Posts Tagged ‘Drug Safety’

Data on Cholesterol Not Always Easy to Explain

Posted by CorDynamics on February 16th, 2015
by Dr. Michael Gralinski, CorDynamics CEO

A cardiovascular news story came out recently and the context of its release was troublesome to me. This article, not surprisingly carried by all major news organizations given the bold proclamation, announced ‘cholesterol may not be as bad as we thought’.

As I read through this piece, I came to the conclusion that we as scientists need to better articulate the actual point of our research and clearly explain our data. In the absence of a clear direction from the scientists, an attention-grabbing headline often misses the mark.

Reading the article, if I hadn’t known better, I would have come away believing cholesterol “was wrongly linked to heart disease” and many guidelines from the government and other advisory bodies were incorrect for decades. The actual findings of the research are quite different from that characterization.

Cholesterol, and specifically LDL/its isoforms, is a substantive contributor to coronary artery disease and stroke. The point of the research not reported in the story was that our bodies produce levels of cholesterol mostly independent of the amount consumed through the diet. Therefore, it may not be as important to highly regulate the amount we are eating – but instead focus on methods to reduce plasma cholesterol/LDL such as exercise, a diet high in fiber or medications if needed.

For decades statins were considered the final weapon in the battle against cholesterol. Unfortunately, we now know this is not the case. Unanticipated side effects following years of exposure, along with greater understanding of hypercholesterolemia’s  pathogenesis, have resulted in a need for new programs in this field – including PCSK9 and BAT inhibitors amongst others.

Compounds from these programs will be under careful scrutiny for undesirable action that has de-railed previous cholesterol projects such as blood pressure increases with CETP inhibition. More on related drug safety studies.

In addition, prudent examination of the large databases have not shown a proven beneficial effect for lowering cholesterol to certain numerical targets. Lifestyle modifications may thus continue to play a large role in lowering overall risk of heart disease prior to pharmacological treatment.

Understanding how to interact with colleagues outside of our field is a skill set needing improvement for many scientists. Explaining our data and what we do is key–whether talking to project teams, investors, clients or simply friends and neighbors.


Filed under: Drug Safety Services | No Comments

Weight Loss Drugs Losing Traction with FDA and Docs?

Posted by CorDynamics on June 20th, 2014

Developing weight-loss drugs to help the estimated 35% of Americans struggling with obesity should be an easy gain for the biotech and pharmaceutical industry. As of late, it seems to be a losing proposition—for a variety of reasons.

Weight Loss Drugs Losing Traction with FDA and Docs?

FDA Extra Cautious with Safety and Marketing Regulations

Cardiovascular side effects are at the heart of the FDAs concern. The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.

A generation ago, doctors were prescribing amphetamine-like stimulants, which were appetite suppressants, but also had very unfavorable cardiovascular side effects. In the 1990s the combination of fenfluramine and phentermine (fen-phen) resulted in appetite suppression as well but caused a pathological change in both cardiac valves and pulmonary arterial function.

This tumultuous history has made worldwide regulators particularly sensitive to cardiovascular safety in this therapeutic area. Case in point and as reported in FierceBiotech last week, Orexigen (OREX) had to wait three long years to take a second shot at an approval for its weight drug NB32, earlier called Contrave. Now the company has to wait another three months for an FDA marketing decision as they talk through a regulatory requirement on tracking cardiovascular outcomes among people taking the therapy.

Prescriptions Thin from Physicians

Doctors have not been prescribing weight-loss medications as often as was expected.  Previous safety concerns combined with marginal reported benefits from patients has made physicians think twice before suggesting the medications.

According to Bloomberg, the average weight loss was only 4 percent to 8 percent above what patients taking placebos demonstrated. While this is medically important, it may not be enough to offset side effects as headaches or upset stomach. Also some insurers are reluctant to cover co-pays for drugs.

It’s an interesting caveat. As drug developers we focus so much on FDA approvals, we have to remember the approval of doctors and patients is important as well.

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How to Conserve Test Article, Time and Money with Telemetry

Posted by CorDynamics on March 11th, 2014

Here’s a familiar dilemma. Your research team detects unanticipated cardiovascular activity in your lead candidate but there is limited test article for follow-up discovery and safety studies.

In these cases, we often suggest either conscious telemetry or an anesthetized preparation in the guinea pig as an effective model for cardiovascular testing, when appropriate. Since they are smaller in size, guinea pigs can serve as a viable species when compound supply is limited.

In some cases, the guinea pig can use five times less compound to conduct studies than amounts needed for their larger counterparts, such as rabbits.

The Conscious Model

Using telemetry to deliver quasi beat-to-beat data, this guinea pig model generates ultra high fidelity QT interval correction. View Conscious Validation Data

The Anesthetized Model

In this preparation, we employ a well-characterized anesthetized method to screen for cardiovascular effects early. Cardiovascular parameters such as blood pressure, heart rate, as well as ECG are measured and cardiac functional assessments can also be provided. View Anesthetized Validation Data

While a plus in terms of compound conservation, the guinea pig’s small size and inherent anatomical obstacles do pose potential roadblocks. This is especially true in the hands of less experienced technical personnel. Guinea pigs have rather obscure vascular access due to the lack of a tail and their orogastric structure can make orally dosing somewhat challenging.

