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Cardiome Pharma Corp.'s strong Phase III data in June with intravenous vernakalant for atrial fibrillation (AF) or atrial flutter after coronary artery bypass graft (CABG) surgery may have opened the door for off-label use in new-onset AF, and also may have cleared a somewhat smoother regulatory path for the product.

The trial, called ACT 2, examined results of using IV vernakalant in patients who developed AF or atrial flutter between 24 hours and seven days after CABG or valve replacement surgery. Of such patients, an estimated 30 percent to 50 percent show arrhythmias, which pass but can cause trouble.

Forty-seven percent of patients in the AF group dosed with vernakalant achieved conversion to normal heart rhythm within 90 minutes, compared to 14 percent of placebo patients, a statistically significant difference (p=0.0001). In the combined AF and flutter groups, the study converted 45 percent of patients to normal heart rhythm within 90 minutes, compared to 15 percent in the placebo group (p=0.0002).

Of the 10 patients in the flutter population, none in the drug group and one in the placebo arm converted to normal rhythm. Of 190 patients randomized, 161 received treatment, and the median time to normal rhythm conversion in the vernakalant group was 12 minutes from the start of dosing.

ACT 2 used the same dosing regimen as ACT1 and ACT3 pivotal trials in new-onset AF, an indication for which the FDA is expected to rule in mid-October, which also is about when Cardiome is expected to disclose interim Phase IIb data with an oral form of vernakalant, a selective ion channel blocker formerly known as RSD1235.

Among patients who got the drug when they showed up with AF and went on to atrial flutter, about a third converted to normal heart rhythm, though Cardiome made no specific claims about flutter efficacy.

Patients tolerated vernakalant well. Only three (2 percent) showed hypotension or reversible heart block, and no cases of torsades de pointes - a dangerous side effect of some anti-arrhythmics - appeared. The French phrase means "twisting of the points," and refers to changes on the electrocardiogram readout. Cardiome said one hypotensive event took place, which is consistent with earlier data.

The solid safety data suggested the oral version of vernakalant might be used to maintain normal rhythm in patients after surgery, possibly for at least a month after patients' operations, to make certain they're out of the woods. Along with the post-CABG patients, those undergoing valve surgeries and thoracic operations face the risk of AF, and might be treated with vernakalant - in sum, about 500,000 patients annually, Cardiome estimated.

At the end of May, Cardiome's partner, Astellas Pharma Canada Inc., an affiliate of Astellas Pharma US Inc., filed a new drug submission with Health Canada for acute conversion of AF. Astellas, a subsidiary of the Tokyo-based Astellas Pharma Inc., holds North American rights to the I.V. formulation, while Cardiome retains rights outside the U.S. and holds worldwide rights on the oral version.

Vernakalant has been in a race to market with Sanofi-Aventis Group's Multaq (dronedarone) for AF, the oral follow-on product to the pharma giant's Cordarone (amiodarone), which lost patent protection in the U.S. in 2002.

There's also Procter & Gamble's Stedicor (azimilide), which has yielded impressive late-stage data, especially from the SHIELD (Shock Inhibition Evaluation with Azimilide) study. Datamonitor expects Stedicor and Cardiome's product to seize the most market share, given safety concerns about Multaq.

The $1 billion market keeps getting bigger, and Duncan Emerton, Datamonitor's senior cardiovascular analyst, said no fewer than five new products for arrhythmia are expected to reach approval between this year and 2010. Vernakalant, Stedicor and Multaq probably will generate sales of more than $500 million each, Emerton said, since each provides enough benefit to make patients skip generics and pay for the better, newer drugs.

In April, Solvay Pharmaceuticals BV, the Belgian pharma firm with an affiliate in the U.S., filed for approval here and overseas of I.V. Pulzium (tedisamil), a multiple potassium channel blocker for conversion of recent onset AF or atrial flutter. CV Therapeutics Inc. is expected to start Phase II trials with its A1 adenosine receptor agonist, tecadenoson, in AF in the second half of this year - though the company said in May that it was cutting research and development costs by 20 percent, and therefore would not start AF trials with Ranexa (ranolazine) until the drug is partnered. Ranexa already is approved for second-line and third-line treatment of chronic angina.

This spring, Datamonitor predicted I.V. vernakalant - then known as RSD1235 - would become a blockbuster by 2012 and take more than 25 percent of the entire anti-arrhythmics market. But that was just before Cardiome got its refusal to file (RTF) letter from the FDA. CEO Bob Rieder said the delaying RTF letter came "more [because] of an execution error" than anything else, and he added that the letter from the agency did "not in any way allude" to inadequacies in the data package. (See BioWorld Financial Watch, July 17, 2006.)

Still, Emerton called the episode "highly embarrassing" for the company, and serves as "a reminder to all pharmaceuticals companies, large and small, that approval is not guaranteed regardless of how much excitement surrounds a product." Datamonitor changed its mind about vernakalant, and forecast that Stedicor will become the top-selling drug in the anti-arrhythmic class by 2015, with Cardiome's product behind.

CIBC Capital Markets, though, expects Cardiome to shine in the second half of this year. A Phase IIb study with oral vernakalant is enrolling well, with interim data expected in the fourth quarter, noted analyst Bret Holley in a research report this month. "Based on strong Phase IIa efficacy data, we believe vernakalant will be effective at the 300-mg and 500-mg doses, minimally," Holley wrote, calling such a development "a tipping point for a major ex-U.S. partnership." He also pointed to a "high likelihood" of the I.V. version's approval in October, with happy expectations for the interim oral data.

Cardiome reported a second-quarter loss per share of 19 cents, compared to CIBC's 19-cent estimate, with revenues of $1 million, also lower than the CIBC guess of $1.7 million.

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