Myogen Inc.'s lead product, enoximone, missed statistical significance in the primary endpoint of a Phase III trial to support an ongoing pair of other, pivotal Phase III studies - but the company said success in secondary endpoints means the study's objective was achieved.
Wall Street may not have gotten the message. The company's stock (NASDAQ:MYOG) fell $5.54 Friday, or 34.5 percent, closing at $10.50.
Because patients given placebo did better than expected, enoximone's benefit was not seen at the primary, 30-day endpoint, said William Freytag, chairman, president and CEO of Denver-based Myogen. But that picture changed later, as patients were followed beyond 30 days.
"It really did surprise us that patients with this level of severity of illness actually could be taken off their IV dependency with no benefit of a drug for as long as 30 days," Freytag told investors during a conference call.
Phase II studies had led the company to expect a lower placebo-response rate. Those earlier trials, which were smaller and held at single sites, might have enrolled sicker patients. In any case, the placebo results in the Phase III study threw Myogen a curve ball, although Joe Turner, chief financial officer for the company, told BioWorld Today "there was a very careful effort to make sure [patients in the Phase III trial] were truly IV-dependent."
The 201-patient study tested enoximone capsules in patients with the most advanced stages of chronic heart failure who were dependent on intravenous inotrope therapy. Inotrope is used to increase the strength of the heart's contractions. The small organic molecule enoximone, an oral inotrope, is an inhibitor of the enzyme phosphodiesterase-3, or PDE3, and designed to do the same thing.
PDE3 is in the same class as PDE5, the enzyme that gained the limelight by way of New York-based Pfizer Inc.'s erectile dysfunction drug, Viagra (sildenafil citrate), and others. Sildenafil enables erections through its 4,000-fold selectivity for PDE5; Myogen's drug specifically targets PDE3, which is involved in heart contractions.
Enoximone not only provides the heart benefits of an inotrope, but also causes vasodilation - opening blood vessels wider through its effects on smooth muscle cells that surround them, resulting in lower pressure against which the heart must pump.
Researchers wanted to find out in the Phase III study, called EMOTE, how effective enoximone would be in weaning patients from intravenous inotrope. The primary endpoint was wean success at 30 days, and enoximone-treated patients showed a success rate of 61 percent, as compared to 51 percent in the placebo-treated group (p = 0.171) - not statistically significant.
However, key secondary endpoints evaluated wean from intravenous inotrope therapy over time rather than at the fixed 30-day point, and here the data were encouraging.
The first secondary endpoint, time to death or restart of intravenous inotrope therapy, showed benefit in favor of enoximone vs. placebo for the 60-day period (p= 0.012), the 75-day period (p = 0.016) and the 90-day period (p = 0.041), but not for the 182-day period (p = 0.188).
Another secondary endpoint, mean total days on intravenous inotrope therapy over the course of the 26-week study, amounted to 28 days in the enoximone-treated group as compared to 49 days in the placebo-treated group (p = 0.049). As patients went beyond 30 days, those weaned with placebo had to be restarted on intravenous inotrope sooner and at a higher rate than patients weaned with enoximone, hence the 43 percent reduction in the mean number of days enoximone patients needed the intravenous treatment.
"I think it's clear these patients were IV-drip dependent, but if you worked hard enough you could probably pull it away from them for up to 30 days," Freytag said. "Eventually the disease catches back up with them again, and enoximone did provide benefit [beyond] that 30-day period."
Safety results also proved encouraging. A total of 38 out of 101 patients died in the enoximone treated group, compared to 31 out of 100 patients in the placebo treated group (p = 0.335), which is neither statistically significant nor enough to alarm Freytag.
"They're at the very end stages of their disease," he said, adding that it's "unlikely any therapy is going to affect their ability to live longer."
The larger question is what the data might mean for Myogen's pivotal Phase III program for enoximone, in which 1,800 with Class III and Class IV heart disease are being studied. Those trials are called ESSENTIAL I and ESSENTIAL II, expected to finish treating patients by the end of this year.
Turner said patients in the EMOTE trial were extremely ill, whereas those in the ESSENTIAL studies are "still quite ill, but not as extreme as was the case with EMOTE. In ESSENTIAL, we're trying to maintain all background therapy, and assess the affects of enoximone on top" of beta-blockers and other therapies.
Is the post-30-day benefit of the drug in sicker, EMOTE patients an indicator that even more benefit is due for less-ill, ESSENTIAL patients, who are getting the same 25-mg and 50-mg doses?
"I'm not sure that it is, frankly," Turner said. "The trial designs are very different." What the EMOTE trial does show, he said, is that the drug is safe and efficacious when used in the low dose they've been developing.
"This class of drugs has been developed in the past at higher doses," and safety problems developed, Turner said. Although the EMOTE trial is not huge, the study "does give us some insight into what's going on."
Freytag cautioned that the company has had the preliminary data for "only a short period of time," and analysis is ongoing. Myogen already markets the intravenous formulation of enoximone, Perfan I.V., for acute decompensated heart failure.
The company, which priced its initial public offering at $70 million in October, has two other late-stage products in the pipeline. Myogen in January began enrolling a pair of pivotal Phase III trials for ambrisentan, a Type A selective endothelin receptor antagonist for pulmonary arterial hypertension. The other drug, darusentan, is an ETA selective endothelin receptor antagonist being developed as an oral therapy for patients with uncontrolled hypertension. A Phase IIb trial with darusentan is expected to start this year in patients with resistant hypertension.