Although the guinea pig is not appropriate for every situation, with careful planning and expert execution, this species does indeed play a valuable role in the successful de-risking funnels employed by a number of our biopharmaceutical clients.

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

CorDynamics to Showcase Cardiovascular Capabilities at SPS 2013

Posted by CorDynamics on September 10th, 2013

CorDynamics heads to Rotterdam for the Safety Pharmacology Society meeting next week, September 16-19th.

Peter Senese, CorDynamics co-founder and chief operating officer, along with Dr. Franz Hock, our European business developer will be on hand in The Netherlands to discuss cardiovascular safety assessments and capabilities:

• Telemetry—dual pressure, respiratory parameters, ECG

• Isolated Langendorff heart

• Electrophysiology, hemodynamics

Of special note, we will also be featuring the latest industry primer: Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays co-edited by Dr. Franz Hock.Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

Among a number of hot topics, the book argues the days of sequential drug development should be a thing of the past, replaced instead with simultaneous data generation combining toxicological, pharmacodynamic and pharmacokinetic data both from a preclinical and clinical environment.

To discuss these topics and more, please stop by our booth. If you’re not attending this year, feel free to contact us for more information.


Filed under: Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments

Simultaneous Data Generation Connects Early Data to the Clinic

Posted by CorDynamics on May 22nd, 2013

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.

Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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.


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

Cracking the Case on Sudden Cardiac Death and Domperidone

Posted by CorDynamics on April 18th, 2013

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 IKr 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 IKr antagonism.

  • Evidence demonstrated domperidone to have a high affinity to IKr 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.

Filed under: Cardiac Ion Channels, Drug Safety Services, Electrophysiology, Langendorff Heart | No 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.

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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

CorDynamics Sets Drug Discovery and Development 2013 Trade Show Calendar

Posted by Theresa Gralinski, Marketing Director at CorDynamics on December 19th, 2012

The CorDynamics team is saying goodbye to a great 2012 and looking forward to more research and collaboration with colleagues in 2013. Closing one calendar and turning to a new one, some of the first dates to fill in are our trade show exhibitions.

As we continue to grow the early-stage drug discovery side of our business, we will again be visiting the Experimental Biology meeting in Boston, April 20-24. I look forward to attending this event and meeting with colleagues focused on linking drug discovery to development.

In addition to EB, we’ll also be exhibiting at SOT, SPS and ACT.

  • Society of Toxicology 52nd Annual Meeting

San Antonio, Texas March 10-14

  • 2013 Safety Pharmacology Society Annual Meeting

Rotterdam, The Netherlands September 16-19

  • American College of Toxicology 34th Annual Meeting

San Antonio, Texas November 3-6

If you’re going to be at any of these meetings, please put us on your calendar.

Wishing you a very Healthy and Happy New Year.

Theresa Gralinski, Marketing Director

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Zofran, The FDA and Return of Cardiovascular Culprit: QT Interval Prolongation

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on December 05th, 2012

I’m often asked: Why should our project team expend finite resources on cardiovascular safety studies for an oncology therapy or GI compound?

Today’s FDA removal of the highest dose form of Zofran (ondansetron) from the market is a prime example.

Cardiovascular Safety Studies Find QT Interval Prolongation

Case Study

The gastrointestinal drug ondansetron is a 5-HT3 (serotonin type 3) receptor antagonist indicated for use in the prevention of chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting.

This is an interesting scenario since ondansetron is often used as adjuvant therapy. For example, an oncology patient has nausea and vomiting induced by chemotherapy treatment. Their physician prescribes ondansetron to mitigate these severe GI side effects.  On top of all these issues, one certainly wishes to avoid prolongation of the QT interval. Thus, Drug 1 (cancer treatment) leads to Drug 2 (treatment for the side effects of Drug 1), which is what causes cardiac effects.

Preclinical QT Interval Prologation with Ondansetron

The literature demonstrates that preclinical models are predictive for the electrocardiographic effects of ondansetron. The FDA stated today that the 32 mg, single IV dose should be avoided due to the risk of QT interval prolongation, which can lead to Torsades de Pointes, an abnormal, potentially fatal heart rhythm. Learn more about QT Interval prolongation. 

Our team has published and worked extensively with preclinical models designed to detect the propensity for QT interval prolongation early in the discovery, preclinical and phase I stages. View data.

Serotonin is involved in many areas of human physiology. Drugs that alter the pharmacology of serotonin must be interrogated for cardiovascular effect regardless of the target for therapy.

Filed under: Drug Safety Services, Electrophysiology, Hemodynamics, Langendorff Heart, Telemetry | No Comments