CDU

An FDA panel recently recommended approval of Kynapid but rejected giving a recommendation to Pulzium to treat atrial fibrillation (AF), a condition in which panel of federal advisers this week told the FDA that it should approve Kynapid and Pulzium to treat atrial fibrillation (AF).

Kynapid (vernakalant) is being co-developed by Cardiome Pharma (Vancouver) and Astellas Pharma U.S. (Deerfield, Illinois). Cardiome granted exclusive licensing rights to the U.S. affiliate of Astellas (Tokyo) in October 2003 to develop and commercialize Kynapid in North America. Cardiome has retained all rights to the intravenous formulations of the drug outside of the U.S., Canada and Mexico.

Pulzium (tedisamil sesquifumurate) is being developed by Solvay Pharmaceuticals (Marietta, Georgia) as a therapy for AF and atrial flutter. While both Kynapid and Pulzium have some degree of effectiveness, at least for AF of short duration, the drugs are "clearly less effective than is electrical conversion," the FDA said in briefing documents.

In addition, the agency said, both products carry risks, specifically proarrhythmic risks.

While Pulzium was found to cause bradycardia and hypotension, which led to at least one study participant death, those adverse effects were less of a concern for Kynapid, he FDA reviewers said.

The FDA's Cardiovascular and Renal Drugs Advisory Committee voted 6 to 2 in favor of approval of the Kynapid, a mixed potassium and sodium channel blocker intended to be administered in the hospital setting. If approved, Kynapid will be the first new therapy in eight years for the conversion of atrial fibrillation to normal sinus rhythm.

While Kynapid was shown to be effective in converting short-term AF, FDA drug reviewers expressed reservations about the drug's safety. The drug caused two cases of ventricular fibrillation, one of which was fatal, in the "highly monitored" study environment, agency scientists said. However, the reviewers noted that it was "very likely" that the fatality was precipitated by the study participant's aortic stenosis and heart failure. But there was not sufficient data available "that would lend support to this hypothesis," the reviewers stated.

In addition, regulators said, because the level of exposure to Kynapid was limited, there is no assurance that other cases of ventricular fibrillation will not occur when exposure to the drug increases and patients with significant structural heart disease are exposed.

In the absence of data, the reviewers said, it can only be assumed that fatal ventricular fibrillation will be observed at a rate of at least one per every 1,000 patients with other risk factors of ventricular arrhythmia administered the drug.

The FDA noted that acute myocardial infarction and advanced heart failure, two of the main causes of atrial fibrillation, were excluded from the Kynapid studies. Therefore, regulators said, the population studied is not representative of the proposed indication for the drug. Other adverse events associated with Kynapid include third-degree atrioventricular block, life-threatening bradycardia, hypotension and possibly ventricular tachycardia and dyspnea, the FDA said.

The agency reviewers advised that if the drug is approved, a post-marketing surveillance program be established to detect serious adverse events, especially cardiac and respiratory effects.

Pulzium, which was examined in four Phase II and five Phase III clinical trials, was found to be effective in both men and women. However, the drug appears to be relatively less effective in women when administered in the same dosing as to men.

Solvay proposed a lower dose in women, but women have somewhat lower rates of conversion at any given dose than men, the FDA said. So, regulators said, lowering the dose in women would appear to reduce any net clinical benefit.

There was "no clear rationale for a sex-specific dosing regimen, particularly when the dose administered is already adjusted for body weight," the FDA said.

Having two dose regimens could lead to a drug administration, error, the agency said, and it voted 7-0 against recommending approval.

Because of the complicated dosing regimen of the drug, Solvay is proposing to establish a risk management plan for Pulzium that includes a physician checklist to ensure that the patient is suitable for treatment with the drug, an arrhythmia diagnostic guide and a healthcare professional website, among others.

COGENT looks at combo, anti-platelet side effects

Cogentus Pharmaceuticals (Menlo Park, California) last month reported the launch of a global Phase III clinical program to evaluate the efficacy/safety of its combination therapy CGT-2168. The program, which includes the COGENT-1 and COGENT-2 trials — COGENT, for Clopidogrel and the Optimization of

Gastrointestinal Events Trial — will enroll over 4,000 patients at sites in the United States, Canada, Europe and South America.

Cogentus described CGT-2168 is a once-daily pill combining the antiplatelet agent clopidogrel (marketed by Bristol-Myers Squibb and Sanofi-Aventis as Plavix) with a gastroprotectant (omeprazole) and designed to reduce the gastrointestinal side effects associated with antiplatelet therapy.

The COGENT trials are designed to measure the incidence of upper gastrointestinal bleeding and ulcers in patients who take CGT-2168 and aspirin compared with patients who take clopidogrel and aspirin, Cogentus saying that "The vast majority of patients who take clopidogrel also take aspirin."

"The benefits of antiplatelet therapy are well established, but the risk of bleeding associated with these treatments has been greatly under-appreciated," said Kim Fox, MD, director of cardiology at Royal Brompton Hospital and professor of clinical cardiology at Imperial College. "The gastrointestinal toxicity from dual antiplatelet therapy can result in patients skipping or stopping their treatment altogether."

