The FDA has drafted a guidance — currently available for public comment — which aims to re-evaluate the endpoints that the agency should consider when determining whether a given heart failure drug should be approved.
If finalized, the guidance holds the potential to facilitate the development of truly innovative cardiovascular medicines. It comes at a unique inflection point, as our understanding of the genetics and the biology of the heart has advanced enough to enable the discovery of more targeted treatments, and our tools for monitoring outcomes are validated to enable the evaluation of heart failure medicines on endpoints other than survival or hospitalization.
It is not hyperbole to say that the advisory could transform the lives of patients suffering from cardiovascular diseases around the world.
When “one-size-fits-all” doesn’t fit
There are 5.7 million people in the United States with heart failure today, according to the CDC. Cardiologists are familiar with patients who may present similar symptoms — whether it’s shortness of breath, dizziness, or fatigue — but whose disease origins, progressions and outcomes are not the same.
Despite this knowledge, the current procedure for evaluating heart failure drugs effectively treats these patients with a “one-size-fits-all” approach. Even still, cardiologists instinctively know that these patients are not the same.
To explain: Heart failure is a clinical syndrome which could result from a variety of mechanical, physical, or biochemical functions. For example, symptoms associated with hypertrophic cardiomyopathy become apparent when the heart muscle enlarges and restricts the heart’s capacity to fill and pump blood to the body.
Contrast this with cardiomyopathies that impair the heart’s function by inflicting damage on its muscles. The two may have symptoms in common, but it makes sense that the treatment should differ, as the underlying causes themselves are different.
Current clinical treatments, such as beta blockers, are directed at managing some of the most common elements of heart failure, rather than zeroing in on the variable conditions that lead to these common symptoms. These medicines have saved and extended lives, but similar to the use of traditional chemotherapy drugs in oncology, they are not sufficient to change the ultimate course of the disease for most. We’ve reached a point where this no longer needs to be the case.
The case for precision medicine
Recent breakthroughs in oncology and immunology show that rather than treating tumors in the same way based on location, the emergence of therapies targeted at genetic mutations and molecular markers — a precision medicine approach — is resulting in dramatic changes in patient outcomes and revolutionizing the way drug developers and oncologist contemplate cancer treatment.
As the agency’s guidance implies, we now have an opportunity to apply a similar approach to heart failure. By looking to the underlying biology of a disease, drug makers will be able to discover and optimize therapeutics that intervene upstream of the symptomology, opening the door to halting or even reversing disease progression. Lighting the way along this path are biomarkers — an indicator of a particular disease state and a tool we have already been using for accurate diagnosis — which can provide us with meaningful and relatively early signals of a given treatment’s efficacy.
This element — utilizing biomarkers to provide earlier indications of success — is crucial. Measuring a heart failure drug’s efficacy based on survival or risk of hospitalization may be dangerous for trial participants by prolonging treatment with potentially ineffective medicines.
By employing well-accepted or validated measures of improvement, along with biomarker measurements, we can not only do better for our patients, but test prospective medications more efficiently and therefore get them to market more rapidly.
And options for non-traditional biomarkers that can support the demonstration of meaningful improvement are making rapid strides. For instance, the advent of digital health tools such as biosensors and wearables are destined to provide real-world evidence of the improvements that matter most to patients and their physicians by of increased activity and/or information related to heart rate.
Our understanding of genetics and the biology of the heart, combined with advancements in diagnostic and monitoring technologies, are only growing. The agency’s interest in re-evaluating regulatory requirements is the first step towards a giant leap in the way that we treat the heart. This should be cause for celebration among patients, doctors, and drug makers alike. We hope for a positive update once the request for public comment closes at the end of the month.
Jay Edelberg, M.D., Ph.D., is the senior vice president of clinical development at MyoKardia. Edelberg is a clinical cardiologist and vascular biologist, having served in leadership roles for two decades in both academic medicine and the biopharmaceutical industry.