Myogen Inc. saw its stock surge by more than 60 percent Thursday on positive Phase IIb data generated by its investigational hypertension drug, darusentan, which works by way of a different mechanism than the range of hypertension products already on the market.
"This is an indication which, by definition, there are no other alternatives," Myogen President and CEO Bill Freytag told BioWorld Today, noting that eligible patients already were taking three other hypertension drugs without relief. "And in spite of that, you still have hypertension that is above targets that have been identified as significantly lowering your risk for cardiovascular complication. To try and address that, you need a mechanism that is not being addressed by those other drugs."
Darusentan, a type-A selective endothelin receptor antagonist, did just that.
The Denver company's stock (NASDAQ:MYOG) gained $8.13 Thursday to close at $21.67, an enthusiastic investor response brought on by top-line results that met the randomized, double-blinded study's primary endpoint. And based on the findings, Myogen expects to soon advance into Phase III studies of those resistant hypertension patients.
A near-term end-of-Phase II meeting already is inked on the company's calendar, and Freytag said "we plan to move expeditiously into Phase III as quickly as possible." He added such evaluations would remain well controlled and include an adequate number of the same types of patients who benefited from darusentan treatment in Phase II.
Those specific data demonstrated that 300 mg of the drug dosed once daily provided statistically significant, placebo-corrected reductions of 11.6 mmHg (p=0.02) in systolic blood pressure and 7.0 mmHg (p<0.001) in diastolic blood pressure. Comparing those reductions to existing hypertension drugs, Freytag said darusentan had a "very powerful effect." Clinically meaningful reductions in systolic and diastolic blood pressure also were observed at earlier time points at lower doses in the U.S.-based study. The product, which inhibits endothelin-induced vasoconstriction, generally was well tolerated, suggesting a favorable safety profile, and there were no observed serum aminotransferase concentrations above two times the upper limit of the normal range.
"In the patient population that we're speaking about," Freytag added, "every millimeter of mercury reduces the risk of cardiovascular complications by a specific number."
A total of 115 patients were enrolled after meeting eligibility requirements that included systolic blood pressure greater than or equal to 140 mmHg and diastolic blood pressure greater than 90 mmHg despite treatment with full doses of three anti-hypertensive medications, one of which was a diuretic, and no other compelling conditions. For diabetics and chronic renal disease patients, systolic and diastolic blood pressures inclusion criteria were more stringent, requiring systolic blood pressure greater than 130 mmHg and diastolic blood pressure greater than 80 mmHg. All patients underwent forced titration every two weeks through 10, 50, 100 and 150 mg of darusentan or placebo until the target 300 mg dose was achieved. Treatment lasted 10 weeks, followed by a two-week drug withdrawal period.
"We find these results to be rather impressive, given the challenging design of this trial," said Freytag, who added that a more complete data disclosure would be forthcoming at a scientific meeting. "To the best of our knowledge, we are not aware of any other hypertensive agent that has ever been shown to have efficacy in this setting."
The company said hypertension affects about 50 million people in the U.S., a patient population that climbs to 1 billion worldwide. Many use several classes of drugs such as diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, central alpha receptor agonists, peripheral alpha antagonists and vasodilators, but Myogen also noted that 20 percent to 30 percent of them fail to achieve blood pressures within the recommended range.
"When you put a patient on a diuretic, an angiotensin receptor blocker and a calcium channel blocker, you're effectively addressing many of the underlying mechanisms at work in hypertension, leaving endothelin still to express its pathogenic properties," Freytag said. Blood level elevation of that small peptide hormone is associated with several cardiovascular disease conditions such as hypertension, pulmonary arterial hypertension, chronic renal disease, coronary artery disease and chronic heart failure. "So I think by going and knocking down the last one, there's a sort of scientific rationale for understanding why one might be able to close the final gap here in the treatment."
In a prior clinical study that included patients with moderate essential hypertension, darusentan demonstrated statistically significant and clinically meaningful dose-dependent reductions in systolic and diastolic blood pressures.
Myogen's rights to the compound come by way of an exclusive worldwide license from Abbott Laboratories, the Abbott Park, Ill.-based pharmaceutical company due milestone payments and potentially royalties down the road, should darusentan reach the market. Freytag said Myogen has the internal capabilities to advance its development to the point of commercialization for the U.S., European and other markets, after which the company might look for partners.
Beyond its latest product developments, the company soon expects to report findings from another of its late-stage programs. Before the end of the year, top-line results are due from the first of two pivotal trials of ambrisentan, a small molecule being developed for pulmonary arterial hypertension. The second Phase III study is scheduled to complete enrollment next quarter, with top-line data due about six months later.
Company officials are hoping that program and its darusentan evaluations prove to be the opposite of enoximone, a product dropped from its pipeline after failing in a trio of Phase III trials earlier this year. Upon releasing those misses, shares in Myogen closed at $6.43, about a third of their present value. (See BioWorld Today, March 29, 2005, and June 28, 2005.)