Cover Story

Precision medicine may change management of CVD for cardiologists, patients

Precision medicine has limited effect on the practice of most cardiologists, but with many initiatives underway, it is expected to change the way cardiology is researched and, eventually, practiced.

Precision medicine, defined by the NIH as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person,” could someday enable cardiologists to make decisions based on highly individualized variables, not just on generalized trial results or guidelines.

“Precision medicine will provide clinicians with increasingly precise information about the molecular mechanism by which a person has developed CVDs, and increasingly precise information about the optimum treatment to deal with their disease,” Elliott M. Antman, MD, FAHA, professor of medicine in the cardiovascular division at Brigham and Women’s Hospital and Harvard Medical School; associate dean for clinical translational research at Harvard Medical School; and immediate past president of the American Heart Association, said in an interview with Cardiology Today.

Efforts such as the NIH’s Precision Medicine Initiative and the AHA’s Institute for Precision Cardiovascular Medicine may be the beginning of a pathway that changes research paradigms and the doctor–patient relationship.

Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, from the University of Florida, says precision medicine trials should change the way patients are recruited and engaged in clinical studies.
Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, from the University of Florida, says precision medicine trials should change the way patients are recruited and engaged in clinical studies.

Source: David Braun Photography.

“The goals of precision medicine are to [provide] more precise information to improve health and, along the way, to facilitate discovery science and make clinical research more efficient,” Antman said. “That information will be provided to health care providers, but, importantly and with increasing significance, that information will also be provided to individuals so they can take charge of their own health more than they do now.”

New research underway

President Barack Obama announced the Precision Medicine Initiative in his January 2015 State of the Union address, during which he called for $215 million to fund in fiscal year 2016, including $130 million for the NIH to develop the PMI Cohort Program, a national, large-scale research participant group.

Enrollment is expected to begin this year, with a goal of including 1 million participants by 2019. The cohort “will be a participant-engaged, data-driven enterprise supporting research at the intersection of human biology, behavior, genetics, environment, data science and computation, and much more to produce new knowledge with the goal of developing more effective ways to prolong health and treat disease,” according to a statement on the NIH website. “The goal of the PMI Cohort Program is to set the foundation for a new way of doing research that fosters open, responsible data sharing with the highest regard to participant privacy, and that puts engaged participants at the center of research efforts.”

Among the diseases to be included in the effort are CVD, diabetes and obesity.

For the pilot phase of the project, the NIH contracted Vanderbilt University and Verily, a subsidiary of Alphabet Inc., to “help establish test methods and technologies for enabling direct recruitment of participants and data sharing with researchers” and to “explore optimal approaches and systems for engaging and enrolling participants,” said Carl J. Pepine, MD, MACC, Chief Medical Editor of Cardiology Today.

According to the NIH website, “this approach will help us learn how to create durable relationships with volunteers, who are partners in the research process, which will be the foundation for a democratized, transformative research environment.”

In addition, Pepine said, the U.S. Health Resources and Services Administration is working with several health institutions to figure out how to bring “underrepresented individuals, families and communities to the cohort.”

Other components of the Precision Medicine Initiative include development of data security principles and framework, development of open standards for electronic health records, an effort by the Veterans Administration and the Department of Defense to develop a research cohort of more than 450,000 veterans called the Million Veteran Program, a guidance from the Office for Civil Rights on individuals’ access to their health information under HIPAA, and a precision cloud-based platform under development by the FDA to “encourage genomics researchers to advance quality standards and achieve more consistent and accurate DNA test results,” according to Pepine.

Setting up infrastructure

When the infrastructure is set up, any U.S. resident will be able to enroll in the PMI Cohort Program, either via the program’s website or a health care provider organization.

According to the NIH, any participant must be willing to share their electronic health records, health survey data and mobile health data on lifestyle habits and environmental exposures. Participants also must undergo a baseline exam to provide vital signs, medication assessment and medical history, and must provide a blood, urine or saliva sample for the genetic component of the initiative.

In return, all participants will receive access to their own study results as well as a summary of data from the entire cohort, with privacy and safety assured by safeguards.

