Vernakalant (iv)
Vernakalant (iv) is the intravenous formulation of an investigational drug being evaluated for the acute conversion of atrial fibrillation (AF). Vernakalant selectively blocks ion channels in the heart that are known to be active during episodes of atrial fibrillation.
Positive top-line results from two pivotal Phase 3 trials for vernakalant (iv), called ACT 1 and ACT 3, were released in Q4-2004 and Q3-2005. Cardiome’s co-development partner Astellas Pharma US, Inc. submitted a New Drug Application for vernakalant (iv) in Q4-2006. Positive top-line results from an additional Phase 3 study evaluating patients with post-operative atrial arrhythmia, called ACT 2, were released in June 2007. An open-label safety study evaluating recent-onset AF patients, called ACT 4, has completed.
ACT 1 Pivotal Phase 3 Trial
Cardiome reported top-line Phase 3 results for the ACT 1 trial for vernakalant (iv) in Q4-2004 and final results in Q1-2005. ACT 1 involved studies in 416 patients, and provided data on the level of safety and effectiveness of vernakalant in the acute treatment of AF and atrial flutter. Fifty two percent of patients with recent onset AF (duration 3 hrs to 7 days) receiving vernakalant (iv) converted to normal heart rhythm, as compared to 4% of placebo patients (p< .001).
In the overall AF study population (AF duration of 3 hours to 45 days) 38% of patients receiving vernakalant (iv) experienced termination of AF as compared to 3% of placebo patients (p< .001). In the longer-term AF population, 8% of vernakalant (iv) patients experienced AF termination, as compared to 0% of placebo patients.
Vernakalant appears to be ineffective in converting atrial flutter patients to normal heart rhythm. Only 1 of 39 patients dosed with vernakalant (iv) converted to normal heart rhythm, while 0 of 15 placebo patients converted to normal heart rhythm.
The ACT 1 study data suggests that vernakalant is also safe and well-tolerated in the targeted patient population. There were no documented cases of drug-related Torsades de Pointes. In the 30-day interval following drug administration, serious adverse events occurred in 18% of placebo patients and 13% of drug group patients. Potentially drug-related serious adverse events occurred in 0% of placebo patients and 1.4% of patients receiving vernakalant.
In the recent-onset AF patients dosed with intravenous vernakalant who converted to normal heart rhythm, the median time to conversion was 11 minutes from the initiation of dosing. Of those recent-onset AF patients dosed with vernakalant who converted to normal heart rhythm within 90 minutes of the initiation of dosing, 1 of 75 patients relapsed to atrial arrhythmia within 24 hours.
ACT 3 Pivotal Phase 3 Trial
Cardiome reported top-line Phase 3 results for vernakalant (iv) for the ACT 3 trial in Q3-2005. ACT 3 was very similar in structure to ACT 1, and involved studies in 276 patients. Fifty one percent of patients with recent onset AF (duration 3 hrs to 7 days) receiving vernakalant (iv) converted to normal heart rhythm, as compared to 4% of placebo patients (p< .001). In the overall AF study population (AF duration of 3 hours to 45 days), 41% of patients receiving vernakalant (iv) experienced termination of AF as compared to 4% of placebo patients (p< .001). In the longer-term AF population, 9% of vernakalant (iv) patients experienced AF termination, as compared to 3% of placebo patients.
In atrial flutter patients, 7% of patients receiving vernakalant (iv) converted to normal heart rhythm, as compared to 0% of placebo patients.
The ACT 3 study data suggests that vernakalant is also safe and well-tolerated in the targeted patient population. There were no documented cases of drug-related Torsades de Pointes. In the 30-day interval following drug administration, serious adverse events occurred in 13% of placebo patients and 10% of drug group patients. Potentially drug-related serious adverse events occurred in 1% of placebo patients and 2% of patients receiving vernakalant.
In the recent-onset AF patients dosed with intravenous vernakalant who converted to normal heart rhythm, the median time to conversion was 8 minutes from the initiation of dosing.
Additional Studies
An additional Phase 3 study, ACT 2 was initiated in Q1-2004, and positive results were released in June 2007. The trial evaluated the efficacy and safety of vernakalant (iv) for the treatment of patients who developed atrial fibrillation or atrial flutter between 24 hours and 7 days following coronary artery bypass graft (CABG) or valve replacement surgery. In the atrial fibrillation population, 47% of patients dosed with vernakalant (iv) experienced conversion to normal heart rhythm within 90 minutes, as compared to 14% of placebo patients, a statistically significant difference (p=0.0001).
The ACT 2 study data suggests that vernakalant (iv) was well-tolerated in the studied patient population. In the 30-day interval following drug administration, serious adverse events occurred in 9% of all patients dosed with vernakalant (iv) and 11% of all placebo patients. Potentially drug-related serious adverse events occurred in 2% of patients who received vernakalant (iv) and 0% of placebo patients. There were no cases of drug-related “Torsades de Pointes”, a specific and well-characterized ventricular arrhythmia.
In Q4-2005, our collaborative partner Astellas initiated an open-label safety study, called ACT 4. This completed study further evaluated the safety of vernakalant (iv) in recent-onset atrial
fibrillation patients, and was intended to augment the safety database associated with the NDA
submission.
* Note: In September 2006, Cardiome announced that RSD1235 has been assigned the name "vernakalant hydrochloride" by the United States Adopted Names (USAN) Council. References to RSD1235 (iv) are now vernakalant (iv), and references to RSD1235 (oral) are now vernakalant (oral).