April 15, 2018 (Vol. 38, No. 8)
Marc Semigran M.D. Chief Medical Officer MyoKardia
Cardiovascular Disease Applications Are Set to Focus on Highly Individualized Variables for Therapy
When President Obama announced the Precision Medicine Initiative at the State of the Union in 2015, it recognized more than a decade of work that scientists and medical researchers had already committed to identify the underlying genetic causes of diseases and specific pathways to treatment. To date, there have been measurable gains in the application of precision medicine approaches across a series of therapeutic areas, most notably oncology.
While there have been significant gains against cancer, precision medicine has produced far less progress in the world’s biggest killer—cardiovascular disease. However, there is reason to believe that soon the treatment paradigm of cardiovascular disease will begin to adopt a focus on highly individualized variables.
The Story So Far
The term “precision medicine” has become a bit of a broad catch phrase, but at its core it is the application of information about an individual’s genes, their expression as proteins, and an environment to prevent, diagnose, and treat disease. In drug discovery, precision medicine is the application of an in-depth understanding of the homogeneity and heterogeneity of a given condition and patient population. In understanding the unifying characteristics underlying disease, targeted therapeutics can be discovered and developed.
This approach has been most widely and successfully utilized in oncology, where tumors now regularly receive in-depth analysis to characterize their origins and genetic profile before a course of treatment is recommended. The approvals of pembrolizumab (Keytruda) for patients with solid tumors that share certain genetic defects, regardless of tumor location, or tisagenlecleucel (Kymriah), a CAR T-cell treatment that uses individual patients’ genetically modified T cells to target and kill leukemia cells, are two noteworthy examples of the strides that have been made in precision medicine treatments for oncology.
The precision medicine approach has also demonstrated traction in certain orphan or rare diseases, perhaps most remarkably in the treatment of cystic fibrosis where the identification of genetic mutations is being used to not only guide prescriptions for the most recently approved therapeutics, but also to predict anticipated patient responses to treatment.
Catching on in Cardiology
Cardiology has been slower to pursue precision medicine treatments, largely because cardiologists have mostly focused thus far on modifying environmental factors that lead to coronary and peripheral arterial disease, such as smoking, obesity, and lack of physical activity. These modifiable risk factors have been identified through large population-based registries and have been fruitful in achieving some reduction in cardiovascular morbidity and mortality.
However, the need for innovative heart disease treatments is critical. Cardiovascular disease remains the world’s biggest killer, and yet only 2% of the breakthrough designations granted by the FDA in 2017 were for drugs intended to treat cardiovascular or renal disease, compared to nearly 30% in oncology and another 20% in hematology.
This may be about to change, in large part because the incentive is already there. Precision medicine approaches are defining distinctive patient subgroups, identifying molecular targets associated with the underpinnings of disease, and revealing biomarkers that can evaluate the effects of cardiovascular drugs earlier in development. This in turn makes it easier for biotechnology and pharmaceutical companies to pursue cardiovascular drug development in a targeted way, where clinical trials may need only hundreds of patients rather than thousands to demonstrate safety and efficacy within a specific subgroup.
The industry is already collaborating on a few solutions. Just last year, the American Heart Association opened its Precision Medicine Platform for use, allowing researchers and physicians from around the world to analyze huge quantities of cardiovascular data from institutions, including Cedars-Sinai Heart Institute, Duke Clinical Research Institute, and Stanford University.
Genetic cardiovascular diseases—such as hypertrophic, restrictive, and dilated cardiomyopathies; inherited heart rhythm disorders, such as LongQT and Brugada syndromes; familial hyperlipidemia; and inherited conditions that cause vascular disease, such as Marfan’s syndrome—have been the initial targets of industrial–academic collaborations to achieve novel breakthroughs in diagnosis and treatment.
Cardiomyopathies, with their reasonably well established genetic factors, provide a case study for such research. For example, one of the first approaches to gene editing as a medical therapeutic is being developed at Oregon Health Sciences University for the treatment of hypertrophic cardiomyopathy. Another example of an industry-academic collaboration is the Sarcomeric Human Cardiomyopathy Registry (SHaRe), an international repository of clinical and laboratory data from investigators at centers all over the world committed to gaining a better understanding of the genetic underpinnings, commonalties, and differences among cardiomyopathy patients. Efforts like these advance the science of precision medicine against specific heart conditions, but they also serve as a blueprint so that other cardiovascular diseases can be approached and treated effectively.
As with any major change in the practice of medicine, precision medicine will have to build slowly toward relevance in the field of cardiology. But the astounding promise of recent gains in other therapeutic areas underscores the potential associated with identifying subgroups of patients who can benefit from a targeted treatment. In cardiovascular disease, precision medicine may result in much-needed innovation in the field and has the potential to eventually change the way we treat heart diseases altogether.