Putting all the pieces together—CorDynamics leveraged our preclinical services to co-publish a paper in the British Journal of Pharmacology.

Collaboration
In collaboration with sponsor Hoffmann-La Roche, CorDynamics conducted both anesthetized canine and non-human primate telemetry studies to determine the molecular mechanism of cardiac arrhythmias observed during the course of a routine preclinical toxicology assessment.

Collaboration + Comprehensive Preclinical Studies
The compound RO5657, a CCR5 antagonist, had induced torsades de pointes (a life threatening cardiac arrhythmia) in normal, healthy animals. Employing a variety of preclinical cardiovascular models, the article investigated how and why a small-molecule compound exhibited cardiac side effects and torsades de pointes during preclinical toxicology studies.

The sponsor came to us to discuss the issues and contracted us to perform both anesthetized canine and non-human primate cardiovascular telemetry studies. The project became a textbook case of collaboration and integration.

Here’s the deal: when conducting screening studies of compounds on ion channels or isolated Langendorff hearts, you often don’t have the luxury to examine the other general toxicology study results concurrently. In this case, once all the studies were completed, we were able to confer and put them into perspective.

In fact, the ion channel and isolated heart interrogations ultimately predicted the anesthetized, telemetry and toxicology study results.

Collaboration + Comprehensive Preclinical Studies = Integrated Risk Assessment

This article confirms the importance of collaborating, taking the information garnered from a variety of safety pharmacology and preclinical toxicology models, and compiling the results to produce an integrated cardiovascular risk assessment.

This type of approach is vital to making rationale project decisions—and ultimately getting a clear, complete picture.

Regards,
Dr. Michael R. Gralinski, CorDynamics CEO

It’s something CorDynamics has been developing in our laboratories. We were pleased to share the resulting PAH model with fellow researchers in a poster presented at last month’s Experimental Biology 2012 conference.

Our poster: Bosentan and Sildenafil Reduce Pulmonary Arterial Hypertension in Rats Induced by Semaxanib and a Low Oxygen Environment.

What did we show?

Oral administration of bosentan and sildenafil reduce PAH induced by semaxanib and a low oxygen environment. We demonstrated that this is a clinically relevant model to evaluate efficacy of test articles.

How did we do it?

It occurred to us that a commercially available hypoxic tent could be turned into a low oxygen chamber that mimics PAH. It worked. From there, we were the first to use bosentan and sildenafil (two approved clinical treatments for pulmonary hypertension) to validate the reduction of PAH in this model.

The result is a new model that is predictive of the human PAH condition.

Continually moving toward finding treatments for PAH—one of the 6,000 orphan diseases—is the wave of the future.

Our belief was underscored this week with GBI Research predicting orphan drugs will represent a significant revenue increase over the next five years—increasing its market share from $2.3 billion in 2010 to $6 billion in 2018.

More importantly, the millions affected by these diseases will have hope for life-improving treatments.

Regards,
Dr. Michael Gralinski, CorDynamics CEO

Certainly, one of the most complicated therapeutic areas is developing heart failure drugs.  Heart failure occurs when, for one reason or the other, the heart cannot properly pump blood throughout the body.

• Systolic heart failure—heart muscles cannot efficiently eject blood to the lungs and body.
• Diastolic heart failure—heart muscles stiffen and do not efficiently fill up with blood.
• Arteriosclerosis—a narrowing of the arteries, restricting the flow of oxygen rich blood to the heart muscle.

When blood isn’t being delivered efficiently through the body, organ systems depending on this supply can be compromised. Fluid begins to build up in the extremities and around the organs. Left untreated or in cases where patients don’t respond to current therapies, quality of life can rapidly decline and the consequences can lead to mortality.

For researchers, developing compounds that effectively target and isolate even one of these mechanisms would be meaningful for this growing population of patients.

It’s a tall order given that heart failure is often the culmination of a variety of other health issues such as, diabetes, obesity, high blood pressure, high cholesterol and smoking. For instance, high blood pressure causes the heart to work harder, ultimately leading to an enlarged heart that is unable to pump efficiently.

