Vernakalant

37238511000001107

New Medicines

Brinavess (EU), Kynapid · Atrial fibrillation (AF)

Information

Brinavess (EU), Kynapid
New molecular entity
Cardiome
Cardiome

Development and Regulatory status

Launched
Launched
Not approved
November 2019
Dec 19 · Correvio Pharma receives a complete response letter (CRL) from the FDA, wherein the latter expressed its inability to approve intravenous vernakalant in its present form, for the treatment of AF. Specifically, the FDA pointed out that the submitted data provided substantial evidence of the drug ´s effectiveness, but lacked comprehensive safety evidence. The FDA recommended that Correvio develop an alternative approach to select patients who are at low risk of adverse cardiovascular reactions, and also suggested the conduction of an additional, potentially uncontrolled, clinical study. Data from the study, which will evaluate the drug ´s cardiovascular risk in the selected patient population would then support an NDA resubmission. The FDA also stated that the risk of serious cardiovascular adverse reactions would have to be much lesser than 1% in the selected patient population. The company, accordingly, intends to meet with the US FDA regarding the specifics and design of the prospective study and intends to enrol both US and ex-US patients [27].
Nov 19 · Launched in UK for rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults. This includes for non-surgery patients (AF ≤7 days duration) and for post-cardiac surgery patients (AF ≤3 days duration). 20mg/ml conc for soln for inf, 25ml vial=£290 [28,29].
Jul 19 · FDA accepts for review the resubmitted NDA for Brinavess. The FDA assigned a target action date of December 24, 2019 under the Prescription Drug User-Fee Act (PDUFA). The application was supported by data from the SPECTRUM trial [27].
Oct 18 · Correvio Pharma announces that based on the pre-NDA discussions, the US FDA agree that no additional studies would be required for the resubmission of the NDA of vernakalant for treatment of AF [27].
Jun 18 · Correvio Pharma receives communication from the FDA regarding the regulatory pathway for Brinavess in the US. The FDA informed the company that it would be permissible to the resubmission of the vernakalant NDA and agreed to schedule a pre-NDA meeting to discuss the content and format of the NDA resubmission. The FDA had advised Correvio to consider collecting data from electronic health records or administrative claims from health systems in countries where vernakalant is marketed as a source of additional data that could be informative to the FDA´s evaluation of the resubmission [27].
Aug 17 · FDA responds to a cardiome proposal for resubmission of a vernakalant NDA stating that the data package proposed by Cardiome would not be sufficient to support a resubmission of the vernakalant NDA. The company will continue to have discussions with the FDA [27].
Mar 13 · Cardiome is forming a small direct sales force to promote Brinavess® in Europe and developing its regulatory strategy for the product [27].
Mar 13 · The FDA placed a clinical hold on vernakalant intravenous in the US, in October 2010. [24]
Sep 12 · Merck & Co returns global marketing & development rights for the IV & oral formulations of vernakalant to Cardiome Pharma Corp [23].
Jul 12 · Unlikely to be available in the UK [22].
Oct 10 · Launched in Europe
Sep 10 · Vernakalant approved in the EU. It can be used for non-surgery pts with AF of 7 days or less & for post-cardiac surgery pts with AF of 3 days or less [19].
Jun 10 · A pharmacovigilance plan for Brinavess will be implemented as part of the marketing authorisation [17].
Jun 10 · EU positive opinion for vernakalant (Brinavess) in rapid conversion of recent onset AF to sinus rhythm in adults with AF of 7 days or less duration & in post-cardiac surgery pts with AF of 3 days or less duration [17].
Aug 09 · New PIIIb study, ACT 5, agreed with FDA [14].
Jul 09 · Filed in EU under centralised procedure [12].
Aug 08 · FDA concerns about potential cardiovascular adverse events have delayed licensing - a new clinical trial might be required (11).
Jan 08 · PIII in EU & US. Filing in US anticipated end 05, early 06 (2). Filed in US Mar 06 for atrial fibrillation (4). FDA found inconsistencies in file, new file accepted Feb 07 (5). Decision from US FDA for use in acute conversion of AF expected Oct 07 (6).
Dec 07 · Recommended for approval in the US (8) .

Category

Selective potassium channel modulator
The prevalence of AF is about 1,300 per 100,000 people. Data suggest 3 to 6% of acute emergency medical admissions in the UK have AF; about 40% of these are newly diagnosed.
Atrial fibrillation (AF)
Intravenous

