Recently, Cynthia Waldman of HCMBeat corresponded with Dr. Srihari S. Naidu of Westchester Medical Center about the second edition of an HCM textbook he recently edited. What follows is a transcript of their correspondence.
Two San Francisco based companies are now conducting clinical trials for three drugs specifically targeting HCM.
MyoKardia, which was founded in 2012 by a group of HCM researchers (including Stanford’s James Spudich, one of the founders of Cytokinetics – the second company conducting a HCM drug trial – see below), was the first entrant into the HCM area with the development of its drug, mavacamten (formerly known as MYK-461).
Mavacamten is currently the subject of the Phase 3 EXPLORER-HCM clinical trial for obstructive HCM, now fully enrolled with results expected in 2020, as well as the Phase 2 MAVERICK-HCM trial for non-obstructive HCM, with results are expected later this year.
And, MyoKardia announced this week that it is will begin testing a second drug for HCM. The new drug, currently known as MYK-224, is the subject of a new Phase 1 clinical trial. This drug targets the sarcomeric proteins of the heart muscle like MyoKardia’s first drug, mavacamten. According to the press release, MYK-224 may provide dosing advantages for some patients over other drugs.
Cytokinetics, a company founded in 1998 which was previously focused on other muscle related conditions like ALS, has decided to set its sights on HCM. Cytokinetics is currently conducting a Phase 1 clinical trial assessing the safety and tolerability of its drug CK-274, a cardiac myosin inhibitor intended to reduce cardiac contractility.
At a recent cardiology meeting in Boston, Cytokinetics presented data showing that CK-274 decreased cardiac contractility in healthy animals.
Stay tuned to HCMBeat for the latest details and updates about these drugs.
UPDATE: Data Presented at August 31, 2019 European Society of Cardiology Congress in Paris
At ESC, MyoKardia announced results from the PIONEER-Open Label Extension study from 12 patients who had been enrolled in the Phase 2 PIONEER-HCM study of mavacamten. These patients were evaluated after a total of 36 weeks on the drug. The study results showed reduction in both resting and provoked left ventricular outflow tract gradients, while left ventricular ejection fraction remained normal at all times. Further, certain biomarkers of heart disease showed improvement with mavacamten treatment. Most strikingly, NT-proBNP, a blood indicator of cardiac wall stress, decreased almost to normal.
DISCLOSURES: HCMBEAT HAS RECEIVED PAST UNRESTRICTED EDUCATIONAL GRANTS FROM MYOKARDIA. ADDITIONALLY, CYNTHIA BURSTEIN WALDMAN OF HCMBEAT SERVES AS A PATIENT ADVISOR ON THE STEERING COMMITTEE FOR MYOKARDIA’S EXPLORER TRIAL.
A recent study by doctors at Toronto’s Hospital for Sick Children suggests that current screening guidelines for children from HCM families are inadequate and should instead recommend earlier screening exams. In the U.S., screening begins at age 12 pursuant to American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. In Europe, screening begins at age 10 pursuant to the European Society of Cardiology (ESC) guidelines.
In particular, the doctors found that out of 524 children who underwent
family screening prior to age 18, 9.9% showed evidence of HCM at first screening and only 1.1% of these children were symptomatic. An additional 28 (5.4%) children developed HCM over 3 years of follow-up, while 41% of major cardiovascular events [death, sudden cardiac death, or need for major interventions such as myectomy, ICD implantation, or heart transplant] occurred in children before the age of 10 year. Therefore, the doctors suggest that certain children appear to be at elevated risk and should be followed from earlier ages.
In particular, the study showed that children at greatest risk are:
- have a pathogenic genetic mutations in MYH7 or MYBCP3
- Have a family history of sudden cardiac death
A companion editorial by Dr. Christopher Semsarian of the University of Sydney in Australia and Dr. Carolyn Ho of the Brigham and Women’s Hospital in Boston points out that even under current guidelines, while screening is optional before age 12 (2011 ACC/AHA Guidelines) or age 10 (2014 ESC Guidelines), screening should still be considered if there is a particularly malignant family history, the child is an athlete or if there are symptoms or other indications of disease.
