A 23-year-old athlete collapsing at a sporting match or right before crossing a finish line is unfortunately not foreign news to many. Hypertrophic cardiomyopathy (HCM) affects an estimated 630,000 people of all ages in the U.S., with as many as 84% undiagnosed.
A bit of physiology: HCM is a genetic condition that occurs when the heart muscle cells enlarge and cause the walls of the ventricles (usually the left ventricle) to thicken, which in turn may block blood flow out of the ventricle even though the ventricle size often remains relatively normal. This results in reduced pumping capacity of the heart, sometimes leading to cardiac arrest. HCM is a progressive disease that can result in shortness of breath, chest pain, inability to participate in normal activities, disabling heart failure, and even stroke. Obstructive HCM (oHCM) is a form of HCM characterized by a dynamic obstruction of the left ventricular outflow tract that results in abnormalities in arterial blood flow. HCM is typically diagnosed by echocardiogram to visually identify the thickening of the heart wall, anatomical blood flow obstruction, and heart valve movement.
To try and improve the statistics, MyoKardia, a clinical-stage biopharmaceutical company pioneering a precision medicine approach to cardiovascular diseases like HCM, developed proprietary machine learning algorithms to improve the diagnosis and understanding of the disease using wrist-worn photoplethysmography optical biosensors (Wavelet Health Wristband) to collect arterial blood flow signature (also known as arterial pulse waves) data in HCM and unaffected patients. The study took baseline arterial pulse wave morphology collected via the investigational wrist biosensors from oHCM patients enrolled in a digital health substudy of the PIONEER-HCM trial (NCT02842242) of mavacamten (formerly MYK-461) to unaffected controls from a Wavelet Health database.
Mavacamten is an orally administered small molecule designed for HCM to reduce left ventricular contractility. More specifically, mavacamten is an allosteric modulator of cardiac myosin (myosin inhibitor) that reduces hypercontractility in HCM patients. MyoKardia has evaluated mavacamten in multiple Phase 1 clinical studies, primarily designed to evaluate safety and tolerability of oral doses of mavacamten, and provide pharmacokinetic and pharmacodynamic data. In April 2016, the U.S. FDA granted Orphan Drug Designation for mavacamten for the treatment of symptomatic oHCM, a subset of HCM. MyoKardia is currently studying mavacamten in the Phase 2 study.
Five minute recordings were obtained at rest, and divided into training and validation data sets by cohort. A beat-by-beat machine learning model was developed using a predefined feature set to calculate an HCM probability score, and an optimal threshold score was determined. The model was evaluated using summary statistics and an ROC (Receiver Operating Characteristic) area-under-curve metric. Presented at a late-breaker session at the American Heart Association (AHA) Scientific Sessions in December 2017, this abstract presented an oHCM machine learning classifier developed based on 42 calculated metrics from the featured arterial pulsewave recordings collected from 14 patients with oHCM at rest and 81 unaffected controls. The pulse wave patterns of patients with oHCM were consistent with the turbulent blood flow and heart rate variability associated with obstruction of the left ventricular outflow tract (LVOT) characteristic of oHCM.
This machine learning model achieved a >95% accuracy (95% specificity and sensitivity) and confirmed an increased probability in oHCM patients compared to unaffected controls, thereby suggesting the possibility of predictive analytics related to the non-invasive detection of oHCM.
Using its precision medicine platform, MyoKardia has aimed to generate a pipeline of therapeutic programs for the chronic treatment of the two most prevalent forms of heritable cardiomyopathy – hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). A cornerstone of the MyoKardia platform is the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a multi-center, international repository of clinical and laboratory data on individuals and families with genetic heart disease, which MyoKardia helped form in 2014. MyoKardia’s mission is to change the world for patients with serious cardiovascular disease through bold and innovative science.
We had the of privilege of speaking to Dr. Robert McDowell, MyoKardia’s Chief Scientific Officer, and Dr. Eric Green, MyoKardia’s Senior Director of Translational Research.
Alice Ferng, Medgadget: Can we start with a bit of background about the company? Who are the founders and how did you all get started working on MyoKardia?
Dr. Robert McDowell, MyoKardia: MyoKardia was founded five years ago by Charles Homcy, MD, a partner at Third Rock Ventures, Leslie Leinwand, PhD, at the BioFrontiers Institute at the University of Colorado, Christine Seidman, MD, with Harvard Medical School and Brigham and Women’s Hospital, Jonathan Seidman, PhD, also from Harvard Medical School, and James Spudich, PhD, with Stanford University.
Together, they shared a vision that there was a lack of therapeutic innovation in treating cardiovascular disease even as the medical need for heart disease treatments continued to be strong. Leveraging their diverse expertise in company formation, myosin motors and heart muscle function, and the role genetics plays in numerous cardiovascular diseases, MyoKardia was founded to discover and development novel therapeutics that could address the underlying biomechanical cause of disease for well-defined patient populations. By aiming to address heart disease in patient subgroups with shared disease characteristics (such as genetic abnormalities) and using translational medicine and biomarker tools to seek early and efficient tests of therapeutic hypotheses, MyoKardia is able to apply the precision medicine approach that has recently been so successful in advancing oncology drug development to unmet needs in cardiovascular disease. The company’s initial product pipeline reflects this approach with lead programs focused on two of the most common heritable cardiomyopathies, hypertrophic cardiomyopathy and dilated cardiomyopathy.
