Tracleer and PPH News Encysive Drug Thelin Meets Study Endpoint
02.14.2005, 08:07 AM Encysive Pharmaceuticals Inc. said Monday that a late-stage trial of pulmonary arterial hypertension treatment Thelin met its primary endpoint, with patients receiving a 100 milligram dose of the experimental drug better able to complete a six-minute walk than those taking a placebo. Encysive shares closed Friday at $10.51 on the Nasdaq, but surged $1.87, or 17.8 percent, to $12.38 in premarket activity. Compared with Actelion's Tracleer, currently the only approved oral treatment for pulmonary arterial hypertension, a 50 mg dose of Thelin improved the walk by 24.2 meters, and Tracleer improved the walk by 29.5 meters. As expected, placebo patients worsened in the six-minute walk over the 18-week period of the trial. Encysive said the 100 mg dose of Thelin continued to demonstrate an encouraging safety profile, with liver function abnormalities occurring in 3 percent of patients in the 100 mg Thelin group, compared with 5 percent in the 50 mg Thelin group, 11 percent in the Tracleer group and 6 percent in the placebo group. Premature discontinuations due to safety or efficacy occurred in four patients at the 100 mg Thelin dose, eight at the 50 mg Thelin dose, nine in the Tracleer group and 11 in the placebo group. "We are extremely pleased with the performance of Thelin in Stride-2," said Bruce D. Given, president and chief executive officer of Encysive. "We will present more details from this trial at appropriate medical meetings over the next several months and we are now focused on filing a New Drug Application with the Food and Drug Administration in April 2005 to seek marketing authorization." Stride-2 was an 18-week Phase III, double-blind safety and efficacy study of Thelin, with 246 patients enrolled at 55 centers in North America, Europe, Israel and Australia. Patients were randomized to receive one of four treatments: 50 mg of Thelin once daily, 100 mg of Thelin once daily, placebo once daily or Tracleer twice daily. Thelin is a small molecule that blocks the action of endothelin, a potent mediator of blood vessel constriction and growth of smooth muscle in vascular walls. Pulmonary arterial hypertension is a condition that involves high blood pressure and structural changes in the walls of the pulmonary arteries, which are the blood vessels that connect the right side of the heart to the lungs. PAH causes shortness of breath, limits activity and is eventually fatal unless treated successfully with heart/lung or lung transplantation. PAH is estimated to afflict about 80,000 to 100,000 people worldwide, many of whom are children and young women.
Long-term treatment with bosentan improves outcomes in pulmonary arterial hypertension
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Pulmonary arterial hypertension (PAH) is a devastating disease that carries a poor prognosis. Untreated, about half of patients die within two years.
Only recently have specific medicines for this disease become available. While effective, the first available therapy, epoprostenol, proved difficult for patients to use because it is delivered on a continuous intravenous basis rather than in a pill form.
Bosentan, a dual endothelin receptor antagonist, is the first approved oral treatment for PAH. In short-term (12-16 week) trials, bosentan has demonstrated improvements in how far patients can walk and how they feel.
This improvement, combined with the convenience of an oral therapy provides a valuable treatment option for patients.
In order to assess the long-term benefit of bosentan, a recent analysis of long-term data was performed. Vallerie McLaughlin (University of Michigan, Ann Arbor, USA) and her American and European colleagues compared the survival in bosentan-treated patients to the survival that would have been predicted based on past clinical experience.
Survival in the treated patients was 96% at one year and 89% at two years. In comparison, the expected survival without treatment was 67% at one year and 58% at two years.
After two years of follow-up, 70% of patients were still on bosentan alone, without the need for additional therapies. Although treatment with bosentan was well tolerated, it was associated with a 10% incidence of elevated liver enzymes thereby requiring monthly liver enzyme monitoring by a simple blood test.
In summary, bosentan, an oral treatment of pulmonary hypertension, improves how patients feel and how long they live.
Analysis of Orthologous Gene Expression between Human Pulmonary Adenocarcinoma and a Carcinogen-Induced Murine Model
Robert S. Stearman*, Lori Dwyer-Nield, Laura Zerbe, Stacy A. Blaine, Zeng Chan, Paul A. Bunn , Jr., Gary L. Johnson, Fred R. Hirsch, Daniel T. Merrick**, Wilbur A. Franklin**, Anna E. Baron, Robert L. Keith*, Raphael A. Nemenoff, Alvin M. Malkinson and Mark W. Geraci*
From the Departments of Medicine/Pulmonary Sciences and Critical Care Medicine,* Pharmaceutical Sciences, Medicine/Renal Medicine, Preventive Medicine and Biometrics, and Pathology,** and the Comprehensive Cancer Center,University of Colorado Health Sciences Center, Denver, Colorado; the Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, Denver Veteran’s Administration Medical Center, Denver, Colorado; and the Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
Human adenocarcinoma (AC) is the most frequently diagnosed human lung cancer, and its absolute incidence is increasing dramatically. Compared to human lung AC, the A/J mouse-urethane model exhibits similar histological appearance and molecular changes. We examined the gene expression profiles of human and murine lung tissues (normal or AC) and compared the two species’ datasets after aligning 7500 orthologous genes. A list of 409 gene classifiers (P value <0.0001), common to both species (joint classifiers), showed significant, positive correlation in expression levels between the two species.
A number of previously reported expression changes were recapitulated in both species, such as changes in glycolytic enzymes and cell-cycle proteins. Unexpectedly, joint classifiers in angiogenesis were uniformly down-regulated in tumor tissues. The eicosanoid pathway enzymes prostacyclin synthase (PGIS) and inducible prostaglandin E2 synthase (PGES) were joint classifiers that showed opposite effects in lung AC (PGIS down-regulated; PGES up-regulated).
Finally, tissue microarrays identified the same protein expression pattern for PGIS and PGES in 108 different non-small cell lung cancer biopsies, and the detection of PGIS had statistically significant prognostic value in patient survival. Thus, the A/J mouse-urethane model reflects significant molecular details of human lung AC, and comparison of changes in orthologous gene expression may provide novel insights into lung carcinogenesis.
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