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(Circulation. 2001;104:1742.)
© 2001 American Heart Association, Inc.
Report From the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9–10, 2001
Professor and ChairDepartment of Biostatistics, University of Washington
Professor of MedicineDivision of Cardiology, University of Colorado Health Science, Center
FDA Director of the Cardio-Renal Drug Products Division
Professor of MedicineUniversity of Alberta
Two new drugs for the treatment of pulmonary hypertension received tentative approval at the 93rd meeting of the US Food and Drug Administration’s (FDA) Advisory Committee Meeting on August 9 to 10, 2001. Although the committee can recommend that the FDA approve the drugs, it is not mandatory that the agency accept that recommendation.
Remodulin
The first drug, Remodulin (trepostinil sodium), which is manufactured by United Therapeutics, was approved by a vote of 6 to 3 in the committee after an animated discussion. Although the study did not achieve its primary end point, ie, a 55 meter increment in a 6-minute walk and there was no trend toward reduced mortality or need for transplantation after Remodulin treatment, the approval was based on an improvement in perceived quality of life, dyspnea score, and a reduction in other symptoms such as syncope and fatigue, coupled with a lack of safety concerns. Because of the recognized poor clinical outcomes for patients with pulmonary hypertension, as well as the complicated and logistic problems associated with the only other FDA-approved therapy for this condition (ie, Flolan), a more liberal approach to approval was used.
Remodulin, or UT-15, is a structural analogue of prostacyclin, which acts as a vasodilator in the pulmonary and systemic circulation. Its terminal half-life is 2 to 4 hours. It is administered as a continuous subcutaneous infusion.
There were two pivotal, placebo-controlled trials considered by the committee. A total of 470 patients with primary or secondary pulmonary hypertension and functional class II to IV symptoms were entered into the 2 studies.
Investigators hoped that after 3 months of therapy, patients in the studies would be able to walk 55 meters more in 6 minutes than they had before the study. However, the treatment group was able to walk only an average of 10 meters more after therapy, less than the prespecified objective. Nor did the studies reach the level of statistical significance for which the researchers had hoped.
Bosentan
The committee voted 10 to 0 to approve a second drug for pulmonary hypertension, bosentan (Tracleer), which is manufactured by Actelion Pharmaceuticals. It is the first orally active, nonpeptide antagonist of endothelin receptors developed to treat the disorder.
In 2 placebo-controlled trials, 246 class III to IV patients with pulmonary hypertension achieved the primary end point of a 44-meter difference in a 6-minute walk between the treatment and placebo groups. The difference was statistically significant at P=0.0002. In addition, patients experienced significant improvements in dyspnea, functional class, and time to worsening symptoms.
The first study involved 32 patients who were randomized in a 2:1 manner to 125 mg of bosentan twice a day or placebo. In the second study, 213 patients were randomized equally to 3 groups. One group took 125 mg BID; a second took 250 mg BID, and a third took placebo. The bosentan groups received 62.5 mg BID for the first 4 weeks of therapy.
The drug did have safety issues, including potential teratogenicity, which requires exclusion of pregnancy before treatment; decreased hemoglobin of unknown cause; liver toxicity with a dose-related increase of liver enzymes in as many as 11% of patients; and many potential interactions with other drugs.
The sponsor will implement a monitoring/surveillance program and identify drugs that should be either avoided or undergo dose adjustment if patients are treated with bosentan.
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