DSMB says vernakalant study okay to continue, but FDA requests full data on adverse event.
Cardiome Pharma confirmed that Astellas Pharma U.S, its North American development partner for the intravenous atrial fibrillation (AF) drug vernakalant hydrochloride (trademarked as Kynapid™ in North America), has suspended patient enrolment into a Phase IIIb trial after one patient suffered cardiogenic shock. While the ACT 5 trial’s independent Data Safety Monitoring Board has reviewed available data and recommended the trial continue, FDA has asked to review full data on the case before deciding on what steps, if any, will be needed to restart the study.
The adverse serious event, which occurred at a South American clinical site, comes just weeks after the intravenous formulation of vernakalant, trademarked as Brinavess™ was granted approval in the EU, Norway, and Iceland for use in the rapid conversion of recent onset AF to sinus rhythm in adults.
The halted Phase IIIb study was scheduled to enrol about 470 patients with recent onset atrial fibrillation across 100 sites. Individual patients with either evidence or a history of congestive heart failure are excluded. The study is being conducted in parallel with a trial evaluating the impact of CYP2D6 genotype on the pharmacodynamics and pharmacokinetics of the drug and its metabolites.
“We and Astellas will work closely with the clinical trial site, the DSMB, and the FDA to review this serious adverse event and seek to resume patient enrolment and treatment in the ACT 5 study as soon as it is appropriate to do so,” notes Doug Janzen, Cardiome president and CEO.
Development of intravenous vernakalant in North America has been partnered with Astellas Pharma under a 2003 licensing agreement. Perhaps ironically, the ACT 5 study was designed as a confirmatory trial to satisfy FDA’s request in 2008 for additional data in support of the drug‘s submitted marketing application. At the time, FDA told Astellas that the Kynapid NDA was approvable, but it wanted additional data relating to the risk of “previously identified events experienced by a subset of patients.” Final design of the ACT 5 study was announced in August 2009.
While Astellas represents Cardiome’s North American partner for intravenous vernakalant, the drug is partnered elsewhere in the world with Merck & Co,, through its Merck Sharpe and Dohme affiliates. This 2009 deal also gave Merck Sharpe and Dohme global rights to the Phase II-stage oral formulation of vernakalant, which is in development as maintenance therapy for the long-term prevention of atrial fibrillation recurrence. Cardiome earned a $30 million milestone payment from Merck on achievement of EU approval of intravenous vernakalant in September.
European clearance was granted on the basis of data from the placebo-controlled ACT I, ACT II, and ACT III studies as well as an active comparator trial, AVRO. In ACT I and III, the efficacy of Brinavess at converting patients from AF to sinus rhythm for a minimum duration of one minute within 90 minutes of initiating therapy was evaluated in 390 hemodynamically stable adult patients with short duration AF (3 hours to 7 days). Both these trials showed vernakalant cardioverted 51% of treated patients, whereas only up to 4% of placebo patients cardioveorted.
The AVRO study compared the effectiveness of intravenous vernakalant with that of amiodarone infusion in subjects with recent onset atrial fibrillation. The primary endpoint was the proportion of patients that achieved sinus rhythm for a minimum duration of one minute within 90 minutes of the first exposure of the study drug. The results showed that treatment with vernakalant converted 51.7%of patients to sinus rhythm at 90 minutes, compared with just 5.2% of patients infused with amiodarone.