Archive for the ‘Atrial Fibrillation’ Category

FDA Rejects Xarelto for Second Time in Less Than a Year

Posted by CorDynamics on March 05th, 2013

FDA Denies Xarelto for Expanded Indications for Acute Coronary Syndromes

The FDA rejected Xarelto (rivaroxaban) for a second time in less than a year as a drug therapy for patients with acute coronary syndromes.

Timeline of Concern

May 2012: By a narrow margin, an FDA Cardiovascular and Renal Drugs Advisory Panel recommended against expanding the marketing indications to prescribe Xarelto as an acute coronary syndrome therapy.

June 2012: The FDA confirmed panel opinion and denied expanding  Xarelto as an acute coronary syndrome therapy, citing concern over incomplete data.

  • The gaps occurred after nearly 1,300 patients dropped out of 15,000+-subject final-phase study and withdrew consent for access to their health information. There were also notable concerns about bleeding risks – in the absence of antidote – for rivaroxaban.

March 2013: FDA rejects Xarelto bid sending a second “complete response letter” which infers even more data is again requested.

Fast Facts
• Xarelto (rivaroxaban) is a factor Xa inhibitor—a blood thinner. The drug is already approved for stroke in patients with nonvalvular atrial fibrillation. It’s also indicated for those undergoing joint replacement surgery to prevent deep vein thrombosis.
• Acute coronary syndrome (ACS) is a catch-all phrase referring to conditions involving coronary artery obstruction.
• The studies under review evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
• If the panel had advised approval it would have meant an endorsement of treating ACS patients with combination therapy (aspirin, thienopyridine and rivaroxaban).

What Does This Mean for Drug Developers?
The earlier potential cardiovascular questions can be answered the better.

Investing in thorough safety and efficacy studies from preclinical all the way through the clinical phases of drug development is key.

Filed under: Atrial Fibrillation, Drug Safety Services, Preclinical Consulting Services | No Comments

FDA Denies Expanding Xarelto for Acute Coronary Syndrome

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on June 26th, 2012

FDA Denies Expanding XareltoThe FDA denied expanding the marketing indications to prescribe Xarelto as an acute coronary syndrome therapy. The decision followed the advice given by an FDA Cardiovascular and Renal Drugs Advisory Panel a month earlier.

Denied – For Now. Why?

• While the details of the denial contained in the FDA complete reponse letter are not yet fully available, it has been widely reported that the Agency had concerns that mirrored the Advisory Panel.

• In May the FDA advisory committee recommended against approval because of incomplete data. The gaps occurred after nearly 1,300 patients dropped out of 15,000+-subject final-phase study and withdrew consent for access to their health information.

• There were also notable concerns about bleeding risks – in the absence of antidote – for rivaroxaban.

Fast Facts
• Xarelto (rivaroxaban) is a factor Xa inhibitor—a blood thinner. The drug already is approved for stroke in patients with nonvalvular atrial fibrillation. It’s also indicated for those undergoing joint replacement surgery to prevent deep vein thrombosis.
• Acute coronary syndrome (ACS) is a catch-all phrase referring to conditions involving coronary artery obstruction.
• The studies under review evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
• If the panel had advised approval it would have meant an endorsement of treating ACS patients with combination therapy (aspirin, thienopyridine and rivaroxaban).

What Does This Mean for Drug Developers?
The earlier potential cardiovascular questions can be answered the better.

Investing in thorough safety and efficacy studies from preclinical all the way through the clinical phases of drug development is key.

Filed under: Atrial Fibrillation, Drug Discovery Services, Drug Safety Services, Preclinical Consulting Services | No Comments

National CPR and AED Awareness Week

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on June 01st, 2012

June 1-7th is National CPR (Cardiopulmonary Resuscitation) and AED (Automated External Defibrillator) Awareness Week.

Most of us understand the life-saving importance of CPR—especially in cases of sudden cardiac arrest.

Equally important is access to AEDs in schools, public spaces, community areas, churches, health clubs, transportation hubs and on playing fields.