“The PMI Cohort Program will be a highly interactive research model, with participants as partners in the development and implementation of the research and with significant representation in the PMI Cohort Program governance and oversight,” according to the NIH website.

With 1 million or more people in the cohort, research for many diseases and healthy states can be facilitated, and there will be “the statistical power to detect associations between genetic and/or environmental exposures and a wide variety of health outcomes,” according to the NIH.

Accomplishments could include measuring risk for a disease based on genetics, environment and the interaction between them; identifying why people respond to the same drug differently; discovering new biomarkers; using mobile health technologies to assess relationships between activity, physiology, environmental exposures and health outcomes; reclassifying diseases and putting them into better context; and creating a platform by which trials of targeted therapies could be conducted, according to the NIH.

An effort involving so much shared data from such a large cohort will naturally raise some concerns about privacy, so the NIH has begun tapping experts to “employ rigorous security testing models, develop participant education with regard to privacy and potential re-identification risk, and clearly articulate response plans in case of a privacy breach,” according to its website.

A working group made a variety of security and privacy recommendations, “including establishing safeguards against unintended release of data and penalties for unauthorized re-identification of participants,” according to the NIH. “These recommendations are intended to ensure the proper use of the data and to set the foundation of trust between participants, researchers and governance.”

Institute for Precision Cardiovascular Medicine

The AHA’s Institute for Precision Cardiovascular Medicine is a multifaceted effort to enable precision studies of CV medicine, award grants for research in this area and to educate researchers, clinicians and the public about findings that emerge from it, Antman told Cardiology Today.

Elliott M. Antman, MD, FAHA
Elliott M. Antman

“The mission of the institute is to serve the integrator function that will enable us to achieve the vision ... that precision medicine will improve the CV health of individuals and populations,” Antman said. “That integrator function has a number of important dimensions to it, [including] to help provide the infrastructure for a digital ecosystem that will support CV science, and delivery of information that will improve CV health. It will include taking a leadership role in setting standards for how this should be done in precision CV medicine, and taking a leadership role in education.”

One consequence of this will be “enhancements and integration of our health care system the way it’s displayed to practitioners,” Antman said, noting that the effort will include shifting electronic health records from a focus on billing and recordkeeping to one on tools for conducting clinical research, including randomization at the point of care and generation of case reports.

“We need to see more work on vertical integration, so that we understand how the various units within a precision medicine system can optimally talk to each other,” he said.

Within the institute, the Cardiovascular Genome Phenome Study has been set up to review and award research grants in precision medicine, Antman said.

In 2014 and 2015, the AHA awarded 21 grants under the program, on subjects ranging from sex-gene interactions for cardiometabolic phenotypes to pharmacogenomics of risk factors for cardiac arrhythmias in global populations.

Although the PMI Cohort Program is focused heavily on recruitment, the AHA institute does not intend to do so because so many CV cohorts exist already, Antman said.

“Simply recruiting these individuals is very important, but not sufficient, because you need to have a mechanism for collecting the data, curating the data, analyzing the data and reporting what you have found to a number of different stakeholders,” he said. “The AHA felt that in cardiology, the focus should be on the integrator function because we have the advantage of a large number of cohorts and a very robust system of clinical trials already in existence.”

Effect on CV conditions

Ultimately, such efforts could change the way cardiologists practice.

Antman cited hypertension management as an example. “We don’t spend a lot of time thinking about the mechanism by which a person’s BP became elevated,” he said. “We follow algorithms ... and we assume that everyone has a common phenotype, hypertension. And we reference the average response reported in clinical trials, where drugs are used to lower BP. The problem with that approach is that individuals develop elevated BP for a variety of reasons. If you treat everybody the same, as though they have a common phenotype, and you apply the average response, you’re missing two important facts. ... First, you are missing the important mechanism by which the person’s BP became elevated. And you’re also missing the expected biologic variation in the magnitude of response to a treatment.”

If those things are known, he said, treatment can be tailored more appropriately to each individual.

Precision medicine may also help to identify individuals who are truly at risk for development of CAD because of high cholesterol, Jonathan C. Fox, MD, PhD, chief medical officer of MyoKardia Inc., in South San Francisco, California, told Cardiology Today.

