Europace Publishes Data Supporting Use Of BRINAVESS™ (Vernakalant) As A First Line Agent For Pharmacological Cardioversion Of Atrial Fibrillation

Vernakalant, MK-6621, RSD 1235

(3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)
ethoxy]cyclohexyl}pyrrolidin-3-ol

C₂₀H₃₁NO₄ ,  349.47, Brinavess , Kynapid

cas no 794466-70-9 
748810-28-8 (HCl)

EMA:Link  click here

PATENT   WO 2004099137

VANCOUVER, Nov. 21, 2013 /PRNewswire/ – Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM) today announced that a publication titled, Pharmacological Cardioversion of Atrial Fibrillation with Vernakalant: Evidence in Support of the ESC Guidelines, was published in Europace, the official Journal of the European Heart Rhythm Association, and was made available in the advanced online article access section. The authors conclude that BRINAVESS is an efficacious and rapid acting pharmacological cardioversion agent, for recent-onset atrial fibrillation (AF,) that can be used first line in patients with little or no underlying cardiovascular disease and in patients with moderate disease, such as stable coronary and hypertensive heart disease.

http://www.prnewswire.com/news-releases/europace-publishes-data-supporting-use-of-brinavess-vernakalant-as-a-first-line-agent-for-pharmacological-cardioversion-of-atrial-fibrillation-232816731.html

Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009.^[1] In September 2012, Merck terminated its agreements with Cardiom and has consequently returned all rights of the drug back to Cardiom.

On 11 December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the USFood and Drug Administration (FDA) voted to recommend the approval of vernakalant,^[2]but in August 2008 the FDA judged that additional information was necessary for approval.^[1] The drug was approved in Europe on 1 September 2010.^[3]

An oral formulation underwent Phase II clinical trials between 2005 and 2008.^[4][5]

Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.^[6]

The drug also blocks atrial sodium channels.^[6]

1.  “Merck and Cardiome Pharma Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation”. FierceBiotech. 9 April 2009. Retrieved 12 October 2010.
2.  “FDA Advisory Committee Recommends Approval of Kynapid for Acute Atrial Fibrillation”. Drugs.com. Retrieved 2008-03-15.
3.  “BRINAVESS (vernakalant) for Infusion Approved in the European Union for Rapid Conversion of Recent Onset Atrial Fibrillation” (Press release). Merck & Co., Inc. 1 September 2010. Retrieved 28 September 2010.
4.  ClinicalTrials.gov NCT00267930 Study of RSD1235-SR for the Prevention of Atrial Fibrillation/Atrial Flutter Recurrence
5.  ClinicalTrials.gov NCT00526136 Vernakalant (Oral) Prevention of Atrial Fibrillation Recurrence Post-Conversion Study
6.  Miki Finnin, Vernakalant: A Novel Agent for the Termination of Atrial Fibrillation: Pharmacology, Medscape Today, retrieved 12 October 2010

• Arzneimittel-Fachinformation (EMA)
• Cheng J.W. Vernakalant in the management of atrial fibrillation. Ann Pharmacother, 2008, 42(4), 533-42Pubmed 
• Dobrev D., Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet, 2010, 375(9721), 1212-23 Pubmed 
• Finnin M. Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm, 2010, 67(14), 1157-64 Pubmed 
• Mason P.K., DiMarco J.P. New pharmacological agents for arrhythmias. Circ Arrhythm Electrophysiol, 2009, 2(5), 588-97 Pubmed 
• Naccarelli G.V., Wolbrette D.L., Samii S., Banchs J.E., Penny-Peterson E., Stevenson R., Gonzalez M.D. Vernakalant – a promising therapy for conversion of recent-onset atrial fibrillation. Expert Opin Investig Drugs, 2008, 17(5), 805-10 Pubmed 
• European Patent No. 1,560,812
• WO 2006138673, WO 200653037
• WO 200597203, WO 200688525
• Vernakalant HydrochlorideDrugs Fut 2007, 32(3): 234

