Vernakalant: RSD 1235, RSD-1235, RSD1235

Vernakalant is an atrial-selective antiarrhythmic drug discovered by Cardiome Pharma (formerly Nortran Pharmaceuticals). Vernakalant may have potential in the treatment of atrial arrhythmias, including acute atrial fibrillation and atrial flutter. Vernakalant is a mixed sodium/potassium channel blocker and selectively blocks ion channels in the heart that are known to be active during episodes of atrial fibrillation. An IV formulation of vernakalant is awaiting registration in the US for the acute conversion of atrial fibrillation. Also, an oral formulation of the compound is in phase II clinical development as a chronic-use product for the maintenance of normal heart rhythm following termination of atrial fibrillation. Cardiome is seeking co-development partners for intravenous vernakalant in the treatment of atrial arrhythmia, atrial fibrillation and atrial flutter in Europe and Japan. In October 2003, Cardiome Pharma and Fujisawa Healthcare, the US subsidiary of Fujisawa Pharmaceutical Co., Ltd (now Astellas Pharma), executed a $US68 million strategic partnership agreement for the co-development of vernakalant. On 1 April 2005, Fujisawa merged with Yamanouchi to form Astellas Pharma. The partnership grants Astellas Pharma exclusive commercialisation rights for vernakalant. Under the terms of the agreement, Cardiome and Astellas Pharma will co-develop vernakalant as an intravenous formulation for the treatment of atrial fibrillation and atrial flutter for North American markets. Astellas Pharma will be financially responsible for 75% of all future clinical development costs, with Cardiome responsible for the remaining 25% of costs. Astellas Pharma will be responsible for the development plan, NDA application (and NDA re-submission costs) and registration, along with the commercial manufacturing, marketing and sale of vernakalant. Cardiome will manage the phase III trials ACT 1 and ACT 2 and will also be responsible for the continued manufacturing of clinical supplies of vernakalant. Cardiome will receive royalties on end-user sales of vernakalant reflective of Cardiome's 25% share of development costs and other financial considerations. Product rights to the IV formulation of vernakalant for markets outside of North America and world rights to the oral formulation of vernakalant for chronic atrial fibrillation are not included within the scope of this partnership. Cardiome intends to form future additional alliances for these product opportunities or maintain such opportunities for commercialisation on its own. Cardiome and Astellas amended their agreement for vernakalant in relation to the re-submission of the NDA with the US FDA. Under the terms of the new agreement, Astellas agreed to fund 100% of the costs associated with re-submission, including engagement and external consultants. Astellas also agreed to modify the timing of the $US10 million NDA milestone to the date of resubmission. In February 2005, Cardiome Pharma received a $US6 million milestone payment from its co-development partner, Fujisawa Healthcare Inc. This milestone payment was triggered by the successful completion of ACT 1.A pivotal phase II trial demonstrated in September 2002 that vernakalant rapidly and effectively terminated recent onset atrial fibrillation and the study met both primary and secondary study endpoints. Following discussions with the FDA, Cardiome initiated three separate phase III clinical trials in order to enable Cardiome to apply for marketing approval for vernakalant. In August 2003, Cardiome Pharma commenced patient dosing in its first phase III efficacy study of vernakalant for the acute treatment of atrial fibrillation. This initial study, called ACT 1 (Atrial fibrillation Conversion Trial 1), measured the safety and efficacy of vernakalant in 416 patients with atrial arrhythmias. The placebo-controlled study was carried out in 45 centers in the US, Canada and Scandinavia. The ACT 1 study included two substudies of 60 patients with atrial flutter and 119 patients with longer term atrial fibrillation. The primary efficacy endpoint was acute conversion of atrial arrhythmia to normal heart rhythm. Cardiome commenced its second phase III efficacy study in March 2004, known as ACT 2. The ACT 2 study in post-cardiac surgery (coronary artery bypass graft) patients with atrial fibrillation, evaluated the safety and efficacy of vernakalant (IV) in the termination of atrial arrhythmias in patients after cardiac surgery. Around 210 patients from 25 centres in the US, Canada and Europe were enrolled in this study. The primary efficacy endpoint was acute conversion of atrial arrhythmias to normal heart rhythm. The ACT 2 study is ongoing. The third phase III study, known as ACT 3 (Atrial arrhythmia Conversion Trial 3), was initiated by Cardiome Pharma in July 2004. In September 2005, Cardiome and Astellas reported that ACT 3 had been completed, achieving its primary endpoint, with over half of the 170 patients with recent-onset atrial fibrillation (AF) who received vernakalant intravenously converting to normal heart rhythm, compared with only 4% in the placebo group. The study was being conducted by co-development partner Astellas Pharma and measured the safety and efficacy of intravenous vernakalant in recent onset atrial arrhythmia patients. The placebo-controlled study was being carried out in 276 patients in more than 50 centres throughout the world.ACT 4, a phase III safety study evaluating safety of IV vernakalant in approximately 120 AF patients from 30 centres in the US, Canada and Europe, was initiated in October 2005. Results from this trial are expected to supplement trial results from the pivotal ACT 1 and 3 trials. This study is ongoing. Cardiome Pharma successfully completed phase I studies for its controlled-release oral formulation of vernakalant in 2005. The oral, controlled-release formulation of vernakalant is expected to help prevent or slow the recurrence of atrial fibrillation, and will be used as a follow-on therapy to intravenous vernakalant.