Background Analysis: US FDA Advisory Committee to Review Correvio’s Brinavess (Vernakalant) for Proposed Treatment of Atrial Fibrillation – DEC 10, 2019 (CRDAC)

Announcement

The US FDA has scheduled a Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting for Tuesday, December 10, 2019 to discuss a new drug application (NDA) for vernakalant HCl solution for intravenous injection (Proposed US Trade Name: Brinavess), resubmitted by Correvio International Sàrl (Correvio), for the proposed indication of rapid conversion of recent onset atrial fibrillation to sinus rhythm for non-surgery patients: atrial fibrillation ≤ 7 days duration, and for post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration.

Product Background

Mechanism of Action

Vernakalant is an antiarrhythmic medicine that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow impulse conduction.

Marketing Authorizations

Vernakalant has received marketing authorizations in 41 countries outside the US. To date, it is not approved for use in the US.

Clinical Trials of Proposed Indication

Top-line results of a post-authorization (European) safety study, named SPECTRUM, are presented below based on a Correvio press release about the NDA resubmission, dated July 25, 2019.

SPECTRUM was a post-authorization safety study that was conducted in Europe. The study evaluated 1,778 patients across a total of 2,009 treatment episodes following administration of Brinavess. According to Correvio, the SPECTRUM data demonstrated that treatment with Brinavess successfully converted 70.2% of those treated atrial fibrillation (AF) patients into normal sinus rhythm. In addition, the company reported that treatment with Brinavess showed a median time to conversion of 11 minutes from the start of the first infusion among patients who successfully converted. The cumulative incidence of health outcomes of interest (defined as significant hypotension, ventricular arrhythmia, atrial flutter, or bradycardia) was reported in 0.8% of patients. Twenty-eight serious adverse events were reported in 26 of the 1,778 patients, and no deaths were reported in the study.

Although the press release highlights the SPECTRUM study results, it also notes the NDA is supported by nine Phase 3 and Phase 2 clinical trials and over 8 years of post-marketing experience in approximately 50,000 treatment patients worldwide. A comprehensive summary of the full data package submitted to the FDA, and detailed analyses by both Correvio and the FDA, will be made available 2 days prior to the CRDAC meeting, in briefing materials posted by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

Regulatory Considerations

On December 11, 2007 the CRDAC reviewed the initial NDA, then sponsored by Astellas Pharma US, Inc, for the proposed indication of use for conversion of AF to normal sinus rhythm. The committee recommended approval, by a vote of 6-Yes and 2-No (Voting question: Should vernakalant be approved for the conversion of AF?). The FDA subsequently denied approval of the NDA.

According to the FDA’s official Meeting Minutes, the CRDAC members who favored approval were asked to comment on what range of durations of AF an approval should apply. The committee majority felt the range should be limited to 3-48 hours, after which the efficacy diminishes. They also recommended that this should clearly be stated on the label. The committee majority was also asked to comment on whether use should extend to patients with recent myocardial infarction (MI) or heart failure (HF). They agreed that the drug should have a narrow indication for approval, which should take into consideration stable hemodynamics and which should not extend to those with recent MI, and they also questioned use in patients with HF. In addition, the committee majority agreed that approval should not extend to atrial flutter. The committee minority who voted against approval cited significant concerns that the safety of the drug was not well characterized.

The committee also discussed the sponsor’s post-marketing plan. Some agreed that additional data on non-Caucasians would be beneficial. There was considerable discussion about the need for additional studies in HF. Though some felt it would be nice to see a controlled HF study, others commented that there are significant efforts in labeling to exclude patients with HF. The committee also discussed questions surrounding drug interactions but felt they did not know enough about the metabolism and concluded drug that drug interactions need to be better defined.

US Regulatory Background

December 24, 2019 - PDUFA goal date (NDA resubmission 022034)

June 24, 2019 – Correvio announced the NDA resubmission (NDA resubmission 022034).

December 11, 2007 – The CRDAC reviewed the initial NDA (NDA 022034).

EU Regulatory Background

January 9, 2010 – The product was authorized for use throughout the EU by the European Medicines Agency (EMA), under the Trade Name: Brinavess. Its current indication is as follows:

Rapid conversion of recent onset atrial fibrillation to sinus rhythm in adults

-For non-surgery patients: atrial fibrillation ≤ 7 days duration

-For post-cardiac surgery patients: atrial fibrillation ≤ 3 days duration

Its current contraindications are as follows:

• Hypersensitivity to the active substance or to any of the excipients.

• Patients with severe aortic stenosis, patients with systolic blood pressure < 100 mm Hg, and patients with heart failure class NYHA III and NYHA IV.

• Patients with prolonged QT at baseline (uncorrected > 440 msec), or severe bradycardia, sinus node dysfunction or second degree and third degree heart block in the absence of a pacemaker.

• Use of intravenous rhythm control antiarrhythmics (class I and class III) within 4 hours prior to, as well as in the first 4 hours after, BRINAVESS administration.

• Acute coronary syndrome (including myocardial infarction) within the last 30 days.

Global Regulatory Background

Overall, Brinavess has received marketing authorizations in 41 countries outside the US.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Correvio International Sàrl Drug Name: vernakalant HCl solution for intravenous injection Drug Class: antiarrhythmic medicine Indication: atrial fibrillation

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.