentan and 14% of the bosentan cohort. Rates of discontinuation due to LFTs were 3% and 9%, respectively.
Clinical worsening during the trial occurred in 22% of sitaxsentan patients and 33% of bosentan patients. Rates of all-cause mortality were 4% and 11%, respectively.
Pulmonary arterial hypertension is a progressive disorder of the pulmonary vasculature characterized by progressive pulmonary vascular remodeling, increased pulmonary vascular resistance, sustained elevations of pulmonary arterial pressure, and progressive dyspnea, leading to profound functional limitations, right ventricular failure and, ultimately, death.
[Presentation title: Chronic Treatment of Pulmonary Arterial Hypertension (PAH) With Sitaxsentan and Bosentan. Abstract A729]
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