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Nitrogen: dark blue, oxygen: red, hydrogen: light blue

NMR

1H NMR (300 MHz, CDCI3) 5 6.75 (m, 3H), 4.22 (m, 1H), 3.87 (s, 3H), 3.85 (m, 3H), 3.74 (m, 1H), 3.57 (m, 1H), 3.32 (td, J =
7.7, 3.5, 1H), 2.96-2.75 (m, 5H), 2.64 (dd, J= 10.0, 5.0, 1H), 2.49-2.37 (m, 2H), 2.05-1.98 (m, 2H), 1.84 (m, 1H), 1.69-1.62 (m, 3H), 1.35-1.19 (m, 4H).

IN

WO 201240846

Arrhythmias are abnormal rhythms of the heart. The term “arrhythmia” refers to a deviation from the normal sequence of initiation and conduction of electrical impulses that cause the heart to beat. Arrhythmias may occur in the atria or the ventricles. Atrial arrhythmias are widespread and relatively benign, although they place the subject at a higher risk of stroke and heart failure. Ventricular arrhythmias are typically less common, but very often fatal.

Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities due to cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these will be first heart attacks and 450,000 will be recurrent attacks. About one-third of the people experiencing these attacks will die of them. At least 250,000 people a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach a hospital. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E.L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(l):264-7 Jan. 1992). Its prevalence is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W.B., Abbot R.D., Savage D.D., McNamara P.M., N. Engl. J. Med. 306(17): 1018-22, 1982; Wolf P.A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R.C., Kistler J.P., Fallon J.T., Friedlich A.L., Fisher CM., American Journal of Cardiology 40(4):509-13, 1977; Wolf P.A., Abbot R.D., Kannel W.B., Archives of Internal Medicine 147(9): 1561 -4, 1987; Wolf P. A., Abbot R.D., Kannel W.B. Stroke. 22(8):983-8, 1991; Cabin H.S., Clubb K.S., Hall C, Perlmutter R.A., Feinstein A.R., American Journal of Cardiology 65(16): 1112-6, 1990).

WO95/08544 discloses a class of aminocyclohexylester compounds as useful in the treatment of arrhythmias.

WO93/ 19056 discloses a class of aminocyclohexylamides as useful in the treatment of arrhythmia and in the inducement of local anaesthesia.

WO99/50225 discloses a class of aminocyclohexylether compounds as useful in the treatment of arrhythmias.

Antiarrhythmic agents have been developed to prevent or alleviate cardiac arrhythmia. For example, Class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. Treatment of ventricular arrhythmia is very important since such an arrhythmia can be fatal. Serious ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) occur most often in the presence of myocardial ischemia and/or infarction. Ventricular fibrillation often occurs in the setting of acute myocardial ischemia, before infarction fully develops. At present, there is no satisfactory pharmacotherapy for the treatment and/or prevention of ventricular fibrillation during acute ischemia. In fact, many Class I antiarrhythmic compounds may actually increase mortality in patients who have had a myocardial infarction.

