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Phase 3 Trials of Enoximone Fall Short
"I want to thank everyone involved in the conduct and execution of these trials," said J. William Freytag, President and Chief Executive Officer of Myogen. "We had high hopes for oral enoximone as a new therapy for the millions of patients who suffer from the debilitating symptoms of advanced chronic heart failure. Our experience with these patients and clinical investigators only heightens our determination to develop innovative disease modifying therapies through our drug discovery program. In addition, we believe the experience, knowledge and organizational resources gained through the enoximone program will be invaluable assets as we continue the clinical development of darusentan and ambrisentan. We look forward to reporting results from these programs later this year."
ESSENTIAL I and II Results
- First co-primary endpoint: time to first cardiovascular hospitalization or all-cause mortality measured across both trials; the relative hazard ratio, enoximone versus placebo, was 0.98 (p = 0.71).
- Second co-primary endpoint: change in submaximal exercise capacity at 6 months measured by six-minute walk distance; the difference in median change from baseline for enoximone compared to placebo was +10.0 meters (p = 0.025) in ESSENTIAL I and +1.5 meters (p = 0.82) in ESSENTIAL II. The pre-specified statistical significance for each trial required p - Third co-primary endpoint: change in patient self assessment of well being at 6 months measured by a patient global assessment instrument; the proportion of patients who reported "marked improvement" for enoximone and placebo, respectively, were 43% and 46% in ESSENTIAL I (p = 0.79) and 29% and 31% in ESSENTIAL II (p = 0.11).
- Safety: all-cause mortality for the combined trials met the pre-specified endpoint of non-inferiority (201 deaths out of 926 patients in the enoximone group and 210 deaths out of 928 patients in the placebo group; hazard ratio = 0.97; 95% confidence intervals = 0.80 and 1.17; p = 0.73).
"These top line data indicate that low-dose oral enoximone is safe in advanced chronic heart failure, but did not produce sufficient efficacy in the patient population studied in the ESSENTIAL trials", said Dr. Michael Bristow, Myogen's Chief Science and Medical Officer. "These trials were state of the art in their design and execution, and it appears that the results reflect a lack of measurable benefit of enoximone in this setting."
Ambrisentan is being evaluated as an oral therapy for patients with pulmonary arterial hypertension in two international Phase 3 pivotal trials, ARIES-1 and ARIES-2. To date, 174 of the targeted 186 patients have been enrolled in ARIES-2. The Company expects to complete patient enrollment in ARIES-2 in July and report top line results by the end of 2005. In addition, the Company expects to complete patient enrollment in ARIES-1 in the fourth quarter of 2005 and report top line results approximately six months thereafter.
Darusentan is being evaluated as an oral therapy for patients with resistant systolic hypertension in a Phase 2b trial conducted in the United States. Patient enrollment (115 patients) was completed in April 2005 and the treatment phase of this trial is expected to be completed on July 8, 2005. The Company expects to report top line results from this trial by the end of August 2005.
Based on termination of further development activities for oral enoximone, the Company expects 2005 operating expenses will be substantially lower than previous guidance. The Company believes current cash, cash equivalents and investments will fund its working capital requirements and capital expenditures through at least the end of the third quarter of 2006.
About the ESSENTIAL Trials
ESSENTIAL I & II were randomized, double-blind, placebo-controlled trials with identical designs, differing only in the geographic location of the study sites. ESSENTIAL I enrolled patients from North and South America and ESSENTIAL II enrolled patients from Western and Eastern Europe. A total of 1,854 patients were enrolled from 211 sites in 16 countries between February 2002 and May 2004.
The ESSENTIAL trials were designed to evaluate the safety and efficacy of low-dose enoximone capsules in patients with NYHA Class III and IV CHF. Patients were randomized in a 1:1 ratio to receive either 25 mg of enoximone or placebo, administered three times a day (t.i.d.). In the absence of contraindications after two weeks of treatment, all patients weighing greater than 50 kg received 50 mg of enoximone or placebo t.i.d. for the duration of the trials.
Source: Myogen, Inc.