Why AEDs?
AEDs  are easy-to-use, often portable devices that require little if no training. The devices administer an electric shock through the chest wall to the heart to restore a normal heart rhythm in sudden cardiac arrest victims. A built-in computer accesses the patient’s heart rhythm, judges whether defibrillation is needed and then administers the shock. Audible and/or visual prompts guide the user through the process.

Why does this matter?
• Every year, more than 300,000 Americans suffer sudden cardiac arrest and 95 percent don’t survive.
• Each minute defibrillation is delayed reduces the likelihood of resuscitation by 10 percent.
• On average, emergency medical services take eight to 10 minutes to arrive.
Sudden Cardiac Arrest is the leading cause of death in youth sports, according to the recent Youth Sports Safety Summit.

What we all need to know.
The cardiac chain of survival is a series of four critical steps.
1. Early access to care (calling 9-1-1 or another emergency number)
2. Early cardiopulmonary resuscitation (CPR)
3. Early defibrillation
4. Early advanced cardiac life support, as needed

Please share this information with others.

 

Filed under: Atrial Fibrillation | No Comments

FDA Panel Advises Against Expanding Use of Xarelto

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on May 24th, 2012

By a narrow margin, an FDA Cardiovascular and Renal Drugs Advisory Panel advised against expanding marketing indications to prescribe Xarelto as an acute coronary syndrome therapy.

Fast Facts
• Xarelto (rivaroxaban) is a factor Xa inhibitor—a blood thinner. The drug already is approved for stroke in patients with nonvalvular atrial fibrillation. It’s also indicated for those undergoing joint replacement surgery to prevent deep vein thrombosis.
• Acute coronary syndrome (ACS) is a catch-all phrase referring to conditions involving coronary artery obstruction.
• The studies under review evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
• If the panel had advised approval it would have meant an endorsement of treating ACS patients with combination therapy (aspirin, thienopyridine and rivaroxaban).

Denied. Why?
The outcome was surprising based on the positive feedback released by FDA staffers earlier in the week.

Although the trial seemed to show the drug helped reduce the risk of dangerous blood clots in patients with serious heart problems, it also suggested an increase in bleeding that made 6 of the 11 panelists hesitate.

Advisors cited clinical study design and incomplete information as reasons for the denial.

The FDA is not required to follow the advice of the committee…but it almost always does.

What Does This Mean for Drug Developers?
Although some of the panelists weren’t convinced, they suggested a second trial might change their decision.

Investing in thorough safety and efficacy studies from preclinical all the way through the clinical phases of drug development is key. The earlier potential cardiovascular questions can be answered the better.

One way or the other, the FDA will always require our industry to get to the heart of the matter.

Filed under: Atrial Fibrillation, Drug Safety Services | No Comments

Society of Toxicology

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on March 23rd, 2012

Society of Toxicology Feedback: Cautiously Optimistic

The takeaway from our productive trade show exhibit at the Society of Toxicology Annual Meeting in San Fransisco, was that the industry as a whole is cautiously optimistic—with an emphasis on the optimistic.

Vendors, clients, colleagues and investors stopped by the CorDynamics booth to check in and share the current state of business at their organizations.

The industry continues to try to balance the need for progress with efficient R&D expenditures.

In spite of constraints on hiring and large capital spending, projects are continuing to move forward with increasing momentum—especially early stage development and discovery endeavors.

Equity investors, a group usually more restrained in their use of financial superlatives, seemed to continue to emphasize caution, but were intrigued to the promise of 2012 and beyond.

Discovering a Return to Discovery

At CorDynamics, we are seeing an early and compelling return to discovery programs that may have been de-prioritized in the recent past. New inquiries in areas such as ischemia and reperfusion injury, along with atrial fibrillation have increased as of late.

Fueling these discovery streams will help to fill the industry pipeline with promising compounds for the upcoming calendar.

 

 

 

Filed under: Atrial Fibrillation, Ischemia Reperfusion Models | No Comments

Fielding Facts About Sudden Cardiac Arrest in Youth Sports

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on December 10th, 2011

 

Sudden Cardiac Arrest is the leading cause of death in youth sports, according to the recent Youth Sports Safety Summit. It’s a frightening reality that many parents and coaches fear, but don’t necessarily understand.