Most of the current drugs on the market work on improving the efficiency of the heart but they don’t necessarily counteract some of the contributing factors of heart disease, like high blood pressure.

We work in the area of heart failure drug discovery with some clients who are taking a more non-traditional approach to treating this condition. An example of this would be using dual pharmacology involving both increasing heart function while simultaneously reducing the extrinsic burdens as mentioned above. 

With more than 5 million Americans, of all ages suffering from heart failure and looking for relief, it’s complicated work of great importance.

Regards,

Dr. Michael Gralinski, CorDynamics CEO

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted in favor of going the extra mile to rule out and minimize the cardiovascular risks potentially associated with obesity drugs.

The directive was passed by a 17 to 6 vote in favor of taking a prudent approach, erring on the side of caution for several reasons:

• The new FDA recommendations for obesity drugs are essentially the same as those currently required for diabetes drugs. This alignment makes sense as some committee members went so far as to argue that obesity could be considered pre-diabetes.

• With obesity growing at an alarming rate, and millions of would-be patients, a high cardiovascular risk profile could be “catastrophic.”

Why the change in direction?

As discussed in an earlier blog about cardiovascular issues hitting the heart of the obesity drug development debate:

• The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.

• Since the 1960s “diet” drugs have been pulled from the market for morbidity and mortality stemming from cardiovascular effects.

Of course the downside of this new outcome is that it could make obesity drug development even more difficult. However, when a new drug does make it to market, this time we will know it’s been thoroughly vetted from a cardiovascular standpoint.

Regards,

Dr. Michael R. Gralinski, CorDynamics CEO

Just by finishing a race and beating previous race times I feel a sense of accomplishment but my greatest reward of this race was seeing my training partner excel in his first race. To pass on the running bug to someone else and watch them succeed is a great feeling. It is rewarding to pass along the knowledge that years of training have accumulated and to have the sport loved by another person. Not only have I been able to pass on the love of the sport but also a commitment to a healthier lifestyle.

Training with another person is also a great way to stay motivated and be kept accountable. I have found new ground in my own training by running with another person. I am less likely to back out of a workout for silly excuses because someone else is expecting me to be there too.

My advice: find a workout buddy and you will both reap the rewards!

Melissa Fisher, CorDynamics Operations Manager

The heart of our business is in the heart of the city of Chicago.

A contract research organization specializing in cardiovascular drug discovery, safety and efficacy in Chicago? Why Chicago?

We believe the city of Big Shoulders gives us big advantages.

Proximity to world-class universities, thought leaders and talent—The University of Chicago, University of Illinois at Chicago, Northwestern University, Loyola University and DePaul.

Access to O’Hare International Airport and daily flights to almost anywhere in the world.

Centrally located in the Midwest for access to clients on both Coasts and worldwide.

Deep roots in the community, where we are proud to attend and sponsor events— a runner in the recent Shamrock Shuffle as well as in the 15th Chicago Half Marathon held in September; Dollar Denim Days in celebration of World Rare Disease Day; the Rock for Rare disease Jesse Malin benefit concert.

Not to mention, Chicago is a great place to welcome guests and colleagues.

If you’ll be in town for the American College of Cardiology Annual Conference, or any other time, let us know. We’d love to meet with you, give you a tour of our facilities and show you some of our favorite Chicago hot spots.

Regards,

Theresa Gralinski, CorDynamics Marketing Director

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.

Regards,

Dr. Michael Gralinski, CorDynamics CEO

Melissa Fisher Runs For the Pot of Gold — Shamrock Shuffle Chicago 2012

In a city with such a rich Irish heritage it dyes the river green, running this Shamrock Shuffle has become a Chicago tradition.

Runners have to have heart in more ways than one as running here this time of year can turn into its own form of March Madness.

“Because this race is so early in the year, it is hard to predict the weather,” admits Melissa. “When I ran the race last year, it was sunny and 70. But, there have been many years where it has been snowy, cold and not to mention windy.”

Even with its cold winters, Chicago ranked on the Forbes Top-10 Cities in America For Runners, for what it has to offer in the spring, summer and fall months.