Further information

Yes
To be confirmed

Trial or other data

Sep 19 · Correvio Pharma reports efficacy and safety data from the phase IV SPECTRUM study [27].
May 18 · Correvio Pharma completes enrolment in its phase IV SPECTRUM study designed to characterise normal conditions of use, dosing and safety following administration of Brinavess (NCT01370629). The primary end point of the trial is to determine the number of participants experiencing significant hypotension, ventricular arrhythmia, atrial flutter and bradycardia in a time frame of first vernakalant infusion up to 24 hours after the last infusion. The prospective, retrospective, post-authorisation safety study was initiated in August 2011 and enrolled 1,778 patients in the EU [27].
Nov 14 · NCT01174160; Double-blind PIII trial in pts with atrial fibrillation randomised a total of 123 pts to receive placebo or vernakalant to assess safety and efficacy and achieved the primary endpoint, showing that of the 111 treated pts with recent-onset AF lasting 3 hours to 7 days, 53% of those receiving an IV dose of BRINAVESS converted to normal heart rhythm within 90 minutes, compared to 12% of placebo patients (95% CI; 23%, 58%, p<0.001). Patients were enrolled in China, India, Hong Kong, South Korea and Taiwan. [26]
Sep 13 · Sep 13, Cardiome reported the publication of positive data, from an open-label study that compared vernakalant IV with oral propafenone and oral flecainide, in the Journal of Atrial Fibrillation. In Oct13, Cardiome reported, in The European Journal of Cardiovascular Medicine, the results of an observational, retrospective study in 251 pts with recent-onset atrial fibrillation who received intravenous vernakalant; 70% of these pts converted, with a median time of 11 minutes. Median time in the emergency department for the pts who converted was 6.5 hours. [25]
Jan 11 · AVRO study published - J Am Coll Cardiol 2011; 57(3): 313-321 [21].
Oct 10 · Pt enrollment in PIIIb RCT (ACT 5 study) suspended. There was a single unexpected serious adverse event of cardiogenic shock experienced by a patient with atrial fibrillation (AF) who received vernakalent injection. The trial’s independent Data Safety Monitoring Board has reviewed the case and recommended the trial continue, however the US FDA has requested that full data regarding this case from the South American clinical site be provided for their review prior to determining what steps, if any, are needed to recommence the study. [20]
Aug 10 · Merck has delayed PIII development for the oral formulation of vernakalant, which was expected to start this summer. Analysts predict that the launch date will also be delayed, from 2015 to at least 2016 [18].
Jun 10 · The most common side effects seen in the first 24 hrs after receiving vernakalant are dysgeusia, sneezing & paraesthesia. Serious side effects, including hypotension, bradycardia & complete AV block occur infrequently. The arrhythmogenic potential of vernakalant appears limited but more information on this potential will be collected from a Post-authorisation Registry study [17].
May 10 · In the PIII AVRO study, 254 pts with symptomatic AF of 3 to 48 hours duration were randomised to vernakalant (3mg/kg over 10 mins then a further 2mg/kg if required) or amiodarone (5mg/kg over 60 mins, then 50mg over 60 mins until pt converts). The primary endpoint was the proportion of pts with conversion to sinus rhythm (SR) within 90 mins – this occurred in 51.7% of the vernakalant gp & 5.2% of the amiodarone gp (p 2 events in either gp) were dysgeusia (6.9% on vernakalant vs. none on placebo); cough (3.4% vs. 1.7%); sneezing (3.4% vs. 0%); atrial fibrillation (3.4% vs. 0%); nausea (2.6% vs. 1.7%); dizziness (2.6% in both); & hypertension (2.6% vs. 0%) [16].
Dec 09 · Headline results from the PIII European comparator AVRO study indicate that IV vernakalant was superior to amiodarone in the conversion of atrial fibrillation to normal heart rhythm within 90 minutes of the start of drug administration [15].
Dec 09 · Cardiome and Merck & Co have signed a license agreement. Merck has exclusive global rights to vernakalant oral for the maintenance of normal heart rhythm in patients with atrial fibrillation and MSD will get exclusive rights outside of the US, Canada and Mexico to IV vernakalant for rapid conversion of acute atrial fibrillation. Merck has exclusive rights to market vernakalant in the EU. Cardiome has retained an option to co-promote vernakalant oral with Merck through a hospital-based sales force in the US [15].
Aug 09 · A confirmatory additional PIII trial, ACT 5, will begin enrolling patients by the end of 2009, with completion expected in 1H of 2011. This trial has resulted from discussions with the FDA and the design of the study, which will enroll 450 patients with recent-onset AF (>3 hours <7days) without a history of CHF, has been agreed under the Special Protocol Assessment process. Further, the study will evaluate the influence of CYP2D6 genotype status on the pharmacokinetics and pharmacodynamics of vernakalant and its metabolites, and also allows for an exploratory analysis of safety and healthcare resource utilization between vernakalant and electrocardioversion (ECV) [14].
Aug 09 · NCT00668759 (AVRO): PIII study evaluating superiority of vernakalant vs amiodarone in the conversion of atrial fibrillation to sinus rhythm within 90 min of the start of the infusion in 240 patients with recent onset atrial fibrillation (3 to 48 hours). The study was started in Apr 2008 in Canada and EU and will complete Aug 2009 [13].
Mar 08 · PIII data from ACT I: Pts in vernakalant group with AF lasting 3-48 hrs had highest conversion rate (62.1%) vs 4.9% in the placebo group. Mean time to conversion in active group was 11 mins. Only 1 of the 75 pts in the active group relapsed. (10).
Mar 08 · PIII data from ACT I. Primary efficacy analysis showed 75/145 vernakalant pts in the short-duration AF group (3hours to 7days) converted to sinus rhythm within 90mins vs. 3/75 in the placebo group.(10)
Mar 08 · PIII study published (9)
Mar 08 · IV formulation for acute setting, oral formulation also in development. Positive reports from placebo controlled trial - conversion to normal heart rhythm occurred in 52% of those receiving IV RSD 1235 compared to 4% of patients receiving placebo (p < 0.001) (3). Phase III trial, ACT 2, acheived primary endpoint in the combined atrial fibrillation and atrial flutter groups: 45% of pts receiving vernakalant converted to normal heart rhythm within 90 minutes vs.15% of placebo pts (7).

Evidence based evaluations