Sudden Cardiac Arrest occurs when the heart’s normal rhythm becomes severely abnormal, compromising cardiac output. These arrhythmias can be generated by a number of triggers, including direct blunt trauma to the chest or exertion stress upon a previously unrecognized vulnerable heart.

Blunt trauma is often the result of an object such as a baseball or hockey puck striking a child in the chest during the very brief period of electrical vulnerability associated with each normal heartbeat—resulting in ‘commotio cordis’, a life threatening arrhythmia that often degenerates into fatal ventricular fibrillation. Appropriate protection equipment or alternate types of baseballs/pucks can reduce the morbidity and mortality of chest trauma in young athletes.

When sports participants experience arrhythmias during exertion stress, it is often associated with previously unrecognized conditions such as hypertrophic cardiomyopathy (a thickened left ventricle usually present via congenital route). Since the cardiomyopathy results in some compromised left ventricular function, an increase in hemodynamic demand places an extra burden on the abnormal heart muscle substrate. This extra burden renders the heart vulnerable to disturbances in electrophysiology, with an increased risk of severe arrhythmias. Hypertrophic cardiomyopathy can be detected by ECG screening, with follow up echocardiography where warranted.

Since screening all children for heart pathophysiology is not practiced in our current health care system, directives from the summit encourage Coaches, teams and schools to implement a strong cardiac chain of survival:

  • Recognize a cardiac emergency and call 911
  • Early CPR
  • Early defibrillation
  • Early advanced cardiac life support

While we run electrophysiology studies to make sure drugs are safe and do not cause sudden cardiac death, we continue to learn more about the condition along the way.

You want may want to checkout www.parentheartwatch.org for more information.

 

 

Filed under: Atrial Fibrillation, Electrophysiology, Hemodynamics | No Comments

American Heart Association Take-Away: Still Seeking Truth About AFib

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on November 17th, 2011

As we’ve discussed in a previous blog, Investigating the Truth About AFib, the path toward targeted efficacy is fraught with hurdles. The reports coming out of the American Heart Association’s Annual Meeting are confirming just that.

Clearly, AFib, AF, Atrial Fibrillation, while being the most common cardiac arrhythmia affecting millions of individuals, is still not commonly understood from a drug development standpoint. Dronedarone, one of the big AHA headliners, is a drug we have used in preclinical investigations as well. In fact, our abstract that was presented at the 2012 Safety Pharmacology Society meeting in Innsbruck featured the use of chronically instrumented dogs to demonstrate the doses of both flecainide and dronedarone that result in changes with atrial, but not ventricular, refractoriness.

Through these types of studies, we are finding one of the long-standing AF roadblocks has been the selectivity of compounds on atrial vs. ventricular electrophysiology. Usually, the goal is to specifically alter the electrical properties of the heart’s upper chambers (atria) while leaving the lower chambers (ventricles) alone. Not nearly enough new chemical entities have this property—thus, the limited good treatment options in this area.

I find much of drug development news features on the negative headlines of drugs that “fail.” As researchers, we learn important discoveries from each study. This ultimately leads us to more effective compounds and gives physicians, a better indication of which medications to prescribe to which patients on a case-by-case basis. Sometimes knowing what doesn’t work, is just as important as knowing what does.

Filed under: Atrial Fibrillation, Drug Discovery Services, Telemetry | No Comments

Investigating the Truth About Afib

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on September 29th, 2011

AFib, AF, Atrial Fibrillation, — It’s the most common cardiac arrhythmia, affecting millions of individuals. Patients with AF rarely exhibit symptoms and are at a five-fold increased risk of stroke due to thrombosis from stagnant flow in the atrium. With such a target profile, the condition is a hot area for drug developers.

As with many disease states, the path toward targeted efficacy is fraught with hurdles. With AF, one of the long-standing roadblocks has been the selectivity of compounds on atrial vs. ventricular electrophysiology. Usually, the goal is to specifically alter the electrical properties of the heart’s upper chambers (atria) while leaving the lower chambers (ventricles) alone. Not nearly enough new chemical entities have this property—thus, the limited good treatment options in this area.

