FDA discussion: Evaluation of the Cardiac Safety for Serotonin Receptor Agonists as GI Therapies.

Written by: Dr. Robert Kleiman, Chief Medical Officer & Vice President, Global Cardiology

A few months ago in November 2011, the FDA brought together a group of gastroenterologists and cardiologists to discuss the history of cardiac safety issues surrounding serotonin 5-HT4 agonists and the design of cardiac safety trials for new 5-HT4 agonists which are currently under development.

There is a great need for drugs to treat GI motility disorders, as there are currently few drugs approved for treatment of these diseases, and several of the drugs which did make it to market have since been withdrawn due to cardiac safety issues.  In particular, Cisapride was introduced in 1993 and withdrawn in 2000 due to QT prolongation and fatal ventricular arrhythmias, and Tegaserod (Zelnorm) was introduced in 2002 and withdrawn in 2007 due to excess ischemic cardiovascular events.

There are currently a number of new 5-HT4 agonists in various stages of development, and there is a great deal of effort to target receptors in the GI tract more specifically in order to try to avoid off target cardiac side effects.  Indications for which these drugs are targeted include chronic idiopathic constipation, irritable bowel syndrome, chronic irritable bowel syndrome with constipation, gastroparesis, and gastroesophageal reflux disease that does not respond to proton pump inhibitors.

As with all new compounds, new 5-HT4 agonists should be carefully assessed for QT prolongation and for drug-drug interactions.  In addition, assessments of risk of excess myocardial infarction, unstable angina and strokes should also be performed.  The ICH S7B and E14 guidances describe the preclinical and clinical assessments which should be performed for all new chemical entities to assess the risk of QT prolongation, including hERG assays and a formal Thorough QT (TQT) trial.

Assays of drug-drug interactions are also well established at this time.

Less clear is how the risk of cardiovascular events should be assessed during drug development.  Possible assessments discussed in this meeting included platelet aggregation assays, evaluation of smooth muscle contraction, as well as large, dedicated cardiovascular safety studies using “enriched” patient populations with pre-existing cardiovascular risk factors or disease.

You can access the Advisory Committees meeting materials on this discussion using the link below: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM286759.pdf

We will be sure to keep you updated on any further discussions regarding the evaluation of the cardiac safety for serotonin receptor agonists as GI therapies.  As always, if you have any questions for Dr. Kleiman or would like more information on how ERT can help support the Thorough QT trial or other centralized cardiac safety needs for your new 5-HT4 agonists in development please visit our website at http://www.ert.com/contact-ert/ or write your questions/comments below.

About ERTglobal

ERT is a global technology-driven provider of health outcomes research services and customizable medical devices supporting biopharmaceutical sponsors and contract research organizations (CROs) to achieve their drug development and healthcare objectives. ERT harnesses leading technology coupled with unrivaled processes and scientific expertise to collect, analyze, and report on clinical data to support the determination of health outcomes critical to the approval, labeling and reimbursement of pharmaceutical products. ERT is the acknowledged industry leader in centralized cardiac safety and respiratory efficacy services and also provides electronic Patient Reported Outcomes (ePRO) and outcomes assessments for multiple modalities across all phases.
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