Semsarian and Ho note that even though screening tests (echocardiograms and EKGs) and non-invasive, there can be both monetary and emotional costs to the family resulting from screening. Hence, they recommend individualization in screening as opposed to a blanket rule; especially given that information relating to genetic status, gender and family history are easily available. Each family situation should be assessed individually, taking into consideration their own set of unique risk factors and their tolerance for risk.
Editor’s Note: HCMBeat recently highlighted this study from the U.K. which similarly concluded that the age of screening children in HCM families should be lowered.
A group of scientists led by Stanford University’s Dr. James Spudich, working together with researchers from the University of California-Santa Barbara, the University of Washington and the Institut Curie in Paris, has recently been awarded a $10 million grant by the National Institute of General Medical Sciences to develop novel treatments for hypertrophic cardiomyopathy (HCM).
The researchers hope that the added resources from this grant will help them find ways to correct pathological heart protein changes they believe to be at the root of HCM. The team then plans to partner with pharmaceutical companies to develop more personalized approaches to HCM treatment.
Dr. Spudich has long been involved in HCM research and has been a founder of two separate companies which are currently engaged in drug trials for potential HCM treatments: MyoKardia and Cytokinetics.
A story about Dr. Spudich and the inspiration for his work was featured in this recent post on HCMBeat.
According to a limited study recently published in Nature, researchers were able to detect obstructive HCM (HOCM) using a noninvasive optical sensor contained in many commercial smartwatches.
How the Technology Works
These watches used photoplethysmography, a noninvasive optical method used to detect blood volume changes in the microvascular bed at the skin surface. The same technology is used in clinical pulse oximeters and is now widely incorporated in commercial smartwatches that have heart rate detection.
According to a paper published last week in JAMA Cardiology, doctors at Tufts University’s HCM Center have been able to identify 95% of their patients at high risk of sudden cardiac death (SCD) from HCM. Tufts applied an updated and modified version of the risk factors enumerated in the American College of Cardiology/American Heart Association Guidelines promulgated in 2011.
According to a story broken by Kaiser Health News this week, due to a reporting waiver granted to Medtronic by the FDA, as many as 50,000 problems with the Medtronic Fidelis lead were not reported to the FDA. Ordinarily, the FDA uses its MAUDE database to collect reports of adverse events in medical devices. In these cases, the MAUDE database was circumvented.
Medtronic responded by saying that instead of using MAUDE, they disclosed the issues in summary fashion to the FDA, as well as reporting them to physicians and to the public.
The following stories provide additional details about this controversy:
This story in the Wall Street Journal about genetic testing shows the speed of changes in the medical community’s understanding of how and whether certain genes cause hereditary disease.
The article quoted Dr. Jodie Ingles, a geneticist from the University of Sydney in Australia who specializes in HCM and has published a recent article on the subject. Dr. Ingles said that 22 out of 33 genes comprising a genetic testing panel commonly used to test for HCM had either limited or no evidence of being disease causative.
This week in the journal Annals of Internal Medicine, MyoKardia reported positive results from its open label phase 2 clinical trial of its drug mavacamten (formerly known as MYK-461) for obstructive hypertrophic cardiomyopathy. The study was conducted at 5 HCM centers and enrolled 21 subjects with obstructive HCM. All subjects saw some degree of improvement to their condition after taking mavacamten.
A recent study published in Circulation suggests that clinical testing of kids who are first degree family members of HCM patients (i.e. siblings and children of those who have already been diagnosed with HCM) could be improved by starting testing at a younger age. And, genetic testing should further improve diagnosis and treatment for this group.
When Stanford biochemist Jim Spudich settled down in bed with a book recommended by his wife, he had no idea that the book would inspire one of the biggest discoveries of his career. Spudich drifted off to sleep while reading The Haunted Mesa, a science fiction novel by Louis L’Amour. His scientific discovery was based on an image he saw in his dreams when the image of a mesa morphed into a myosin molecule.