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Ventricular Fibrillation and Atrial Fibrillation : Emerging Antiarrhythmics In The Context of Current Devices, Interventions and Pharmacological AgentsPublished by: LeadDiscovery Published: May. 1, 2006 - 69 Pages Table of Contents
AbstractAlthough ventricular and atrial fibrillation represent the most common cardiac arrhymias and are associated with amongst the highest rates of cardiovascular morbidity and mortality, treatment options are suboptimal. New opportunities are however approaching the market, notably Cardiome’s RSD1235, paving the way for development by others.This report discusses current pharmacological and interventional treatments of ventricular and atrial fibrillation paying especial attention to unmet needs and drivers of future development. The report then provides a detailed proof of concept of emerging molecular targets for next generation therapeutics and critical profiles of pipeline candidates. The report is of equal use to companies with developmental and marketed devices and those involved in drug development. For the former the report sets out the competitive landscape while on the other hand it identifies areas where pharmacological and interventional approaches can meet; on the other hand the report represents an invaluable intelligence tool to those companies looking to develop novel and more effective antiarrhythmics. The report was produced with both research and business development personnel in mind. Scope of the report: This report provides
1. Recent research has clearly identified a large number of molecules involved in maintaining normal sinus rhythm: The report provides a thorough and up to data evaluation of the molecular basis of normal sinus rhythm. The different phases of the cardiac action potential are discussed along with the various currents that govern these phases and in turn the ion channels that carry these currents. The aim is to provide the reader with a firm understanding of cardiac electrophysiology in order to make clear the mechanisms underlying arrhythmias and insight into therapeutic targets discussed later in the report. 2. Atrial fibrillation represents a massive market albeit presenting with distinct subtypes each suitable for different clinical approaches: The report provides detailed figures identifying the number of patients with atrial fibrillation in the 7 major pharmaceutical markets (US, Japan, UK, France, Germany Italy and Spain) plus forecast growth in these numbers. The report then goes on to discuss the symptoms and consequences of atrial fibrillation and importantly defines and quantifies the various subtypes of disease. This represents a key point since each subtype is likely to benefit from different therapeutic approaches. 3. Bench level research has now revealed multiple targets for the treatment of atrial fibrillation: The report discusses the pathophysiology of atrial fibrillation. In addition to presenting electrical and structural changes, the report offers a detailed look at molecular changes that underlie atrial fibrillation. Changes in ion channel activity as well as gap junctions, neural control and structural abnormalities are all discussed. The report also gives a detailed account of the involvement of the rennin-angiotensin metabolic pathway in disease etiology. This pathway is already recognized as key to both the etiology and treatment of other cardiovascular disease; its possible involvement in atrial fibrillation is of significant interest as prudent use of currently available drugs could reduce risk factors of atrial fibrillation as well as the progression of disease. Furthermore the demonstration that ACE inhibitors or angiotensin receptor blockers are effective treatments of atrial fibrillation could dramatically expand the already massive market for such classes. 4. Clinical data suggests that rate control is preferable to rhythm control but is this really the case? Three main pharmacological approaches to atrial fibrillation are currently practiced: rhythm control; rate control and anticoagulation. The report only touches on the later as it is covered in another report “Atrial Fibrillation - Future Advances in Stroke Prevention”. The two different approaches of rhythm and rate control are discussed in detail and currently employed therapeutics from the two classes are critically profiled. Key clinical data, efficacy and adverse effects are compared. The report also describes the major clinical trials comparing the two different approaches. These studies have concluded that rhythm control failed to offer greater efficacy than rate control and that antiarrhythmics were associated with more severe adverse effects. These data underpin current guidelines which are discussed in the report. There are however major limitations to these trials. We uncover these and conclude that contrary to current guidelines rhythm control, especially with improved therapeutics may represent the way forward. 5. Potassium channel blockers present new opportunities for rhythm control and improved treatments of atrial fibrillation: Advances in our understanding of cardiovascular electrophysiology offer the drug development sector new opportunities for the development of antiarrhythmics. Data presented in this report particularly favor the development of Kv1.5 and Kv4.3 blockers. Both of these channels are selective to the atrium offering greater targeting and hence a reduced risk of adverse effects. The most persuasive proof of concept for developing Kv1.5 and/or Kv4.3 blockers is the successful development of Cardiome’s RSD1235 which is set to enter the market in the near future. Sanofi-Aventis’ amiodarone analogue is also set to enter the market but whether such an approach will dramatically alter the landscape of atrial fibrillation therapeutics is, we believe, doubtful. 