Posts Tagged ‘Cardiovascular Studies’

PAH Data Download: The Ins and Outs of Multiple Models

Posted by CorDynamics on October 15th, 2014

Over the past 5 years our laboratories have conducted numerous studies with various models of pulmonary hypertension.

We are looking forward to sharing some our findings next week at the Safety Pharmacology Society Annual meeting in Washington, D.C. in a lunch and learn on Monday, October 20th.

We will be discussing results from our monocrotaline and hypoxia experiments as well as sharing our large datasets generated from clinical treatments in our gold standard model–the hypoxia/VEGF receptor antagonist exposed rat.  These results are very compelling – and show differential effects of sildenafil at 3, 4, 6 and 12 weeks into the hypoxia/VEGF model.


Over the past year, our labs have also conducted studies with an alternative preclinical model of PAH – the athymic nude rat treated with VEGF receptor antagonist. This model may be applicable to a certain subset of PAH patients where inflammation appears to play a major pathogenic role.

If you are at SPS – stop over for some lunch accompanied by an in depth data dissection from various models of pulmonary arterial hypertension.

For those that are not attending – check our website after the SPS meeting where you’ll be able to download the slide deck from our presentation.

Filed under: Drug Discovery Services, Drug Safety Services, Pulmonary Arterial Hypertension | No Comments

ILSI/HESI Proarrhythmia Paradigm Raises More Questions Than Answers

Posted by CorDynamics on September 05th, 2013

At the end of July 2013, ILSI/HESI co-sponsored a meeting in Washington D.C. along with the Cardiac Safety Research Consortium / USFDA entitled “Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment during Drug Development without the Thorough QT Study”.

Essentially, the agenda was a discussion of the ‘paradigm shift’ and ‘proposed testing schema’ under consideration to improve the cardiovascular risk assessment of new chemical entities submitted for marketing licensing. The scheduling of the meeting indicates dissatisfaction, either perceived or real, with the current cardiovascular safety testing funnel.

I was not at the meeting due to a calendar conflict. Although I was frustrated as the topic is certainly germane to our business interests, the organizers posted the presentations and slides online. In hindsight, viewing the slides objectively unencumbered by discussions and sidebars gave me an unfiltered look.

After further view, I found the arguments to contradict one another. On one hand, the presentation highlighted potential consequences of not changing the current testing scheme as: the ‘perversion of lead selection’ and ‘NOT fulfilling the public health need.’ However, the presenters also stated there have been ‘no QT-related withdrawals’ and ‘reductions in post-marketing reports of arrhythmias’ as evidenced by E14 and S7B successes.

Frankly, which is it? Aren’t the reduction of QT-related withdrawals and reduction in post-marketing reports of arrhythmias fulfilling the public health need and informing drug developers who are making lead optimization decisions? Like most things it’s probably somewhere in the middle.

So, here are some questions:

1. If cardiovascular risk reduction has indeed improved – arguably the accurate metric of public health need – is the concern actually that the industry has become too conservative resulting in weak pipelines?

2. Where is the data demonstrating computer simulations of cardiac myocytes – or computer simulations of whole hearts–are more complex and integrative than in vitro or in vivo proarrhythmia models? With what information are these computer simulations being programmed? I would argue the animal models, when designed appropriately, likely contain the vulnerable substrate(s) similar to the susceptible population (the public) necessary to facilitate or induce triggered arrhythmias.

3. Speaking of proarrhythmia— what happened to the examination of in vivo proarrhythmia models? Is the database and methodology accrued over 30+ years just considered too complex with too few people to understand it?

4. The oft-used descriptor of the hERG assay’s potential as a red herring is that ‘many of the 100 most-prescribed drugs are hERG blockers’. Is somebody testing the 100 most-prescribed drugs in stem cells and in silico models? Are the results any different?

There are questions sure to be discussed vociferously in the months ahead.

The slide deck from the investment community representative makes the most sense at face value.

• Reduce uncertainly as far and as early as possible

• Make test batteries efficient and effective

• Create international benchmarks

Ironically, these were the exact same calls to arms for generating ICH S7A, S7B, and E14 in 2000 and 2005.


Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart, Telemetry | 2 Comments

FDA Welcomes New Class of Diabetes Drugs

Posted by CorDynamics on April 03rd, 2013

Invokana (canagliflozin) has been approved by the FDA for patients with Type II diabetes—with two cardiovascular caveats.

