Date: 2016-07-11
Type of information: Results
phase: 1
Announcement: results
Company: Myokardia (USA - CA)
Product: MYK-461
Action
mechanism: MYK-461 is a first-in-class, oral, selective, small molecule allosteric modulator of cardiac myosin designed to treat patients with hypertrophic cardiomyopathy caused by one of the most common molecular mechanisms of disease. MyoKardia is currently evaluating MYK-461 in three Phase 1 clinical trials, which are primarily designed to evaluate the safety and tolerability of MYK-461 and are expected to provide data on its pharmacokinetic and pharmacodynamic profile.
Disease: hypertrophic cardiomyopathy
Therapeutic area: Cardiovascular diseases
Country:
Trial details:
Latest
news: * On July 11, 2016, MyoKardia announced clinical data from its two recently completed Phase 1 trials in its MYK-461 hypertrophic cardiomyopathy (HCM) development program and advancement to the Company’s Phase 2 PIONEER-HCM Study. Data from the trials suggest favorable tolerability of single doses of MYK-461 in healthy volunteers and HCM patients. Additionally, repeat daily doses of MYK-461 were well tolerated for up to 28 days in healthy volunteers across a pharmacologically active dose range, with reductions in cardiac contractility sustained throughout the study period. The data also indicated a dose-dependent reduction in contractility consistent with the magnitude of reduction that the scientific literature indicates may confer a meaningful clinical benefit. Based on these data, MyoKardia plans to initiate its PIONEER-HCM study of MYK-461 in the second half of this year. The Phase 2 study will focus on symptomatic, obstructive HCM (oHCM), for which the FDA has granted MYK-461 Orphan Drug Designation. "Based on the scientific literature and our own research, we believe an agent that produces a modest reduction in contractility, for example, a relative reduction in left ventricular ejection fraction of 5 percent to 10 percent, has potential as a treatment for HCM patients,” Dr. Fox said. “Given these results, we plan to further study the potential for MYK-461 to clinically benefit HCM patients in the Phase 2 PIONEER-HCM trial at daily doses consistent with those studied in our multiple ascending dose trial.” * On October 6, 2015, MyoKardia announced initial clinical data from two Phase 1 trials of MYK-461, the Company’s lead product candidate, which targets the underlying cause of hypertrophic cardiomyopathy. In both trials, MYK-461 was well tolerated with dose- proportional pharmacokinetics. MYK-461 has demonstrated clinical proof of mechanism in reducing cardiac muscle contractility, an important biomarker of disease. In the first-in-human, double-blind, placebo-controlled trial evaluating single oral doses in 48 healthy adult volunteers (36 active, 12 placebo), MyoKardia has completed dosing in six cohorts at doses of up to 48 mg of MYK-461 or matching placebo. Clinical proof of mechanism was demonstrated at doses of 12 mg and above by dose-dependent pharmacodynamic activity, as assessed by three different echocardiographic biomarkers of contractility. MYK-461 was well tolerated at all dose levels and there were no serious adverse events or clinically meaningful findings in vital signs, electrocardiogram recordings or safety laboratory tests. MYK-461 demonstrated a dose-linear and dose-proportional pharmacokinetic profile, with low inter-subject variability. Additionally, MyoKardia initiated an open label, single ascending dose trial of MYK-461 in adult patients with hypertrophic cardiomyopathy. Observations from the first two patients dosed at 48 mg were similar to those from healthy volunteers treated at the same dose. * On March 3, 2015, MyoKardia announced it has initiated dosing in a Phase 1 clinical trial of MYK-461. MYK-461 is the first ever therapy designed to target the underlying cause of hypertrophic cardiomyopathy. Patients with hypertrophic cardiomyopathy are born with a mutation that causes over-contraction of the heart muscle cells, leading to thickening and stiffening of the heart muscle.Complications of hypertrophic cardiomyopathy include progressive heart failure, abnormal heart rhythms, stroke and sudden cardiac death. MYK- 461 is the first potential treatment in MyoKardia’s HCM portfolio to enter clinical development. MYK-461 has been designed to correct one of the most common molecular mechanisms causing HCM, and the clinical program will evaluate patients whose disease is caused by this specific mechanism, as identified by genetic screening. MyoKardia will use genetic testing to identify patients with this specific disease mechanism.
MyoKardia has studied MYK-461 in 86 healthy volunteers and 15 HCM patients across three Phase 1 studies. The first two studies, one in healthy volunteers and another in HCM patients, were designed to establish the preliminary safety and tolerability of single oral doses of MYK-461. Secondary objectives included establishing the preliminary pharmacokinetic, or PK, and pharmacodynamic, or PD, profiles of MYK-461. A subsequent trial evaluated the safety, tolerability, PK and PD profiles of multiple ascending oral doses of MYK-461 in healthy volunteers.
The studies have demonstrated tolerability across a dose range for both single doses up to 144 mg and repeat doses of up to 25 mg for up to 28 days. In our studies of healthy volunteers, all adverse events reported were mild or moderate. In our study of HCM patients, one serious adverse event was reported, a vasovagal reaction that spontaneously resolved, in a patient at the highest single dose tested (144 mg).
Clinical proof of mechanism was observed overall as a dose-dependent reduction in cardiac contractility following single oral doses, both in healthy volunteers and HCM patients. All 15 HCM patients in our single ascending dose study demonstrated reductions in excess cardiac contractility. Furthermore, we observed achievement of stable reductions in contractility following repeat dosing to steady state in healthy volunteers in the two highest-dose cohorts of our multiple ascending dose study, confirming proof of mechanism for multiple doses. As previously noted, the scientific literature and MyoKardia’s research suggest that an agent that produces a modest reduction of cardiac contractility (e.g. 5 percent to 10 percent relative reduction as measured by left ventricular ejection fraction, or LVEF) has potential as a treatment for HCM patients.
In our Phase 1 single dose study, two HCM patients, both with a history of LVOT obstruction, had provocable gradients before administration of a single 96 mg dose of MYK-461 (28 mmHg and 42 mmHg, respectively). In both patients, their gradients were reduced following dosing (to 5 mmHg and 9 mmHg, respectively). Relief of LVOT obstruction is associated with lower mortality, improved exercise capacity and symptom relief in oHCM patients. MyoKardia plans to explore obstruction relief as a primary endpoint in the Phase 2 PIONEER-HCM study.
