West Coast Editor
Positive Phase III data with the intravenous form of vernakalant for atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery heartened investors about the selective ion channel blocker's position in the race with Sanofi-aventis Group's Multaq, and put the product in line for off-label use if approved for new-onset AF this fall.
Vancouver, British Columbia-based Cardiome's shares (NASAQ:CRME) rose 52 cents Monday to close at $10.41.
The Phase III trial, called ACT 2, tested I.V. vernakalant in patients who developed AF, or atrial flutter, between 24 hours and seven days after CABG or valve replacement surgery. Thirty percent to 50 percent of such patients show arrhythmic, which pass but can cause trouble.
In the AF group, 47 percent of patients dosed with vernakalant got conversion to normal heart rhythm within 90 minutes, as 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 a 15 percent result 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 heart 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.
"If patients end up getting the drug when they present with AF and go to atrial flutter, approximately one-third of them do go on to convert [to normal rhythm], so we're trying to sort out the difference there," Cardiome Chief Medical Officer Charles Fisher told investors during a conference call, but Cardiome is not yet making specific claims about flutter efficacy.
Vernakalant was well tolerated, too. Only three patients (2 percent) showed hypotension or reversible heart block, and no cases of torsades de pointes - a dangerous side effect of some anti-arrhythmics. (The French phrase means "twisting of the points," and refers to the look of the electrocardiogram.) Cardiome said one hypotensive event took place, a finding consistent with earlier data.
CEO Bob Rieder called the results from all studies done so far "surprisingly consistent," yielding roughly a 50 percent conversion rate. The same dosing regimen was used in ACT 2 as was used in the ACT1 and ACT3 pivotal trials in new-onset AF, an indication for which the FDA is expected to rule in mid-October - around the time Cardiome is expected to disclose interim Phase IIb data with an oral form of vernakalant, formerly RSD1235.
Strong safety data from the latest trial enforced the "attractive thought" of proposing that the oral version be used to maintain normal rhythm in patients after surgery, Fisher said. "I don't want to get into specifics prematurely, but I think the time frame we would look at would be at least a month" of treating postoperative patients until they are clear of risk, he said.
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, the company estimated.
At the end of May, Cardiome said its partner, Astellas Pharma Canada Inc., an affiliate of Deerfield Ill.-based 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 intravenous formulation of vernakalant. Cardiome retains rights outside the U.S. and holds worldwide rights on the oral version.
With new Phase III data in hand, Astellas and Cardiome will be talking with the FDA about the next steps. CIBC World Markets predicted another trial would be necessary, though analyst Bret Holley wrote in a research report that enrollment probably would be "substantially more rapid" than ACT-2's, which took about three years.
Doug Janzen, chief business officer for Cardiome, pointed out that New York-based Pfizer Inc. did a similar-size study in the same patient group and spent about three and a half years finishing it.
"It's hard to prospectively get patients to sign up for a complication they may not have, post-surgery," he said. "Likewise, sites have to do five times the work for one-fifth of the pay." With results such as ACT 2's in hand, "things will likely go faster, but it will always be that bit of an issue, because you can't pre-identify which patients will go into [AF] and which ones won't."
Paris-based Sanofi plans to resubmit next year its oral Multaq (dronedarone), a second-generation version of the standard treatment for chronic AF, Cordarone (amiodarone), which lost patent protection in the U.S. in 2002. Last September, the FDA issued a non-approvable letter for Multaq, setting the drug's potential approval back at least two years. (See BioWorld Today, Sept. 5, 2006.)
Cardiome last month reported a first-quarter loss per share of 20 cents, compared to CIBC's estimate of 19 cents, and posted revenues of $1.5 million, lower than the $1.8 million expected by CIBC, with expenses of $14.4 million. The company had $125 million in cash and cash equivalents at the end of the period, having raised about $84 million in a public offering at the start of the year. (See BioWorld Today, Jan. 19, 2007.)