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.
There were two groups of patients enrolled in the study: The first group of patients took only mavacamten, while the second group continued on a beta-blocker while also taking mavacamten.
The group of patients taking only mavacamten saw their post-exercise left ventricular outflow tract gradient fall from an average of 103 mm HG to an average of 19 mmHG after 12 weeks, with their left ventricular ejection fraction reduced by about 15%. Peak Vo2 measurements increased by an average of 3.5 mL/kg/min.
The group of patients taking beta blockers along with mavacamten saw more modest improvements, with their post exercise left ventricular outflow tract gradient falling from an average of 86 mmHG to 64 mmHG, with the average left ventricular ejection fraction falling 6%. Peak Vo2 measurements increased an average of 1.7 mL/kg/min.
The study found that shortness of breath was improved in both group of patients.
While the drug was well tolerated, the the most common side effects were decreased ejection fraction at higher doses and atrial fibrillation.
See previous stories about this drug here on HCMBeat:
MyoKardia Announces Positive Result for Mavacamten for Treatment of HOCM
MyoKardia Drug Moves to Next Phase
Encouraging Results for MyoKardia HCM Drug
DISCLOSURES: HCMBEAT HAS RECEIVED 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 conducted in the U.K. evaluated whether the anti-anginal drug trimetazidine would improve symptoms and exercise capacity for those patients with non-obstructive hypertrophic cardiomyopathy.
Unfortunately, this study which was conducted by Dr. Perry Elliott and his colleagues at University College London, found that trimetatazidine did not improve exercise capacity in these patients. Following the results of this study, trimetazidine will now join ranolazine and spironolactone in the compost heap of drugs which tried and failed to improve HCM symptoms. While a third drug, perhexiline, was found to improve symptoms for non-obstructive HCM, its limitations, including potentially serious side effects, stand in the way of its common usage.
In a companion editorial to this study entitled “Non-Obstructive Hypertrophic Cardiomyopathy-the High Hanging Fruit,” Dr. Sharlene Day of the University of Michigan’s HCM Center discusses the difficulties seen in drug trials related to non-obstructive HCM.
Though seemingly a more benign form of the disease, in fact, patients with non-obstructive HCM share a similar risk of sudden death and heart failure with their obstructed counterparts. Because treatments available to treat non-obstructive disease have been largely limited to beta blockers, calcium channel blockers and diuretics, there is a great need for new medications directed at this problem.
The problem with setting up HCM Drug trials is complicated by several factors:
- Different Types of HCM: There appear to be multiple kinds of HCM. Some are genetic and some are not. We are now at a place where treatments for HCM should become more individualized.
- Difficulty in Recruitment: It is difficult to recruit enough patients to take part in these trials. Patients often travel considerable distances for care at dedicated HCM Centers. Multi-center trials provide a potential way to get around this issue.
- Duration of HCM: HCM is a disease process which takes place over decades which is not easily studied in a clinical trial of limited duration.
- The Unknown: Timing of interventions may be critical, and it is hard to know the proper window of time to target. The bottom line is that there is still so much that is unknown, HCM researchers much continually adapt as knowledge of the disease process unfolds.
In conclusion, Dr. Day suggests that while medical researchers continue to test new drugs and push forward studies of HCM, physicians should counsel their patients that in addition to medication, lifestyle choices like proper nutrition and exercise will improve their clinical course and the overall outlook for HCM patients.
EpiCor Therapeutics, a Irish biotech start-up, is investigating whether 5-azacytidine, a drug previously used to treat bone marrow disorders, may reverse the hypertrophy of HCM. According to the researchers, the drug targets the mechanisms that drive the abnormal thickening of the heart muscle by inhibiting DNA methylation, thereby reducing the growth of cardiac cells.
EpiCor’s work with 5-azacytidine was declared the overall winner of the 2016 Venture Launch Accelerator Programme at Ireland’s University College Dublin where it won the 2016 Start-Up of the Year Award.
So far, EpiCor has gotten approximately €550,000 ($690,000 U.S.) in capitalization from Enterprise Ireland’s Commercialization Fund. The next step for the drug would be to obtain regulatory approval and then, clinical trials.
MyoKardia’s experimental drug MYK-461, currently in Stage 2 trials for humans, has now been shown to eliminate left ventricular obstruction in five cats with HCM. It has already been shown to inhibit traits of HCM in mice.
Addressing these findings, Associate Professor Joshua Stern, chief of the Cardiology Service at the University of California, Davis, veterinary hospital, stated:
“There has been little to no progress in advancing the treatment of HCM in humans or animals for many years,” Stern said. “This study brings new hope for cats and people.”
Based on these positive results, U.C.Davis is hoping to conduct a clinical trial of MYK-461 to determine whether it could become the standard of care for cats with HCM.
The full text of the article published in Plos One can be found here.
Eleclazine: The Liberty HCM Trial
It appears to be the end of the road for the Gilead drug eleclazine, a late sodium channel inhibitor previously known as GS-6615. Eleclazine, with properties similar to the anti-angina drug ranolazine (which was approved by the FDA in 2006), was the subject of a recently terminated HCM clinical trial known as Liberty-HCM. The HCM eleclazine study focused on whether the drug would improve symptoms and exercise capacity in patients with HCM by increasing their peak oxygen uptake, resulting in improved VO2 max readings on exercise testing. The HCM study began enrolling patients in February 2015. Data collection had been scheduled to continue through June 2017. Continue reading “End of the Road for Eleclazine and Liberty HCM Study”
MyoKardia, a San Francisco based bio-phamaceutical company developing drugs specifically for HCM and other genetic cardiomyopathies, announced data from their Stage 1 trials showing that the drug, MYK-461, benefits patients with HCM.
Specifically they found that the drug reduced ejection fractions and left ventricular outflow tract gradients in certain of the 101 individuals who participated in their Phase 1 trials.
The next step for the drug is to try to duplicate these findings in Phase 2 trials which will commence later this year.