Jonathan C. Fox, MD, PhD
Jonathan C. Fox

“If you look at the population distribution of cholesterol values of people who experience MI or stroke vs. those who have not, there’s a lot of overlap,” he said. “There is this large group of people for whom the cholesterol values span the same range, but some go on to experience an event and others don’t. We don’t understand very well what are the other things that drive that. Our ability to tackle problems like those will improve as we get better at profiling the right patients and better understanding the benefits and risks.”

Another question that precision medicine may help cardiologists better answer is who benefits most from antiplatelet agents in terms of reduced risk for thrombotic events and who is most at risk for serious bleeding events as a result of those therapies, Fox said.

“As we learn more about human genetics, we’re going to get better at figuring that out, I’m convinced,” he said.

Effect on research

The trend toward precision medicine will likely change how clinical trials are conducted, according to Pepine. He noted that there will be increased emphasis on pragmatic trials, which could combine with comparative-effectiveness data, data sharing, data standards, electronic health records and genomics in a precision medicine approach.

Pragmatic trials are designed to measure the degree of an intervention’s beneficial effect in clinical practice, he said.

“Such trials seek to maximize external validity to ensure generalizability of results,” Pepine said. “However, the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability.”

Pragmatic trials maximize external validity by having few exclusion criteria and by allowing clinicians leeway in interpreting the intervention and how it should be applied to patients, he said.

Tips for maximizing internal validity include “decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias in non-blinded trials though baseline data collection prior to randomization, and automating outcomes assessment” through techniques such as 24-hour ambulatory BP monitoring and blinding data analysis, according to Pepine.

A notable ongoing pragmatic trial is ADAPTABLE, the first study conducted through the National Patient-Centered Clinical Research Network (PCORnet), which will attempt to determine the optimal dose of aspirin for secondary prevention of CVD. It is funded by the Patient-Centered Outcomes Research Institute (PCORI).

Up to 20,000 patients with prior MI or obstructive CAD plus at least one other risk factor will be randomly assigned aspirin 81 mg/day or 325 mg/day and followed up to 30 months for death, hospitalization for MI or stroke and gastrointestinal bleeding. Existing data sources will be used to collect baseline characteristics.

The trial includes an Internet portal for patients and physicians to collect and monitor data. Researchers will collect patient-reported outcomes, use existing data and patient-reported outcomes at follow-up, and perform mechanistic studies, which may include genetic testing and platelet physiology studies.

Treatments for rarer diseases

There are now drugs in the pipeline that have been developed using a precision medicine approach. As one might expect from initial efforts in a new paradigm, they tend to be based on research into a simple relationship; for example, between a single gene and a single phenotype.

One example is MYK-461 (MyoKardia), a novel therapy for treatment of hypertrophic cardiomyopathy. It was developed to address “a known causal pathway with identified molecular targets in that pathway,” Fox said. “Autosomal-dominant mutations encoding contractile proteins of the heart can cause hypertrophic cardiomyopathy.”

Specifically, by studying the mechanistic properties of mutations in sarcomere proteins that can cause hypertrophic cardiomyopathy, researchers targeted a specific biomechanical function altered by mutation and identified a small molecule, which they named MYK-461, that specifically modulates that function, correcting for the effects of mutations.

They have tested it in mice with several of the specific mutations seen in humans.

The researchers found that the molecule counteracted the effect of the mutations and suppressed development of ventricular hypertrophy, cardiomyocyte disarray and myocardial fibrosis. The molecule also reversed the hypertrophy in mice who had already developed it.

The next step, Fox said, is determining which humans could most benefit.

“We’re focusing on the subgroup with obstructive hypertrophic cardiomyopathy,” he said. “In those people, the abnormal thickening of the heart muscle in the left ventricle impedes the exit of blood from the heart, which can be measured as a pressure difference or gradient between the LV and the aorta.”

Currently, he said, the only proven treatments are myectomy, an open-heart surgical procedure, or alcohol septal ablation, an invasive procedure that essentially causes a localized MI, so a medication to relieve the obstruction could address an unmet need in a well-profiled, high-risk population.

