Washington Editor

Myogen Inc. is beginning darusentan's pivotal development for resistant hypertension, a condition in which patients fail to achieve their blood pressure goals despite adhering to appropriate three-drug regimens that include a diuretic.

Labeled DORADO (DAR-311), the international Phase III trial is designed to test darusentan's effectiveness as an add-on therapy in reducing systolic blood pressure in resistant hypertension patients currently treated with full doses of four or more antihypertensive medications. The double-blind study's primary endpoint is a measure of the change from baseline to week 14 in trough-sitting systolic blood pressure as compared to placebo.

"Even with an adequate regimen of drugs, and very good drugs, they still cannot get their blood pressures into a target range," said Derek Cole, the company's director of investor relations. Of an estimated 39 million hypertensive patients treated in the U.S. these days, he noted that about 6 million to 7 million are taking three or more drugs. Such treatments include diuretics, ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, central alpha receptor agonists, peripheral alpha antagonists and vasodilators.

Still, it is thought that between 4 million and 10 million fail to reach their blood pressure goals, a recently identified group that makes up the basis for the evolving indication. Darusentan is expected to fill that void for patients who are at "significant risk" of further cardiovascular complications as a result of their high blood pressure, Cole told BioWorld Today.

Patients are eligible to enroll if they have a systolic blood pressure greater than or equal to 140 mm Hg and no other compelling conditions. For patients with diabetes and/or chronic kidney disease, the blood pressure inclusion criterion is a systolic blood pressure greater than 130 mm Hg.

About 352 patients will be randomized to receive either 50-mg, 100-mg or 300-mg doses of darusentan once a day or placebo in a 7:7:7:11 ratio. The treatment period lasts 14 weeks, after which they can enroll in a long-term safety study. Patients will be treated and followed for safety for at least six months, with a mean exposure expected to be in excess of a year.

Cole said it is difficult to speculate on a timeline for completing the study, but noted that a Phase IIb trial that included about a third as many patients took eight months to reach its enrollment goals.

The Denver-based biopharmaceutical company plans to begin a second international Phase III trial in the fourth quarter. That study, labeled DAR-312, will include more than twice as many patients who are taking three antihypertensive therapies. In addition to placebo, it will feature an active comparator arm.

Darusentan is a non-sulfonamide, propanoic-acid class, type-A selective endothelin receptor antagonist (ERA) that is delivered orally. Phase IIb findings showed "a robust response," Cole said. Both a 150-mg dose after eight weeks and a 300-mg dose at 10 weeks provided statistically significant, placebo-corrected reductions in systolic blood pressure and 24-hour ambulatory blood pressure monitoring. Clinically meaningful reductions in systolic and diastolic blood pressure also were observed at earlier time points at lower doses.

Additional results from the study, called DAR-201, have been reported in recent months at meetings of the American College of Cardiology and the American Society of Hypertension.

The cardiovascular-focused company has rights to the drug per terms of a license from Abbott Laboratories, of Abbott Park, Ill.

Beyond darusentan, Myogen has ambrisentan in late-stage clinical development for pulmonary arterial hypertension. Results from an initial Phase III study showed once-daily dosing of 5 mg of ambrisentan produced a 59.4-meter improvement in the placebo-corrected mean change in six-minute walk distance at 12 weeks compared to baseline (p=0.0002). Data from the second Phase III trial showed similar results. A new drug application is scheduled for a fourth-quarter filing. (See BioWorld Today, Dec. 13, 2005.)

Per terms of a recent deal, Myogen still has control of that selective ERA drug's exclusive rights in the U.S., and has partnered the compound for all other territories with GlaxoSmithKline plc. In return, Myogen has marketing and distribution rights to the London pharmaceutical firm's Flolan (epoprostenol sodium) in the U.S., allowing the former to build sales and marketing capabilities ahead of a regulatory decision on ambrisentan. (See BioWorld Today, March 8, 2006.)

On Monday, Myogen's shares (Nasdaq:MYOG) lost 76 cents to close at $31.15.