Safety qualms in MyoKardia mid-stage study cause investors to pause
Ahead of the pivotal data readout of MyoKardia’s lead drug, mavacamten, in patients with obstructive hypertrophic cardiomyopathy (HCM), investors took issue with the drug’s safety profile in a separate Phase II non-obstructive HCM study.
Mavacamten is expected to break new ground in heart disease — a field monopolized by large pharmaceutical companies largely due to the long, arduous and expensive trials that are commonplace in heart drug development. Unlike other developers focusing on common heart disorders, MyoKardia’s treatment is also targeting a so-far untapped disease — hypertrophic cardiomyopathy — a genetic condition in which heart muscle thickens, making it harder for the organ to pump blood to the rest of the body.
On Monday, MyoKardia disclosed data from the 59-patient, placebo-controlled MAVERICK-HCM study, which was in patients with non-obstructive HCM. In this population of patients, which accounts for a third of all HCM patients, the heart contracts extravagantly and the left ventricle thickens, limiting the organ’s ability to pump blood to meet the body’s needs, although there is no physical obstruction present in the outflow tract of the left ventricle.
The drug’s impact on ejection fraction — the percentage of blood that’s pumped out of a filled ventricle (typically the left ventricle, the heart’s main pumping chamber) with each heartbeat — triggered safety concerns, after MyoKardia said five patients on the drug arm saw transient ejection fraction reductions below the protocol-defined threshold of 45%. A left ventricle ejection fraction of 55% or higher is considered normal, according to the Mayo Clinic.
Shares of the South San Francisco drug developer $MYOK slipped 7.6% to $55.45 in Tuesday premarket trading.
Study data also showed the rate of side-effects in the mavacamten-treated patients also exceeded those in the placeb0 group, although serious adverse events occurred twice as frequently in the placebo arm as compared to patients receiving mavacamten.
Overall, the trial achieved the main goal of establishing safety and tolerability of mavacamten in non-obstructive HCM in the 16 week treatment period, the company said, adding that “meaningful reductions” in biomarkers of cardiac stress were observed across the mavacamten cohorts and “clear signals of clinical benefit” were observed in a subgroup with elevated cardiac filling pressures and in a pre-specified group of patients at higher risk for morbidity and mortality.
In addition, patients given mavacamten also experienced markedly lower levels of the biomarker NT-proBNP (p=0.004). NT-proBNP is a validated marker of cardiac wall stress that is correlated with increased rates of heart failure-related hospitalizations and progression to end-stage disease and stroke.
“The MAVERICK study more than doubles mavacamten’s safety database and the drug appears reasonably well tolerated, although we expect investors will look for additional clarity on rates of arrhythmia and the 5 cases of transient LVEF declines under 45% to further explore the overall safety of mava,” Credit Suisse analyst Martin Auster wrote in a note.
MyoKardia chief Tassos Gianakakos expressed his satisfaction with the MAVERICK data, suggesting that evidence of mavacamten’s beneficial impact on parameters of diastolic function, and placebo response observations have enhanced his confidence in mavacamten’s performance in the obstructive HCM pivotal study.
Detailed MAVERICK data will be presented at a scientific conference. Based on these results, however, MyoKardia plans to consult with the FDA and sort out the steps it needs to take the drug to market — for which a regulatory update will be provided in 2020. Meanwhile, the company also plans to test mavacamten in defined groups of patients with non-obstructive HCM and heart failure with preserved ejection fraction (HFpEF).
“While this news is encouraging, it’s not fully clear to us how dosing in this setting will be determined. Full MAVERICK data presentation could be a meaningful catalyst next year, as we think lack of specifics may lead investors to heavily discount potential label expansion strategies for now,” Auster said.
MyoKardia’s approach to research is to develop drugs for genetically defined patient groups, which is also reflected in its second program, MYK-491, under development for dilated cardiomyopathy.
In January, MyoKardia disclosed that Sanofi was walking away from their heart drug partnership forged in 2014. The partnership involved the development of up to three programs through discovery and into clinical development for the treatment of hypertrophic cardiomyopathy and dilated cardiomyopathy. In July, MyoKardia said it had regained the US royalty rights to two products from the French drugmaker for $50 million upfront.