CorDynamics

Simultaneous Data Generation Connects Early Data to the Clinic

Safety aspects have increasingly become an outstanding issue in the drug discovery and development arena with the FDA and the EMEA placing a clear emphasis on their importance.

The point is illustrated in the book Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays, co-authored by Dr. Franz Hock, CorDynamics European Business Development Director.

Sequential Development: The Paradigm of the Past

Up until 15 years ago, drug discovery and evaluation was a single, sequential process starting with the selection of the most active compound from a series of newly synthesized agents by means of special pharmacological assays.

• Safety aspects were addressed by pharmacological testing of the selected compound in high doses in assays directed at targets other than the intended indication of the new compound.

• These tests were followed by pharmacokinetic studies, which were mainly aimed at confirming a suitable half-life and oral activity.

• Safety aspects relied mostly on toxicity studies, which however gave information on changes of organ structure rather than on organ function.

• Toxicological and pharmacokinetic studies were adapted to the progress of studies in clinical pharmacology and clinical trials.

Simultaneous Data Generation: Today’s Paradigm

The sequential way of working has been replaced by simultaneous generation of data.

• Concurrent safety, pharmacodynamic and pharmacokinetic data is generated.

• If need be, bench-to-bedside and bedside-to-bench approaches can be facilitated to connect preclinical and clinical data as early as possible.

• Rather than a separation into toxicology, pharmacokinetics and clinical applications, a connectivity between all these disciplines is embraced.

This new paradigm is seen as mandatory in the eyes of regulatory bodies as well as among academic thought-leaders and drug development executives.

The industry as a whole has come to understand there is no real safety evaluation possible without combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and from a clinical environment.

To learn more on the topic or to order Dr. Hock’s book, click here.

Cracking the Case on Sudden Cardiac Death and Domperidone

by Liomar Neves, Senior Scientist

Recently, the Journal of Cardiovascular Pharmacology published an original article investigating sudden cardiac death and QT interval prolongation associated with domperidone that caught the attention of our CorDynamics team.

The Report

Domperidone is a dopamine receptor antagonist not approved by FDA for sale in the US market, but is widely used in more than 100 countries. Its purported benefits are as a gastrointestinal prokinetic agent, an anti-nausea and vomiting therapeutic and more recently it has been used to promote lactation.

However, the compound has been associated with disturbances in ventricular electrophysiology. These include increases in QT interval and cardiac rhythm disturbances.

In this recent preclinical study, the authors confirm that domperidone prolongs action potential duration and suggests that the IC₅₀ for blocking the hERG channel I_Kr may be lower than previously reported.

New Evidence

The study also involved the use of prolonged domperidone exposure times, longer cycle lengths to examine reverse-use dependence, and use of rabbit hearts that are naturally heightened for sensitivity to I_Kr antagonism.

• Evidence demonstrated domperidone to have a high affinity to I_Kr and low safety margin, thus increasing risk of drug-induced long QT syndrome and potential proarrhythmogenesis.

• Additionally, the report brings attention to the limited benefits of domperidone for gastrointestinal disturbances and highlights the risk of using a low safety margin drug for a non-threatening target such as promotion of lactation.

The authors concluded the report by urging other regulatory agencies to take the FDA’s approach and ban domperidone’s use.

FDA Welcomes New Class of Diabetes Drugs

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.

Running a Healthy Lifestyle: No Excuses

by Melissa Fisher, CorDynamics Operations Manager

I have attended the Society of Toxicology (SOT) ToxExpo for several years now with CorDynamics. This year I headed to San Antonio and spent several productive days “manning” our booth,welcoming new clients, finally meeting current clients face-to-face for the first time, as well as talking to our vendors.

A few years ago this meeting started to do a race called ” The Past Presidents 5K run/walk” held early in the morning to kick off the start of the meeting.  I had contemplated running this before but had quietly talked myself out of it, using the usual excuses:

“It’s too early.”

“I don’t want to run before spending all day on my feet.”

Since my unofficial new year’s resolution was to push past my excuses, I signed up.

Just like any other race they offered official chip timing, which added a little extra competition to it, and a nice T-shirt with the race logo on it.   This race was a breath of fresh air with less than 200 participants. (I am used to running large races with 6000 + participants.)

As promised it was an early start but like a quote I read recently:

“I never regret a workout, but I regret not getting up for one.”

I knew I wasn’t going to win but when I compete I always feel like I have accomplished something great.  My goal was to run a little faster than I normally do and I finished in 28 min and 10 sec—the fastest I’ve ever run a 5K.  It’s rewarding to see the years of physical and mental training pay off.