  1. Leading up to approval, FDA reviewers highlighted the increased risk of cardiovascular problems to patients on the therapy as it lowered blood sugar but raised cholesterol in clinical trials.
  2. A complete cardiovascular outcomes trial must be conducted.

Ivonkana is at the head of the new class of SGLT2 inhibitors.

These inhibitors block a protein associated with the reabsorption of glucose in kidneys to help diabetics clear blood sugars more efficiently.

“Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”

In a statement regarding the approval of Invokana, the FDA is requesting five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research Equity Act (PREA), including a pharmacokinetic and pharmacodynamic study and a safety and efficacy study.

Filed under: Drug Safety Services | No Comments

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

Heart Failure Success Poses Complexities for Drug Developers

Posted by CorDynamics on February 28th, 2013

We covered the complexities surrounding heart failure drug development in a blog we published last summer.  In it, we pointed out:

 Once developers clear the hurdle of finding a compound with promise, the bar is set high for proving their efficacy and superiority over existing drugs to gain regulatory approval.

 Most heart failure medicines have to go through a variety of different measures for efficacy. One of which is “quality of life” as measured by the American Heart Association ratings for heart failure.

For example: Can bedridden patients begin to get out of bed and move around more?

Unfortunately for researchers working on spironolactone, recent reports illustrate this case in point.

In patients experiencing heart failure with preserved ejection fraction, spironolactone did in fact demonstrate improved left ventricular diastolic function but did not have any effect on heart failure symptoms, quality of life, depressive symptoms or hospitalizations.

Although the trial did show improvements in diastolic abnormalities of the left ventricle, the lack of clinical improvements means researchers will most likely conduct further studies, perhaps with patients in more advanced stages of heart failure.

We work in the area of heart failure 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.


Filed under: Drug Discovery Services, Heart Failure | No Comments

Spotlight: FDA Approves Orphan Drug for Rare Cholesterol Disease

Posted by CorDynamics on January 14th, 2013

When the FDA gave the green light to an orphan drug with approval of Juxtapid (lomitapide) it marked a 16-year high of drug approvals by the US Agency in 2012.

Thirty-nine new chemical entities were approved last year, with many of them being therapies for rare diseases. This underscores our industry’s increased focus on specialized, niche products.

FDA Orphan Drugs Rare Diseases Cholesterol

The drug meets the previously unmet needs of patients, usually children. with homozygous familial hypercholesterolemia (HoFH) who are unable to remove LDL cholesterol—often known as the “bad” cholesterol—from the blood.

Lomitapide works as an anti-cholesterol agent by inhibiting the microsomal triglyceride transfer protein. This moiety is necessary for assembly of very low density lipoprotein (VLDL) in the liver. VLDL is converted in the blood stream to LDL. Patients with HoFH are at severe risk for atherosclerosis (hardening of the arteries), which causes heart attacks, strokes and other serious vascular conditions usually before the onset of puberty.

HoFH occurs at a rate of approximately 1:1,000,000 in the general population.

Points to Consider

  • The efficacy of Juxtapid increases in conjunction with diet changes and other cholesterol lowering treatments.
  • The FDA is requiring three post-marketing studies, including a long-term registry of HoFH patients taking Juxtapid to determine the long-term safety.
  • Due to lingering questions on the safety of Juxtapid, the FDA insisted a ‘black-warning’ be added to the drug’s labeling.
Filed under: Drug Safety Services, Heart Failure | No Comments

5 Signs Drug Development Outsourcing is In

Posted by Theresa Gralinski, Marketing Director at CorDynamics on November 14th, 2012

I spent most of last week at the American College of Toxicology meeting in Orlando taking the industry’s proverbial temperature.

Over the last four years this meeting’s attendees seemed concerned about feverishly downsizing, feverishly cutting budgets or feverishly outsourcing. People just didn’t feel well. This year attendees seemed to be “feeling” healthy and more optimistic.

Preclinical CRO Drug Development Outsourcing

I saw five clear signs that industry outsourcing is officially IN.

1. Back to Business—With mass waves of downsizing behind a number of our colleagues, clients and competitors, the focus of discussions turned to current programs and upcoming projects.

2. Changing Roles—Longtime  friends were embracing new positions, translating their pharma drug safety and drug discovery experience into success at virtual biotechs or contract research organizations.