6. The dynamic field of interventional approaches offers alternatives to pharmacology: The main competition for novel pharmacological approaches to atrial fibrillation has emerged in the form of interventional approaches. The report describes this dynamic field in detail. Catheter ablation of atrial fibrillation became the standard curative approach to atrial fibrillation however in early 2004 the occurrence of fistulae between the left atrium and the esophagus emerged as a serious risk and interventional approaches have shifted towards surgical procedures. In particular the development of Minimaze procedures is currently in its ascendancy and efforts are being targeted at improving energy-delivery systems to allow ablation of cardiac tissue under minimally invasive conditions. Very recently CryoCath Technologies have reported data on their Arctic Front catheter technology which may swing attitudes back towards catheter ablation. We compare the efficacy and safety of the major interventional approaches to pharmacological treatment and importantly discuss the appropriateness of treatment in different subtypes of atrial fibrillation. Although highly effective, the challenge to interventional approaches will be matching the numbers of physicians able to offer these treatments with the large number of patients requiring treatment. 7. Ventricular fibrillation represents a major cause of death: Ventricular fibrillation causes more than 70% of out-of-hospital cardiac arrests and is responsible for 220,000 deaths each year in the US . This report discuses the causes and current treatments of this arrhythmia. We also discuss the underlying electrical mechanisms. 8. Acute treatment of ventricular fibrillation is benefiting from improved use of defibrillators and will continue to do so with the emergence of better alternatives to amiodarone: The primary objectives in ventricular fibrillation patients are to restore sinus rhythm rapidly and to reduce the chance of future episodes. Electrical defibrillation remains the cornerstone in acute treatment of ventricular fibrillation. Guidelines dictate that the antiarrhythmic, amiodarone, should be employed in conjunction with defibrillation however the use of this agent has met with resistance, the rational for which is discussed. In contrast the use of defibrillators has benefited from major advances. Notably, the FDA granted marketing clearance for the first time for the over-the-counter sale of an automatic external defibrillator which is suitable for use by non-medical personnel. This advance is causing major growth in this market. We evaluate the potential molecular targets for future pharmacological treatments of ventricular fibrillation. Ventricular fibrillation frequently and rapidly ensues myocardial infarction and hence targeting the link between ischemia and arrhythmia would be expected to offer a rational approach to resuscitation. We believe that one of the most attractive opportunities at present involves the targeting of Kir6.2, the potassium channel that underlies cardiac K(ATP) currents. The most advanced candidate for the treatment of ventricular fibrillation is rotigaptide which increases gap junction intracellular communication. Ventricular fibrillation is thought to involve two phases: electrical and then metabolic. CPR is able to take patients back from metabolic failure to the electrical phase and we believe that sodium-selective sodium/hydrogen exchanger represents an area of interest for improving the treatment of patients in the metabolic phase. 9. Limited R&D of alternative or adjuncts to ICDs represents a major problem: Careful post resuscitative care is essential to survival because studies have shown a 50% repeat in-hospital arrest rate for people admitted after a ventricular fibrillation event. Likewise ventricular fibrillation usually occurs after hospital discharge. Most survivors of ventricular fibrillation are therefore candidates for implantable cardioverter defibrillators (ICDs). We discuss the clinical evidence leading to the surging use and market for these devices. Likewise we also evaluate their limitations and unmet needs. Notably, although implanted ICDs are effective it is estimated that up to 50% of ICD recipients eventually require concomitant antiarrhythmic drug therapy to reduce the number of delivered shocks. The therapy of choice is amiodarone and a primary driver for the drug development sector is currently to develop new antiarrhythmic agents with reduced adverse effects that will have a greater rate of adherence than amiodarone. In general however research of new molecular targets for adjuncts to or replacements of ICDs is quite sparse. We find this surprising and given the large numbers of patients suitable for ICDs and the fact that only 10% are actually recipients, we hope that this report will prompt companies to research and develop novel agents able to prevent ventricular fibrillation as monotherapies or as adjuncts to ICDs. 10. The market for antiarrhythmic agents has plummeted with patent expiries: Wyeth’s intravenous amiodarone formulation, Cordarone was first agent in this class to be marketed in the US in 1985. The US market for injectable amiodarone reached a peak in 2002, however in 2002, the amiodarone patent expired and six generics came to market. Generic competition has contributed to a plummeting market for amiodarone consequently sotalol overtook amiodarone as the leading antiarrhythmic in the US in 2004. Sales of antiarrhythmics have however been dropping as a class. The report describes sales of antiarrhythmics from 2002 to 2005 and forecasts sales to 2009. The report also provides a breakdown of the antiarrhythmics by therapeutic agent. 11. The pipeline of new treatments of atrial and ventricular arrhythmias is currently limited but is expected to expand: Overall given the prevalence and serious consequences of the two major arrhythmias it is perhaps surprising that fewer than 10 new candidates are in clinical development. These agents are all evaluated. We believe that this pipeline will expand in the future as companies exploit novel molecular targets such as those evaluated in this report. Get Full Details About This Report >> |
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