I plan on doing this race again next year—maybe I can get some of my co-workers, colleagues and industry pals to do it too!

FDA Warns Azithromycin May Prolong QT Interval

It’s been almost a week since our return from the 2013 Society of Toxicology meeting in San Antonio. While we try to keep up with things outside the trade show, it’s hard to do.

However, one news item caught my eye during the week. In fact, it was nearly impossible to miss as the lead or top level item on all the news channels.

The FDA warned the public that the antibiotic azithromycin could cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm.

In a nutshell – QT interval prolongation.

The revised label has the most robust description yet of the drug’s ability to prolong QT interval in certain subsets of patients. Which got me thinking…

So many people have taken azithromycin over the years with great success. It works effectively for taking care of common respiratory infections. Azithromycin is literally a lifesaver in developing and yet-to-develop areas for conditions such as river blindness and community related infections where compliance can be nominal.

How could the industry have missed the QT interval prolongation in azithromycin?

The answer is actually straightforward.

First, azithromycin was approved on a wide basis in 1991. This was a number of years before stringent screening for safety pharmacology effects were in place.

Second, the adverse effects appear to limited to a small subset of patients – likely related to the vulnerable substrate hypothesis for proarrhythmogenesis. But when you actually take a close look at the preclinical data – the effects of azithromycin on QT interval prolongation are indeed there to see.

Whether it’s an isolated heart protocol or a telemetry investigation, there are numerous reports from preclinical studies showing that the azithromycin prolongs QT interval under certain conditions. Additional investigations confirm the clinical database—the compound is thankfully associated with very little proarrhythmic activity.

FDA Rejects Xarelto for Second Time in Less Than a Year

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.

Heart Failure Success Poses Complexities for Drug Developers

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.

The Motivation to Keep on Running

For us mere mortal runners staying motivated can be a challenge.  Some tips for staying enthusiastic range from buying a full length mirror at home or writing a blog to hold yourself accountable. (Only one of the reasons that I’m doing this).

However, the number one way I stay motivated is signing up for races.

The last thing I want to do is show up on race day having done little to no training.  Not to mention, it is impossible to run 13.1 miles without training.

There is a big reason that the 13.1 distance has become so popular in the last few years.  The training isn’t as daunting as a full 26.2 miles but there is also no way to run 13.1 miles without training.  Having signed up and paid for a race (thanks for sponsoring me CorDynamics) holds you accountable to get there on race day and have a great time.

I just signed up for my first 13.1 this year.  It will be the Christie Clinic Illinois Marathon in Champaign, Illinois on April 27th.  I have plans to run in another new state this year also.  I am shooting for the Madison Mini Marathon in Madison, Wisconsin on August 17th.  These races will be my 3rd and 4th half marathons and will certainly not be my last.  Also up this year will be another Shamrock Shuffle run here in Chi-town.

Looks like I have a very busy season ahead of me.  What will you be signing up for this year? How will you stay motivated to keep on running.

Pulmonary Arterial Hypertension Model Targets Disease Reversal

Finding Treatments for an Orphan Drug

We have added a powerful capability to our most requested small animal pulmonary arterial hypertension model – measuring pulmonary artery pressure via single or dual channel telemetry.

The hypoxia-semaxanib rat assessment has rapidly become the most requested assay among our Pulmonary Arterial Hypertension offerings. PAH — an orphan disease, with unmet medical treatment—is characterized by increased blood pressure in the arteries of lungs, causing dizziness, shortness of breath and can lead to heart failure.

CorDynamics was the first laboratory to report the protective effects of bosentan and sildenafil in this model.

In an effort to refine the data, we have now added the option to include daily readings of pulmonary artery pressures.

 View Data

Why is this important in the discovery of new therapeutics for PAH?

While a terminal assessment of pulmonary pressure provides end-stage confirmation of efficacy, interim measurements of the PAH temporal course can be critical when timing the initiation of reversal therapy.

Our daily data demonstrate that the variability associated with the model is small, even over six weeks of hypoxia. Animals progressed through development of PAH in a similar linear fashion.  After six weeks in hypoxia, systolic pulmonary pressure increased greater than 400% versus baseline. In addition, right ventricular hypertrophy was robust. The low variability helps in the assessment of test article efficacy – and allows for better distribution of dose levels without having to add inordinate experimental numbers.

As we approach another celebration of World Rare Disease Day on February 28^th it’s gratifying to have something new to report in the campaign to develop an orphan drug for PAH.