West Coast Editor
Three months after Myogen Inc.'s lead drug candidate for heart failure, enoximone, missed statistical significance in the primary endpoint of a Phase III trial - an event the company blamed on unexpected improvements in patients given placebo - the compound has failed in top-line results from two more Phase III studies.
William Freytag, president and CEO of Denver-based Myogen, said the company found the most recent data "surprising, given the encouraging results in prior studies" with the drug. He told investors during a conference call that the trials' design was "exemplary," but the oral drug didn't work and the company is giving up on it.
The company's stock (NASDAQ:MYOG) closed Monday at $6.43, down 57 cents, after trading as low as $5.21. Lazard Freres & Co. LLC in New York downgraded the stock to "hold," while First Albany Capital, also in New York, maintained its "buy" rating but lowered the price target from $13 to $8, finding much of the value in Myogen's other drug, ambrisentan for pulmonary arterial hypertension (PAH).
However, Martin Auster, analyst with Wachovia Securities in Baltimore, upgraded the stock to "outperform," also citing ambrisentan's potential.
Although enoximone's safety was proved well enough in first data from the trials known as ESSENTIAL I and II, the results did not turn up a statistically significant benefit in any of three co-primary endpoints. Myogen is stopping development of enoximone capsules and turning its resources to ambrisentan and to darusentan for resistant hypertension.
Specifically, in the latest enoximone results, the first co-primary endpoint was time to first cardiovascular hospitalization or all-cause mortality measured across both trials. The relative hazard ratio, enoximone vs. placebo, was 0.98 (p=0.71).
The second endpoint was change in submaximal exercise capacity at six months, measured by six-minute walk distance; the difference in median change from baseline for enoximone compared to placebo was +10 meters (p=0.025) in ESSENTIAL I and +1.5 meters (p=0.82) in ESSENTIAL II. Pre-specified statistical significance for each trial required p<0.02.
The third endpoint was change in patient self-assessment of well-being at six months measured by a patient global assessment instrument. Patients who reported "marked improvement" for enoximone and placebo, respectively, were 43 percent and 46 percent in ESSENTIAL I (p=0.79) and 29 percent and 31 percent in ESSENTIAL II (p=0.11).
In late March, enoximone missed statistical significance in the primary endpoint of a Phase III trial called EMOTE, which was designed to support the two ESSENTIAL studies, but the company said EMOTE's success in secondary endpoints meant the study's objective was achieved. Still, the stock took a 34.5 percent hit, ending that day at $10.50. (See BioWorld Today, March 29, 2005.)
Myogen's marketed product, Perfan I.V., is an intravenous formulation of enoximone for acute decompensated heart failure.
As for the other compounds in the company's pipeline, enrollment began in January 2004 for its two 186-patient Phase III trials with ambrisentan, a Type A selective endothelin receptor antagonist. The ARIES-2 trial, in Europe and South America, remains on schedule. But enrollment in ARIES-1 has met a six-month delay due to difficulties finding the right patients. (See BioWorld Today, Feb. 4, 2005.)
Freytag said 174 of 186 patients are enrolled in ARIES-2, and enrollment is expected to complete in July, with top-line data by the end of this year. ARIES-1 enrollment will be done in the fourth quarter, with top-line data six months later.
In an ongoing Phase IIb trial is darusentan, an oral endothelin-A-selective receptor antagonist, as a therapy for patients with hypertension that cannot be controlled by other anti-hypertensive products. Enrollment in that trial was completed in April, Freytag said, and the treatment phase will be finished next month, with top-line results by the end of August.
Joe Turner, Myogen's chief financial officer, said the company's burn rate will drop to about $16 million per quarter.
"There's a lot of volatility to cash flow projections," he added, but $16 million is "approximately right as an average."
Marketing plans for ambrisentan still are shaping up, Freytag said, though Myogen probably can handle the U.S. side of the effort - although Wachovia analyst Auster pointed out in a research note that "the asset value of ambrisentan could be particularly attractive to a more experienced drug developer with an existing/growing presence in the PAH market." The drug "could be a strong complement to a PDE-5 or prostacyclin franchise."
Freytag said the matter of overseas marketing is "an open issue," adding that the firm has "plenty of time to figure out exactly what we want to do there."