“We’ve made huge strides in reducing morbidity and mortality from common CVDs like MI, stroke and the sequelae of hypertension,” Fox said. “We had to attack those big problems first, and the cardiology community has been very successful at that. One of the unintended consequences of that effort was that less common CVDs, including genetic diseases that cause CVD, were ... not given as much attention. So now we are trying to design treatments for less common or rare CVDs.”

Change is coming

There is much excitement about how precision medicine will change the practice of cardiology and improve patient care, but no one is expecting major changes to happen quickly. The NIH itself cautions against expecting rapid results from the PMI Cohort Program.

“While we have seen great progress, it can take many years to understand the contribution of a single unique variable on a given disease or treatment. It will take even more time to develop new treatments and methods of disease prevention,” the NIH wrote on its website. “By launching a study of the size and scope [of the PMI Cohort Program], we hope to accelerate our understanding of disease onset and progression, treatment response and health outcomes.”

Understanding disease and identifying the right patients will be crucial for precision medicine efforts to work.

“Whether the economics work out in favor of precision medicine depends on two things: the difficulty and the cost of finding the best candidates who will benefit from specific, tailored treatments,” Robert L. Ohsfeldt, PhD, health economist and professor in the department of health policy and management at Texas A&M School of Public Health in College Station, Texas, said in a press release. “If you could figure out in advance which treatments work and which don’t, then you could avoid spending money on things that don’t work and improve outcomes. That’s the promise of precision medicine.”

If all goes as planned, cardiologists will eventually have more treatments in their armamentarium that will be targeted to people who are highly likely to benefit from the therapy and highly unlikely to experience risk from it.

“To me, the goal is simple,” Fox said. “It’s to identify the people who need the treatment the most and who stand to benefit the most, and to avoid ... exposing people to side effects who don’t stand to gain.” – by Erik Swain

Disclosures: Fox reports being an employee and shareholder of MyoKardia. Antman and Pepine report no relevant financial disclosures.

Precision medicine has limited effect on the practice of most cardiologists, but with many initiatives underway, it is expected to change the way cardiology is researched and, eventually, practiced.

Precision medicine, defined by the NIH as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person,” could someday enable cardiologists to make decisions based on highly individualized variables, not just on generalized trial results or guidelines.

“Precision medicine will provide clinicians with increasingly precise information about the molecular mechanism by which a person has developed CVDs, and increasingly precise information about the optimum treatment to deal with their disease,” Elliott M. Antman, MD, FAHA, professor of medicine in the cardiovascular division at Brigham and Women’s Hospital and Harvard Medical School; associate dean for clinical translational research at Harvard Medical School; and immediate past president of the American Heart Association, said in an interview with Cardiology Today.

Efforts such as the NIH’s Precision Medicine Initiative and the AHA’s Institute for Precision Cardiovascular Medicine may be the beginning of a pathway that changes research paradigms and the doctor–patient relationship.

Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, from the University of Florida, says precision medicine trials should change the way patients are recruited and engaged in clinical studies.
Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, from the University of Florida, says precision medicine trials should change the way patients are recruited and engaged in clinical studies.

Source: David Braun Photography.

“The goals of precision medicine are to [provide] more precise information to improve health and, along the way, to facilitate discovery science and make clinical research more efficient,” Antman said. “That information will be provided to health care providers, but, importantly and with increasing significance, that information will also be provided to individuals so they can take charge of their own health more than they do now.”

New research underway

President Barack Obama announced the Precision Medicine Initiative in his January 2015 State of the Union address, during which he called for $215 million to fund in fiscal year 2016, including $130 million for the NIH to develop the PMI Cohort Program, a national, large-scale research participant group.

Enrollment is expected to begin this year, with a goal of including 1 million participants by 2019. The cohort “will be a participant-engaged, data-driven enterprise supporting research at the intersection of human biology, behavior, genetics, environment, data science and computation, and much more to produce new knowledge with the goal of developing more effective ways to prolong health and treat disease,” according to a statement on the NIH website. “The goal of the PMI Cohort Program is to set the foundation for a new way of doing research that fosters open, responsible data sharing with the highest regard to participant privacy, and that puts engaged participants at the center of research efforts.”