Medgadget: What is your role, and what got you interested in working on HCM?
Dr. McDowell: I am currently the Chief Scientific Officer at MyoKardia, and have been with the company since its inception. I became attracted to working on HCM because I believed that the elements were in place to improve patients’ lives: our Founders had identified how the genetic drivers of disease produced common defects in contraction and relaxation; the sarcomere appeared to be a druggable system that could be tuned with small molecules; and we were able to measure the pharmacodynamic activity of our compounds in real-time using echocardiography and other techniques. The time was therefore right to test the therapeutic hypothesis using translational tools with strong predictive value in the clinic.
Medgadget: What is MyoKardia’s mission and goal?
Dr. McDowell: MyoKardia’s mission is to change the world for patients with serious cardiovascular disease through bold and innovative science.
Medgadget: Did you start looking at HCM initially? Or other cardiovascular diseases?
Dr. McDowell: We knew that heritable cardiomyopathies, like HCM, are caused by genetic mutations in a few key cardiac proteins, including myosin, troponin, and cardiac myosin binding protein-C. Two of MyoKardia’s founders brought an understanding of the genetics associated with these diseases and our other founders brought an understanding the molecular motors that control contraction and relaxation of the heart. With that as a foundation, our researchers were able to discover small molecules that could address the biomechanical cause of HCM.
HCM is genetically driven and estimated to affect 630,000 people (or ~1:500) in the United States. The disease is characterized by thickened heart muscle, excessive contractility, and impaired relaxation. Our lead drug, mavacamten, modulates the function of cardiac myosin, the motor protein that drives heart muscle contraction. Our initial treatment population for mavacamten is obstructive HCM (oHCM), in which the left ventricular outflow tract becomes blocked. Approximately two-thirds of the total HCM population has oHCM and the genetic mutations underlying disease manifest in a common dysfunction, making it well suited to a precision medicines approach. The medical need for targeted therapeutics is acute. Patients with oHCM are typically treated with beta blockers, which slow the heart but do little to change the hypercontractility that is underlying oHCM. The only available direct treatment for oHCM are open-heart surgical procedures that remove the obstruction and/or cut back the thickened walls of the heart.
Medgadget: Tell me more about the PIONEER-HCM study.
Dr. McDowell: The PIONEER study was a Phase 2 clinical trial in patients with symptomatic, obstructive HCM. The objective of the study was to ascertain if regular dosing of mavacamten could alleviate obstruction of the left ventricular outflow tract (measured as an LVOT gradient), as well as other signs and symptoms of HCM, peak VO2, a measurement of exercise capacity and New York Heart Association classification. The results were clinically meaningful: All patients taking mavacamten experienced a significant improvement in their post-exercise LVOT gradient, peak VO2 and 80 percent improved their NYHA classification. As part of the PIONEER study, we also wanted to study whether we could use a wrist-worn biosensor that tracked pulsewaves to differentiate between patients with oHCM and people without the condition.
Medgadget: What about the substudy? What was the purpose and findings?
Dr. Eric Green, MyoKardia: The substudy evaluated the arterial pulsewave pattern as measured by photoplethysmography (PPG) in oHCM patients as compared to healthy volunteers. Abnormal arterial flow patterns have been previously observed in oHCM patients using established tools such as echocardiography. The purpose of this substudy was to investigate whether a non-invasive investigational PPG wristband, similar to commercially available digital health wearables, could detect these patterns and potentially supplement standard measures of disease.
In this study, we collected PPG pulse wave traces from patients with oHCM and healthy volunteers. Using automated analyses, we extracted details about the shape and pattern of the tracings and applied machine learning to identify differences in these features between oHCM patients and healthy volunteers. We found that a sensitive and specific signature of arterial blood flow in oHCM could be identified with the combination of a wrist-worn PPG biosensor and machine learning algorithms.
Medgadget: Have you compared the results of the biosensor created by Wavelet Health with results collected from another similar PPG device?
Dr. Green: This initial study was conducted in collaboration with Wavelet Health using their investigational wrist-worn PPG sensor. We have not formally evaluated other PPG devices. In future work, we intend to validate these findings using other similar devices.
Medgadget: With up to a 98% accuracy reported using Wavelet Health biosensor worn on the wrist to provide data – how would something like a Polar chest strap fare?
Dr. Green: For this study we perform analysis on the optical PPG waveform corresponding to arterial blood flow. Polar chest straps calculate heart rate by measuring the electrical signals associated with beating of the heart. This is an effective way to measure heart rate, but it does not provide information about the pattern of blood flowing out of the heart so would not be useful for this study.
Medgadget: What are the disadvantages of using a PPG device?
Dr. Green: Challenges associated with using the PPG signal include that it can be affected by movement, skin tone and ambient light.
Medgadget: What’s next for MyoKardia?
Dr. McDowell: This year we are advancing mavacamten into a Phase 3 pivotal trial in oHCM, known as EXPLORER. We will also begin testing mavacamten in a Phase 2 clinical trial in a second indication, non-obstructive HCM. In addition to our work with mavacamten, our second clinical-stage compound, MYK-491, is progressing through Phase 1 studies and we anticipate initiating a Phase 2 trial of MYK-491 in dilated cardiomyopathy, or DCM, in the second half of the year. Our research team remains committed to the discovery and development of innovative cardiovascular medicines, and over the next year or so, we expect to be able to share more about those activities.
Link: MyoKardia homepage…
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