3. New CROs and Consultants Join the Ranks—We welcomed new CROs to the “club” and I met with quite a few toxicologists who have decided to work as consultants to share their expertise to meet the anticipated demand.

4. Buzzwords—Collaboration. Customized. Experience. Responsive. Did I say collaboration?

5. Social Media…Really?—Admittedly the industry is still skeptical of the idea in a regulated industry. However with more drug developers looking for external services, vendors and CROs want to be easily found. (Shameless examples: cardiovascular CRO, prolonged QT interval, cardiovascular pharmacology.) Social media is a good way to get the message out.

I polled attendees on their comfort levels with the top social media platforms. Results: LinkedIn=Great; Blogging=Good; Twitter=So-So; Facebook=No Thanks.

Did you get a different temperature reading from the meeting? Or, did you sense a healthier optimism as well? Feel free to comment here or you can find me on Linkedin.


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

Drug Discovery Generates Good Science, Business and Drug Development

Posted by Theresa Gralinski, Marketing Director at CorDynamics on August 08th, 2012

In my mind, the pharmaceutical and biotech industry can be reduced down to one elegant equation: good science + good business decisions = good drug development.

Good Science.
As the marketing director for CorDynamics, I spend a lot of my time discussing our innovative preclinical cardiovascular drug discovery and drug safety models. It’s our reason for being. My job is to communicate our capabilities and the good science we generate to clients, colleagues and potential customers.

Good Science=Good Business Decisions
As a member of the Healthcare Business Women’s—Chicago Chapter I’ve attended a number meetings led by dynamic senior healthcare and pharmaceutical executives discussing how to navigate our changing industry.

After each of these events, my underlying takeaway is that tough business decisions can be made easier when armed with good science.

When the science is solid and reliable—in our case from a cardiovascular drug discovery and drug safety side—it can be a useful guide for folks faced with extreme budget and timeline constraints.

It’s our job as the cardiovascular CRO, to understand the pressures on our clients as well as the need to be flexible, affordable and most importantly, collaborative in the work outsourced to us.

Good Science + Good Business Decisions = Good Drug Development
Earlier this year, I flew 2,000 miles to be with an aging parent undergoing surgery. I tried not to think of all the science, education and yes, business decisions that would go into this one procedure. All went well. As I headed to the pharmacy to pick up the prescriptions necessary to inspire a full recovery and greater wellness, I walked away with tangible proof of my theory.

Filed under: Drug Discovery Services, Drug Safety Services | No Comments

Cardiovascular Safety Studies Crucial for Oncology Drug Development

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

I recently attended a Fierce Biotech webinar about Special Studies in Cancer Patients and Cardiac Safety. The presentation covered a wide range of solid information on cardiac safety as it relates to oncology clinical trials.

Time and again, we have clients wondering if they need to conduct thorough cardiovascular preclinical safety studies for oncology compounds. In most cases the answer is yes; and the panelists on the webinar agreed.

In fact, as the panelists discussed, preclinical data is crucial to driving the design of clinical trials in oncology programs. If, for example, in vivo preclinical studies indicated some cardiac toxicity or reduced cardiac function, this may warrant consideration of additional analyses such as echocardiograms or cardiac enzyme panels in the clinical program.

Oftentimes in the past, the nonclinical cardiovascular battery for oncology agents consisted of actions on a single ion channel and an in vivo cardiovascular assessment along with standard toxicology studies. This was in contrast to the comprehensive risk assessments submitted for the more ‘traditional’ drug targets, such as depression or anti-infective agents, to name a few.

The overriding thought process behind these data packages could usually be distilled in project team meetings to somewhat misplaced logic in isolation, such as ‘it [the compound] is for cancer’ or ‘these patients usually have more consequential things to worry about than CV effects’.

While on some level those statements may occasionally be appropriate, recent events prove once again that the physiological processes controlling both cancerous and normal cells are not entirely discrete. These events also serve to demonstrate the unintended clinical consequences of truncated early development.

As one of the cardiology panelists noted – we need to be both efficient, yet cautious, in our design of oncology clinical trials regarding the issue of cardiac safety. Since we often don’t fully understand the off-target consequences of interfering with cancer mechanisms, it is prudent to provide as much useful information a priori (from preclinical studies) to rationally design these trials.


Filed under: Drug Safety Services | No Comments