A gorgeous 18-mile path along Lake Michigan and flat terrain.

Plenty of competition—different races are held on back-to-back days on weekends during prime running season.

Vibrant running community—training clubs, running associations and social clubs that often lead to post-run beers at one of the city’s many pubs.

The good news about training in Chicago for Chicago races: You are ready for anything.

“It was so windy yesterday, I felt like I was running backwards,” says Melissa. “During my training run two weekends ago, it was snowing, but it was pretty.”

I’m pretty sure I speak for the majority of the CorD team when I say: Thanks Melissa for taking on this challenge on our behalf.

May the road rise up to meet you, may the wind be always at your back and may your heart-healthy lifestyle carry you far….

Theresa Gralinski, CorDynamics Marketing Manager and Fair-Weather-Runner

Once again, potential cardiovascular issues are at the heart of the matter.

For years, the development of effective and safe obesity treatments for the target patient population, has stymied researchers. A generation ago, doctors were prescribing aminoxaphen. Patients were purchasing versions of products such as Dexatrim^®. Both contained stimulant compounds that were indeed appetite suppressants, but also had very unfavorable cardiovascular side effects.

In the 1960s, aminoxaphen was associated with numerous cases of fatal pulmonary hypertension. Subsequently, phenylpropanolamine and ephedra, the active ingredients in older versions of Dexatrim^® (also in many other OTC products including decongestants) were shown to raise risk of stroke and high blood pressure. Aminoxaphen was removed from the market, and all products containing either PPA or ephedra have been reformulated.

The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.

The most recent demonstration of this conundrum occurred in the 1990s and involved the use of the no-longer-available fenfluramine.  Fenfluramine causes serotonin release from nerve terminals and prevents its re-uptake. The combination of this compound with phentermine (Fen-Phen) resulted in appetite suppression— an effective treatment for obesity. However, this pharmacology also caused a pathological change in both cardiac valves and pulmonary arterial function. As a result, there was again sufficient morbidity and mortality with an obesity treatment.

Obesity, clearly detrimental to cardiovascular health, is rising at an alarming rate. Current drug developers are working hard to bring forward effective compounds with a favorable safety profile. Regulatory agencies are being called on to facilitate some options for this prevalent health concern.

Hopefully, these new compounds and mechanisms of action will eventually help those who haven’t otherwise found a therapy that works.

Regards,

Dr. Michael Gralinski, CorDynamics CEO

It’s World Rare Disease Day and supporters of all ages are coming together to raise awareness. From my point of view, the next generation makes the future look bright.

Today, I find myself back at the University of Michigan Medical School talking with pharmacology graduate students. Many of these future researchers will dedicate their careers to developing the very drugs and therapies needed to help those struggling with unmet medical needs.

My seminar is entitled “World Rare Disease Day: Current Pharmacological Targets and Animal Models of Pulmonary Arterial Hypertension.”

I talk about my Michigan history and the career path that took me from grad student, to post doc, to industry researcher and ultimately entrepreneur. From the CorDynamics point of view, I discuss the extensive preclinical and discovery studies done for clients researching treatments for pulmonary arterial hypertension—an orphan disease.

Meanwhile, back in Illinois, kids at Spencer Loomis Elementary School are helping other kids in the hopes of eradicating some of these diseases in their lifetimes. For Dollar Denim Days, the students are purchasing denim ribbons as well as wearing their favorite pair of jeans in a nod to the Global Genes Project. The proceeds will go toward research on Rett Syndrome, a rare genetic disorder of the nervous system and the diagnosis given to the 3-year-old daughter of a former teacher at the school.

Inspired, CorDynamics pledged to match the funds raised by the Spencer Loomis Elementary students.

In the interest of full disclosure, the teacher was my oldest son’s kindergarten teacher and my youngest son still attends the school. Not to mention, Rett Syndrome is often associated with a dangerous heart condition that we regularly research—long QT syndrome.

Odds are, most of us are connected to one of the nearly 30 million Americans affected by a rare disease. From one generation to the next, I believe these connections will lead to solutions and cures.

Regards,

Dr. Michael R. Gralinski, CorDynamics CEO