One way of investigating test articles from both a safety and discovery perspective is to use an instrumented animal equipped to provide information on complete cardiac electrophysiology. These models are effective since they provide a detailed interrogation on these parameters, alongside tolerability and PK/PD information.

For a more in-depth look at how an in vivo model can provide a comprehensive safety and discovery investigation in one experiment, check out our abstract to be presented at the 2012 Safety Pharmacology Society meeting in Innsbruck. We used chronically instrumented dogs to demonstrate the doses of both flecainide and dronedarone that result in changes with atrial, but not ventricular, refractoriness.

Getting to the heart of atrial fibrillation will go a long way in helping researchers make good scientific decisions and drug companies make good business decisions so physicans can guide patients in making the best health decisions.

 

Filed under: Atrial Fibrillation, Drug Discovery Services, Drug Safety Services, Electrophysiology, Telemetry | No Comments

Telemetry Models Effective in Discovery Interrogations

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on May 24th, 2010

Project teams often ask about the utility of radiotelemetry in cardiovascular studies, where this effective paradigm can be a part of clients’ drug discovery and development plans. The CorDynamics team has a vast level of expertise in this area. Our laboratories feature dedicated telemetry suites where we conduct studies in six small- and large-animal species.

Over the last few years we’ve expanded the integration of our unique telemetry expertise into drug discovery studies. For cardiovascular efficacy interrogations in particular, telemetry studies provide a wealth of data and insight.

Taking atrial fibrillation as an example, we have used telemetry to facilitate the development of a chronic disease model.  More specifically, we combine the measurement of atrial electrophysiological parameters with more traditional telemetry variables to optimize the interrogation of new chemical entities in the model.

If you have a discovery project that could be enhanced by telemetry, let us know. We’d be happy to discuss the possibilities.

Filed under: Atrial Fibrillation, Drug Discovery Services, Electrophysiology, Telemetry | No Comments

Several Models Shed Light on Potential Pulmonary Hypertension Therapies

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on March 24th, 2010

This week I’ve been in both Southern California and Western Europe – visiting exclusively with current clients to discuss their ongoing work in our laboratories. What’s interesting was the amount of renewed interest and discussion around very early-stage programs, including those nowhere near ready for GLP safety studies. What a difference from a year ago.

Overall, we’ve seen a promising uptick in the number and scope of typical IND-enabling CV safety studies along with their associated screening endeavors and mechanistic follow-ups. The supply of capital is loosening up for a number of biotechs, and larger Pharma companies continue to hone their pipelines via acquisition and the revisiting of projects previously placed on hold.

The demand for our discovery services has swelled noticeably since the start of 4Q’09 as well. You may recall a recent writing detailing our experimental offerings in pulmonary arterial hypertension. What started as a methods development expedition for one client more than two years ago has now blossomed into critical outsourcing relationships with multiple biopharmaceutical companies using several well-established paradigms in this therapeutic area.

But we’ve not been content with only PAH Discovery work; as of this writing, our laboratories are also actively conducting efficacy experiments in ischemia/reperfusion injury, thrombosis, congestive heart failure, and atrial fibrillation  — with the latter two areas strongly leveraging our expertise in advanced conscious instrumented models.

I had the pleasure of attending the 2009 American Heart Association Scientific Sessions in Orlando during November. While sitting down with a current small biotech client – they also noted the window of progress opening again. For them, this meant the ability to finally start vetting promising compounds across therapeutic platforms rather than just focusing on a single area that’s been successful. For the industry as a whole, the ability to have multiple backup strategies in the case of primary failure will be critical as we navigate toward recovery.

I look forward to the 2010 Western Pharmacology Society meeting in San Diego during February. We exhibited at this meeting when it was held in Honolulu a few years ago, and the organizers use a brilliant tactic to break up the agenda and maximize the attendance. There are sessions during the morning and evening, with free time during the day to enjoy the locale. I hope to see you there.

 

Filed under: Atrial Fibrillation, Drug Discovery Services, Heart Failure, Ischemia Reperfusion Models, Pulmonary Arterial Hypertension, Thrombosis | No Comments