The Food and Drug Administration (FDA)’s Cardiovascular and Renal Drugs Advisory Committee voted 2 to 11 against the approval of Brinavess (vernakalant hydrochloride; Correvio Pharma) for the rapid conversion of recent onset atrial fibrillation (AF) to sinus rhythm in non-cardiac surgery patients (AF ≤ 7 days duration) and post-cardiac surgery patients (AF ≤ 3 days duration).
Brinavess is an intravenously-administered antiarrhythmic drug that prolongs atrial refractoriness and slows impulse conduction in a rate-dependent fashion. The Company resubmitted the New Drug Application (NDA) in July 2019 after the FDA issued a Refusal to File letter in August 2017 based on an incomplete data package.
The resubmitted NDA included data from the SPECTRUM study conducted in Europe that evaluated 1778 patients across a total of 2009 treatment episodes following Brinavess administration. Results showed that Brinavess successfully converted 70.2% of patients into normal sinus rhythm (median time to conversion of 11 minutes). The Company also included data from nine phase 3 and phase 2 trials that were conducted over the last 8 years.
However, in meeting documents, the FDA pointed out that the SPECTRUM trial, which was meant to reassure the Agency of the safety of vernakalant, did not provide that reassurance due to “significant limitations in the registry design (eg, non-consecutive enrollment) leading to selection bias.” Previous trials have reported serious vernakalant-induced cardiovascular adverse events including hypotension, bradycardia, ventricular arrhythmia, conduction disturbance, and death.
In their risk mitigation strategy, the Company proposed that use of vernakalant should be contraindicated in patients with systolic blood pressure <100, in those with severe heart failure, aortic stenosis, severe bradycardia or heart block, QT prolongation, acute coronary syndrome in the last 30 days, or with concomitant Class I or III antiarrhythmics (4 hours before or after administration). In addition, a “Pre-Infusion Checklist” was proposed to clearly outline the contraindications to healthcare providers.
“There is insufficient evidence to suggest that the contraindications proposed (and highlighted in the “Pre-Infusion Checklist”) would sufficiently mitigate the risk of serious vernakalant-related events,” the FDA stated, adding that cardiovascular adverse events have been reported in patients with no apparent baseline structural heart disease, hypotension, or bradycardia. Moreover, in one patient, treatment with vernakalant led to ventricular arrhythmia, cardiogenic shock and death; the patient had no apparent structural heart disease and no contraindications to treatment.
Commenting on the vote, Mark H.N. Corrigan, MD, Chief Executive Officer of Correvio, said, “We are disappointed with today’s outcome because we believe in the strength of the data we presented today for Brinavess. We remain confident in the safety and efficacy of the agent in the countries where it is approved and currently marketed.”
Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act (PDUFA) date of December 24, 2019 has been assigned to the application.
For more information visit fda.gov.
This article originally appeared on MPR