Posts Tagged ‘Heart Failure’

Does the FDA Refer to Disease-State Models to Determine Safety?

Posted by CorDynamics on April 22nd, 2015

The answer is: sometimes.

FDA Orphan Drugs Rare Diseases Cholesterol

A few months ago I attended an excellent Safety Pharmacology Society webinar (Nov 2014, “Cardiac Safety Testing Models”) where the non-clinical examination of cardiac contractility was discussed.

Dr. Philip Gatti, from the US FDA, concluded that compounds with putative inotropic effects should undergo “better utilization of in vitro systems (Langendorff or wedge preps) or use of animal models of heart failure which would enhance sensitivity to such drug effects.

Our labs have interrogated the cardiovascular effects of test articles in a variety of underlying pathophysiological states, including subjects with hypertension to those with impaired respiratory capacity.

One of the more frequent drug safety conditions we are asked to model is the compromised or failing heart. Many project teams need to know if their compounds affect left ventricular hemodynamics in the presence of pre-existing cardiac dysfunction. Sometimes these properties may not exist in the normal subject. However, they may be present in the target population.

We have conducted these studies using multiple models, including the post-infarcted heart, hypertrophy following hemodynamic overload (such as transverse aortic constriction), and tachypaced-induced cardiomyopathy.

Similar questions are usually asked:

  • Is it appropriate to examine drug safety in animals with ‘disease-state’?
  • Is this a current regulatory expectation?
  • Is there a differential effect compared to ‘normal’ animals?

Using these approaches, we have uncovered substantive areas of concern while also mitigating issues that previously appeared insurmountable.

We know there is an important role for using the ‘disease-state’ subject in cardiovascular safety pharmacology assessments.

While most preclinical studies will continue to use normal animals for risk assessment, the inclusion of disease models where appropriate can help unmask notable toxicities that may only occur in the target patient population.

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

Burgeoning Heart Failure Treatment Goes Beyond Relieving Hemodynamic Load

Posted by CorDynamics on September 09th, 2014

The recent heart failure announcement of the PARADIGM-HF lit up the news sites, and for good reason.

crackingheart

PARADIGM-HF is a clinical trial designed to assess the composite outcome of death or hospitalization in >8000 AHA Class II-IV heart failure patients assigned to receive either enalapril or a novel combined angiotensin receptor antagonist–neprilysin inhibitor. The trial, detailed in The New England Journal of Medicine, was stopped early due to an “overwhelming” benefit from receiving the angiotensin receptor antagonist–neprilysin inhibitor.

Angiotensin receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors have been used in the treatment of heart failure for many years. So what was special about this new method of attacking the disease? The neprilysin inhibitor aspect appears to be critical for the superior efficacy.

Neprilysin inhibition causes an increase in circulating levels of natriuretic peptides. Natriuretic peptides are a family of moieties that cause increased levels of sodium to be excreted by the kidneys. In addition they are vasodilators, inhibit renin-angiotensin-aldosterone axis function and have anti-hypertrophic properties among other effects. One can see why this approach may be beneficial to the failing heart.

Going beyond simply relieving hemodynamic load, increasing our understanding of the complex pathophysiology involving cardiac dysfunction and failure will lead to improved treatments for the > 20 million patients with this condition.

Filed under: Drug Discovery Services, Heart Failure, Hemodynamics | 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

Have a Solution to Heart Failure? Prove It.

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on May 23rd, 2012

Failures of the heart inspire authors, musicians and directors.

Likewise, discovering new therapies for the complexities of heart failure inspires drug developers to search for new therapeutic compounds.

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?

The ultimate test for pending heart failure therapies are morbidity and mortality trials. Does the compound delay or prevent morbidity (the disease) as well as mortality. These comprehensive trials require patients numbering in the thousands. Studies of this scope, with high recruitment costs and long treatment periods, are an incredibly expensive investment.

Why try? According to the American Heart Association, the need is great and growing.
• An estimated 5.7 Americans, of all ages, suffer from heart disease.
• Heart failure is the fastest-growing clinical cardiac disease entity in the United States, affecting 2% of the population.
• In 2010, the estimated total cost of heart failure in the US was $39.2 billion, representing 1-2% of all health care expenditures.

Heart failure therapies may be hard to get, but for a number of our clients, these numbers make it worth the passionate pursuit.

 

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

Complexities of Developing Heart Failure Drugs

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on April 17th, 2012

Matters of the heart—especially broken ones—are always complicated.

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.

 

 

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

Some Cancer Drugs Cause Cardiovascular Side Effects

Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 24th, 2010

A number of years ago, it was a fairly common industry practice within oncology development programs to provide nonclinical data from quite cursory examinations of unanticipated cardiovascular effects in support of new drug candidates. Oftentimes, the nonclinical cardiovascular battery consisted of actions on a single ion channel and the combination of in vivo cardiovascular assessment with a standard toxicology study. 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 unique. These events also serve to demonstrate the unintended clinical consequences of truncated early development.

In 2006, reports surfaced on the development of acute left ventricular dysfunction and heart failure in small numbers of patients taking imatinib (Gleevec) for the treatment of chronic myelogenous leukemia. Upon nonclinical mechanistic examination of imatinib’s direct effects on ventricular cardiomyocytes, it was discovered that the compound interfered with intracellular mitochondrial function. As such, imatinib is not classified as a negative inotropic agent but can be characterized as directly cardiotoxic – at least as it relates to left ventricular function – due to the decrease in hemodynamics upon repetitive exposure in the aforementioned patients. Medical oncologists are now armed with this information and appropriate safeguards can be instituted to reduce the likelihood of cardiotoxicity during dosing with imatinib. The literature also contains compelling reports of a structurally modified version of imatinib that does not interfere with cardiomyocyte mitochondria in vitro.

More recently, we’ve begun to understand the basis for other unanticipated cancer pharmacology including the hypertension associated with vascular endothelial growth factor inhibition. Compounds, such as Avastin, Sutent, or Nexavar, work as anti-tumor agents by inhibiting the stimulation of blood vessels supporting malignant growth. They also happen to disrupt the nitric oxide pathway – a key process regulating mean arterial blood pressure.

While some of these toxicities likely could not have been predicted via traditional nonclinical activities, the operating philosophy that certain targeted pharmacology or therapeutic areas may require less robust major organ system interrogations can have unfortunate consequences. At the very least, it reduces the opportunity to vet the possibility of these side effects. For example, the increase in survival following some of the recent advances in oncology treatment needs to be considered in the context of lasting cardiovascular effects.

We don’t want to be solving one problem now only to create others down the road. It’s well recognized that this is easier said than done – but at the very least it needs to be kept in mind during the strive for balance between efficacy and safety in this challenging therapeutic area.

 

Filed under: Drug Safety Services | No Comments