Among the diseases to be included in the effort are CVD, diabetes and obesity.

For the pilot phase of the project, the NIH contracted Vanderbilt University and Verily, a subsidiary of Alphabet Inc., to “help establish test methods and technologies for enabling direct recruitment of participants and data sharing with researchers” and to “explore optimal approaches and systems for engaging and enrolling participants,” said Carl J. Pepine, MD, MACC, Chief Medical Editor of Cardiology Today.

According to the NIH website, “this approach will help us learn how to create durable relationships with volunteers, who are partners in the research process, which will be the foundation for a democratized, transformative research environment.”

In addition, Pepine said, the U.S. Health Resources and Services Administration is working with several health institutions to figure out how to bring “underrepresented individuals, families and communities to the cohort.”

Other components of the Precision Medicine Initiative include development of data security principles and framework, development of open standards for electronic health records, an effort by the Veterans Administration and the Department of Defense to develop a research cohort of more than 450,000 veterans called the Million Veteran Program, a guidance from the Office for Civil Rights on individuals’ access to their health information under HIPAA, and a precision cloud-based platform under development by the FDA to “encourage genomics researchers to advance quality standards and achieve more consistent and accurate DNA test results,” according to Pepine.

PAGE BREAK

Setting up infrastructure

When the infrastructure is set up, any U.S. resident will be able to enroll in the PMI Cohort Program, either via the program’s website or a health care provider organization.

According to the NIH, any participant must be willing to share their electronic health records, health survey data and mobile health data on lifestyle habits and environmental exposures. Participants also must undergo a baseline exam to provide vital signs, medication assessment and medical history, and must provide a blood, urine or saliva sample for the genetic component of the initiative.

In return, all participants will receive access to their own study results as well as a summary of data from the entire cohort, with privacy and safety assured by safeguards.

“The PMI Cohort Program will be a highly interactive research model, with participants as partners in the development and implementation of the research and with significant representation in the PMI Cohort Program governance and oversight,” according to the NIH website.

With 1 million or more people in the cohort, research for many diseases and healthy states can be facilitated, and there will be “the statistical power to detect associations between genetic and/or environmental exposures and a wide variety of health outcomes,” according to the NIH.

Accomplishments could include measuring risk for a disease based on genetics, environment and the interaction between them; identifying why people respond to the same drug differently; discovering new biomarkers; using mobile health technologies to assess relationships between activity, physiology, environmental exposures and health outcomes; reclassifying diseases and putting them into better context; and creating a platform by which trials of targeted therapies could be conducted, according to the NIH.

An effort involving so much shared data from such a large cohort will naturally raise some concerns about privacy, so the NIH has begun tapping experts to “employ rigorous security testing models, develop participant education with regard to privacy and potential re-identification risk, and clearly articulate response plans in case of a privacy breach,” according to its website.

A working group made a variety of security and privacy recommendations, “including establishing safeguards against unintended release of data and penalties for unauthorized re-identification of participants,” according to the NIH. “These recommendations are intended to ensure the proper use of the data and to set the foundation of trust between participants, researchers and governance.”

Institute for Precision Cardiovascular Medicine

The AHA’s Institute for Precision Cardiovascular Medicine is a multifaceted effort to enable precision studies of CV medicine, award grants for research in this area and to educate researchers, clinicians and the public about findings that emerge from it, Antman told Cardiology Today.

Elliott M. Antman, MD, FAHA
Elliott M. Antman

“The mission of the institute is to serve the integrator function that will enable us to achieve the vision ... that precision medicine will improve the CV health of individuals and populations,” Antman said. “That integrator function has a number of important dimensions to it, [including] to help provide the infrastructure for a digital ecosystem that will support CV science, and delivery of information that will improve CV health. It will include taking a leadership role in setting standards for how this should be done in precision CV medicine, and taking a leadership role in education.”

One consequence of this will be “enhancements and integration of our health care system the way it’s displayed to practitioners,” Antman said, noting that the effort will include shifting electronic health records from a focus on billing and recordkeeping to one on tools for conducting clinical research, including randomization at the point of care and generation of case reports.