Actelion advances Clazosentan into Phase III vasospasm study

Despite the apparent failure of clazosentan (Pivlaz) to demonstrate clinical benefit in a Phase IIb study last year, Actelion (Allschwil, Switzerland) is moving the endothelin receptor antagonist into a pivotal Phase III trial to evaluate its effect on reducing vasospasm-related morbidity and mortality in patients at risk of vasospasm following aneurysmal subarachnoid hemorrhage.

All doses of the compound attained the primary endpoint of reducing cerebral vasospasm in the 413-patient Phase IIb trial last year, although, on initial reading, it failed to translate into the hoped-for clinical benefit. However, a subsequent analysis revealed that a failure to distinguish between vasospasm-related morbidity and morbidity arising from the initial hemorrhage was the problem.

"Absence of trend was not due to medical reasons but was due to the way the data were read," Actelion spokesman Roland Haefeli told said. "We actually did see the benefit once we had the secondary analysis done." The discrepancy arose, he said, because the trial data were interpreted in a decentralized fashion. When a centralized reading by key experts was conducted, "the variability disappeared," he said, although the study was not powered to demonstrate statistical significance.

Every year, more than 80,000 people in the U.S., the European Union and Japan have an aneurysmal subarachnoid hemorrhage, with bleeding into the area surrounding the brain. Some two-thirds of these, Actelion said, are at risk of experiencing vasospasm, an uncontrollable tightening of the brain blood vessels that can lead to permanent disability or death. Existing treatment options are limited.

The rationale for using an endothelin receptor antagonist is based on the fact that endothelin is a potent vasoconstrictor, and elevated levels of the compound have been observed in the cerebrospinal fluid of individuals who have experienced vasospasm.

The upcoming study, called CONSCIOUS-2 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage 2), will recruit a minimum of 765 patients via 100 centers in the European Union, Canada, Asia, Australia and New Zealand. Discussions with the FDA are ongoing, Actelion said, and the company hopes to add another 24 centers in the U.S.

Analyst Denise Anderson, of Kepler Equities (Zurich), said the overall morbidity and mortality data in the earlier Phase IIb study might have been influenced both by the diversity of the patients enrolled and treatments employed. So, for the Phase III trial, "they are going to narrow those parameters," she said.

Patients will be randomized, in a 2-to-1 ratio, to receive 5 mg per hour of clazosentan — the middle dose from the Phase IIb study — or placebo, administered intravenously over 14 days following an episode of aneurysmal subarachnoid hemorrhage. Results from the study could become available by the second half of 2009. As yet, Anderson is not attaching any value to the program, apart from its contribution to Actelion's overall pipeline valuation. "It is a very risky trial. It is a very difficult condition to treat," she said. Moreover, the fact that the "FDA is not on board yet" is "disappointing," she added.

The move triggers a milestone payment of CHF15 million ($13.3 million) to former shareholders of Axovan (Allschwil), which Actelion acquired in 2003.

In brief ...

• Cardiome Pharma (Vancouver) said interim results from its Phase IIb trial with oral vernakalant to prevent recurrence of atrial fibrillation (AF), originally due in 4Q07, will not be disclosed until March of 2008, with final data in the middle of the next year. By delaying the data for one quarter, Cardiome expects to add roughly 20% more patients into the interim analysis than originally planned, making more data available on patients with longer-term exposure...
• CV Therapeutics (Palo Alto, California) reported that the FDA will review a supplemental new drug application claiming potential anti-arrhythmic benefit for Ranexa (ranolazine extended-release tablets). Ranexa is approved for second-line use in chronic angina, and the FDA is reviewing an sNDA seeking to expand the label to first-line use in angina as well as an NDA seeking to add a claim of reduction of hemoglobin A1c in coronary artery disease patients with diabetes. The expected action date for the two sNDAs and the NDA is July 27, 2008...
• Stem Cell Therapeutics (Calgary) has received a "no objection" letter from Health Canada for the REGENESIS trial, a Phase II prospective, randomized, double-blind, placebo-controlled study of NTx-265, a human chorionic gonadotropin and epoetin alfa in acute ischemic stroke patients investigation efficacy/safety endpoints. The goal is to have full enrollment of 120 patients completed before the end of next year...
• Advanced Cell Technology (Los Angeles) said it is seeking international partners for its myoblast program for treating heart failure, its hemangioblast program for the treatment of blood and cardiovascular indications and its retinal pigment epithelium program for treating degenerative retinal disease...
• Synthetic Blood International (Costa Mesa, California) said the Virginia Commonwealth University Reanimation Engineering Shock Center (VCURES) has received $1.3 million under a previously awarded U.S. Office of Naval Research grant for the treatment and prevention of decompression sickness with Oxycyte, the company's perfluorocarbon therapeutic oxygen carrier and blood substitute. Synthetic Blood said it has begun the process of manufacturing and shipping Oxycyte to VCURES for use in the studies.
  The company, in conjunction with VCURES, is planning a 100-150-patient, double-blind, multicenter, placebo-controlled Phase IIb study to compare Oxycyte with present-day advanced