Class la, Ic and HI antiarrhythmic drugs have been used to convert recent onset AF to sinus rhythm and prevent recurrence of the arrhythmia (Fuch and Podrid, 1992; Nattel S., Hadjis T., Talajic M., Drugs 48(3):345-7l, 1994). However, drug therapy is often limited by adverse effects, including the possibility of increased mortality, and inadequate efficacy (Feld G.K., Circulation. <°3(<5):2248-50, 1990; Coplen S.E., Antman E.M., Berlin J.A., Hewitt P., Chalmers T.C., Circulation 1991; S3(2):714 and Circulation 82(4):1106-16, 1990; Flaker G.C., Blackshear J.L., McBride R., Kronmal R.A., Halperin J.L., Hart R.G., Journal of the American College of Cardiology 20(3):527-32, 1992; CAST, N. Engl. J. Med. 321:406, 1989; Nattel S., Cardiovascular Research. 37(3):567 -77, 1998). Conversion rates for Class I antiarrhythmics range between 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48(3)345-71, 1994; Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology. 9(8 Suppl):S 104-8, 1998). Class ILT antiarrhythmics appear to be more effective for terminating atrial flutter than for AF and are generally regarded as less effective than Class I drugs for terminating of AF (Nattel S., Hadjis T., Talajic M., Drugs. 48(3):345-71, 1994; Capucci A., Aschieri D., Villani G.Q., Drugs & Aging 13(l):5l- 70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. Conversion rates for these drugs range between 30-50% for recent onset AF (Capucci A., Aschieri D., Nillani G.Q., Drugs & Aging J3(l):5l-70, 1998), and they are also associated with a risk of the induction of Torsades de Pointes ventricular tachyarrhythmias. For ibutilide, the risk of ventricular proarrhythmia is estimated at ~4.4%, with ~1.7% of patients requiring cardioversion for refractory ventricular arrhythmias (Kowey P.R., NanderLugt J.T., Luderer J.R., American Journal of Cardiology 78(8A):46-52, 1996). Such events are particularly tragic in the case of AF as this arrhythmia is rarely a fatal in and of itself.

 

Atrial fibrillation is the most common arrhythmia encountered in clinical practice. It has been estimated that 2.2 million individuals in the United States have paroxysmal or persistent atrial fibrillation. The prevalence of atrial fibrillation is estimated at 0.4% of the general population, and increases with age. Atrial fibrillation is usually associated with age and general physical condition, rather than with a specific cardiac event, as is often the case with ventricular arrhythmia. While not directly life threatening, atrial arrhythmias can cause discomfort and can lead to stroke or congestive heart failure, and increase overall morbidity.

There are two general therapeutic strategies used in treating subjects with atrial fibrillation. One strategy is to allow the atrial fibrillation to continue and to control the ventricular response rate by slowing the conduction through the atrioventricular (AV) node with digoxin, calcium channel blockers or beta-blockers; this is referred to as rate control. The other strategy, known as rhythm control, seeks to convert the atrial fibrillation and then maintain normal sinus rhythm, thus attempting to avoid the morbidity associated with chronic atrial fibrillation. The main disadvantage of the rhythm control strategy is related to the toxicities and proarrhythmic potential of the anti-arrhythmic drugs used in this strategy. Most drugs currently used to prevent atrial or ventricular arrhythmias have effects on the entire heart muscle, including both healthy and damaged tissue. These drugs, which globally block ion channels in the heart, have long been associated with life-threatening ventricular arrhythmia, leading to increased, rather than decreased, mortality in broad subject populations. There is therefore a long recognized need for antiarrhythmic drugs that are more selective for the tissue responsible for the arrhythmia, leaving the rest of the heart to function normally, less likely to cause ventricular arrhythmias.

One specific class of ion channel modulating compounds selective for the tissue responsible for arrhythmia has been described in U.S. Pat. No. 7,057,053, including the ion channel modulating compound known as vernakalant hydrochloride. Vernakalant hydrochloride is the non-proprietary name adopted by the United States Adopted Name (USAN) council for the ion channel modulating compound (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxyphenethoxy)-cyclohexane monohydrochloride, which compound has the following formula:

Vernakalant hydrochloride may also be referred to as “vernakalant” herein.

Vernakalant hydrochloride modifies atrial electrical activity through a combination of concentration-, voltage- and frequency-dependent blockade of sodium channels and blockade of potassium channels, including, e.g., the ultra-rapidly activating (l_Kur) and transient outward (l_to) channels. These combined effects prolong atrial refractoriness and rate-dependently slow atrial conduction. This unique profile provides an effective anti-fibrillatory approach suitable for conversion of atrial fibrillation and the prevention of atrial fibrillation.

C₂₀H₃₂ClNO₄, M_r = 385.9 g/mol