“We need to see more work on vertical integration, so that we understand how the various units within a precision medicine system can optimally talk to each other,” he said.

PAGE BREAK

Within the institute, the Cardiovascular Genome Phenome Study has been set up to review and award research grants in precision medicine, Antman said.

In 2014 and 2015, the AHA awarded 21 grants under the program, on subjects ranging from sex-gene interactions for cardiometabolic phenotypes to pharmacogenomics of risk factors for cardiac arrhythmias in global populations.

Although the PMI Cohort Program is focused heavily on recruitment, the AHA institute does not intend to do so because so many CV cohorts exist already, Antman said.

“Simply recruiting these individuals is very important, but not sufficient, because you need to have a mechanism for collecting the data, curating the data, analyzing the data and reporting what you have found to a number of different stakeholders,” he said. “The AHA felt that in cardiology, the focus should be on the integrator function because we have the advantage of a large number of cohorts and a very robust system of clinical trials already in existence.”

Effect on CV conditions

Ultimately, such efforts could change the way cardiologists practice.

Antman cited hypertension management as an example. “We don’t spend a lot of time thinking about the mechanism by which a person’s BP became elevated,” he said. “We follow algorithms ... and we assume that everyone has a common phenotype, hypertension. And we reference the average response reported in clinical trials, where drugs are used to lower BP. The problem with that approach is that individuals develop elevated BP for a variety of reasons. If you treat everybody the same, as though they have a common phenotype, and you apply the average response, you’re missing two important facts. ... First, you are missing the important mechanism by which the person’s BP became elevated. And you’re also missing the expected biologic variation in the magnitude of response to a treatment.”

If those things are known, he said, treatment can be tailored more appropriately to each individual.

Precision medicine may also help to identify individuals who are truly at risk for development of CAD because of high cholesterol, Jonathan C. Fox, MD, PhD, chief medical officer of MyoKardia Inc., in South San Francisco, California, told Cardiology Today.

Jonathan C. Fox, MD, PhD
Jonathan C. Fox

“If you look at the population distribution of cholesterol values of people who experience MI or stroke vs. those who have not, there’s a lot of overlap,” he said. “There is this large group of people for whom the cholesterol values span the same range, but some go on to experience an event and others don’t. We don’t understand very well what are the other things that drive that. Our ability to tackle problems like those will improve as we get better at profiling the right patients and better understanding the benefits and risks.”

Another question that precision medicine may help cardiologists better answer is who benefits most from antiplatelet agents in terms of reduced risk for thrombotic events and who is most at risk for serious bleeding events as a result of those therapies, Fox said.

“As we learn more about human genetics, we’re going to get better at figuring that out, I’m convinced,” he said.

Effect on research

The trend toward precision medicine will likely change how clinical trials are conducted, according to Pepine. He noted that there will be increased emphasis on pragmatic trials, which could combine with comparative-effectiveness data, data sharing, data standards, electronic health records and genomics in a precision medicine approach.

Pragmatic trials are designed to measure the degree of an intervention’s beneficial effect in clinical practice, he said.

“Such trials seek to maximize external validity to ensure generalizability of results,” Pepine said. “However, the danger of pragmatic trials is that internal validity may be overly compromised in the effort to ensure generalizability.”

PAGE BREAK

Pragmatic trials maximize external validity by having few exclusion criteria and by allowing clinicians leeway in interpreting the intervention and how it should be applied to patients, he said.

Tips for maximizing internal validity include “decreasing contamination bias through cluster randomization, and decreasing observer and assessment bias in non-blinded trials though baseline data collection prior to randomization, and automating outcomes assessment” through techniques such as 24-hour ambulatory BP monitoring and blinding data analysis, according to Pepine.

A notable ongoing pragmatic trial is ADAPTABLE, the first study conducted through the National Patient-Centered Clinical Research Network (PCORnet), which will attempt to determine the optimal dose of aspirin for secondary prevention of CVD. It is funded by the Patient-Centered Outcomes Research Institute (PCORI).

Up to 20,000 patients with prior MI or obstructive CAD plus at least one other risk factor will be randomly assigned aspirin 81 mg/day or 325 mg/day and followed up to 30 months for death, hospitalization for MI or stroke and gastrointestinal bleeding. Existing data sources will be used to collect baseline characteristics.

The trial includes an Internet portal for patients and physicians to collect and monitor data. Researchers will collect patient-reported outcomes, use existing data and patient-reported outcomes at follow-up, and perform mechanistic studies, which may include genetic testing and platelet physiology studies.

Treatments for rarer diseases

There are now drugs in the pipeline that have been developed using a precision medicine approach. As one might expect from initial efforts in a new paradigm, they tend to be based on research into a simple relationship; for example, between a single gene and a single phenotype.

One example is MYK-461 (MyoKardia), a novel therapy for treatment of hypertrophic cardiomyopathy. It was developed to address “a known causal pathway with identified molecular targets in that pathway,” Fox said. “Autosomal-dominant mutations encoding contractile proteins of the heart can cause hypertrophic cardiomyopathy.”

Specifically, by studying the mechanistic properties of mutations in sarcomere proteins that can cause hypertrophic cardiomyopathy, researchers targeted a specific biomechanical function altered by mutation and identified a small molecule, which they named MYK-461, that specifically modulates that function, correcting for the effects of mutations.

They have tested it in mice with several of the specific mutations seen in humans.

The researchers found that the molecule counteracted the effect of the mutations and suppressed development of ventricular hypertrophy, cardiomyocyte disarray and myocardial fibrosis. The molecule also reversed the hypertrophy in mice who had already developed it.

The next step, Fox said, is determining which humans could most benefit.

“We’re focusing on the subgroup with obstructive hypertrophic cardiomyopathy,” he said. “In those people, the abnormal thickening of the heart muscle in the left ventricle impedes the exit of blood from the heart, which can be measured as a pressure difference or gradient between the LV and the aorta.”

Currently, he said, the only proven treatments are myectomy, an open-heart surgical procedure, or alcohol septal ablation, an invasive procedure that essentially causes a localized MI, so a medication to relieve the obstruction could address an unmet need in a well-profiled, high-risk population.

“We’ve made huge strides in reducing morbidity and mortality from common CVDs like MI, stroke and the sequelae of hypertension,” Fox said. “We had to attack those big problems first, and the cardiology community has been very successful at that. One of the unintended consequences of that effort was that less common CVDs, including genetic diseases that cause CVD, were ... not given as much attention. So now we are trying to design treatments for less common or rare CVDs.”

PAGE BREAK

Change is coming

There is much excitement about how precision medicine will change the practice of cardiology and improve patient care, but no one is expecting major changes to happen quickly. The NIH itself cautions against expecting rapid results from the PMI Cohort Program.

“While we have seen great progress, it can take many years to understand the contribution of a single unique variable on a given disease or treatment. It will take even more time to develop new treatments and methods of disease prevention,” the NIH wrote on its website. “By launching a study of the size and scope [of the PMI Cohort Program], we hope to accelerate our understanding of disease onset and progression, treatment response and health outcomes.”

Understanding disease and identifying the right patients will be crucial for precision medicine efforts to work.

“Whether the economics work out in favor of precision medicine depends on two things: the difficulty and the cost of finding the best candidates who will benefit from specific, tailored treatments,” Robert L. Ohsfeldt, PhD, health economist and professor in the department of health policy and management at Texas A&M School of Public Health in College Station, Texas, said in a press release. “If you could figure out in advance which treatments work and which don’t, then you could avoid spending money on things that don’t work and improve outcomes. That’s the promise of precision medicine.”

If all goes as planned, cardiologists will eventually have more treatments in their armamentarium that will be targeted to people who are highly likely to benefit from the therapy and highly unlikely to experience risk from it.

“To me, the goal is simple,” Fox said. “It’s to identify the people who need the treatment the most and who stand to benefit the most, and to avoid ... exposing people to side effects who don’t stand to gain.” – by Erik Swain

Disclosures: Fox reports being an employee and shareholder of MyoKardia. Antman and Pepine report no relevant financial disclosures.