MyoKardia Readies First-Ever Hypertrophic Cardiomyopathy Drug For US Filing
Executive Summary
The Phase III EXPLORER-HCM trial evaluating mavacamten in obstructive hypertrophic cardiomyopathy (oHCM) succeeded on all primary and secondary endpoints.
MyoKardia Inc. plans to file mavacamten with the US Food and Drug Administration in the first quarter of 2021 based on results from the Phase III EXPLORER-HCM clinical trial in obstructive hypertrophic cardiomyopathy (oHCM). The company reported on 11 May that patients treated with the oral drug were less likely to experience shortness of breath than those who received placebo in the pivotal trial, and half of the patients treated with mavacamten were deemed asymptomatic by the end of the study.
The EXPLORER-HCM results show that the allosteric modulator of cardiac myosin improved patients’ heart function and symptoms while proving at least as safe as placebo. MyoKardia’s stock closed up 58.6% at $96.90 per share in response to the positive results.
“EXPLORER has provided the clear and compelling evidence we have been looking for to questions like ‘Would we see a statistically significant difference versus placebo in symptoms and in function?’ The answer is yes,” CEO Tassos Gianakakos said during MyoKardia’s 11 May call to review the data.
Hypertrophic cardiomyopathy (HCM), diagnosed in about 100,000 people in the US, is characterized by excessive contraction of the heart muscle and a reduced ability of the left ventricle to fill with blood. About two-thirds of HCM patients have oHCM, in which the left ventricular outflow tract (LVOT) becomes obstructed by the enlarged and diseased heart, restricting the flow of blood to the rest of the body. Non-obstructive HCM is driven by diastolic impairment due to the enlarged, stiffened heart.
Patients with both types of HCM experience fatigue and shortness of breath with any kind of exertion and have increased risks of atrial fibrillation, stroke, heart failure and sudden cardiac death. Mavacamten is designed to slow down cardiac muscle contractions that cause the heart to become enlarged and stiff, so that a greater percentage of oxygenated blood can flow to the rest of the body.
In addition to the pivotal EXPLORER-HCM study in oHCM, MyoKardia is testing mavacamten in non-obstructive HCM in the Phase II MAVERICK-HCM study, but initiation of the Phase III VALOR-HCM study in this indication as well as a Phase II proof-of-concept study in heart failure with preserved ejection fraction (HFpEF) has been delayed by the COVID-19 pandemic.
EXPLORER Design And Positive Results
EXPLORER-HCM enrolled 251 patients with a diagnosis of New York Heart Association (NYHA) Class II or III (symptomatic) oHCM and LVOT peak gradient (resting and/or provoked) of 50mmHg or greater. Patients were randomized for treatment with mavacamten or placebo with a starting dose of 5mg once daily that could be lowered to 2.5mg or increased to as much as 15mg based on a combination of residual LVOT gradient, drug plasma concentration and left ventricular ejection fraction (LVEF) levels.
The primary endpoint for EXPLORER-HCM was a composite analysis of mavacamten’s effects on cardiomyopathy symptoms and heart function versus placebo defined by 1) an improvement of at least 1.5mL/kg/minute in peak VO2 (maximum oxygen used in exercise) accompanied by an improvement of at least one NYHA functional class or 2) improvement of at least 3mL/kg/minute improvement of peak VO2 with no worsening in NYHA functional class.
The composite endpoint was achieved by more than twice as many mavacamten patients than those who were treated with a placebo – 37% versus 17% (p=0.0005).
Breaking down the primary endpoint components, an improvement in NYHA class of one or more was achieved by 65% of mavacamten-treated patients and 31% in the placebo group, while 50% in the mavacamten arm achieved NYHA Class I (asymptomatic) status versus 21% in the placebo arm (p<0.0001). Peak VO2 change from baseline was a mean of 1.4 mL/kg/minute for mavacamten and a mean of -0.05 for placebo (p=0.0006).
Informa’s Biomedtracker pointed out in an 11 May review of the EXPLORER results that the improvements in VO2 were particularly impressive: “Peak exercise is a very difficult metric to change, as observed in previous cardiovascular trials, [so] it will be interesting to see whether all patients followed this positive trend in peak VO2.”
Secondary endpoints – which were all met – included improvements in post-exercise LVOT peak gradient, NYHA functional classification, peak VO2, the Kansas City Cardiomyopathy Clinical Summary Score (KCCQ-CSS), and the HCM Symptom Questionnaire Shortness of Breath Domain Score (HCMSQ-SoB). The HCMSQ-SoB is a questionnaire developed by MyoKardia. (See table below for results.)
Biomedtracker noted that in terms of the improvement in LVOT, “74% of treated patients compared to 21% on placebo achieved LVOT levels below 50mmHg, the threshold for surgery; an endpoint likely to be of particular interest for payers, given the significant cost-saving of taking a medication versus surgery. Fifty-seven percent of patients had a reduced LVOT to below 30mmHg, which is no longer considered obstructive, according to diagnostic guidelines. Furthermore, a complete response, defined by asymptomatic (NYHA class I) and obstruction reduced below 30mmHg, was observed in 27% of patients compared to 1% placebo. This again reinforces mavacamten’s robust efficacy in treating oHCM patients.”
The Biomedtracker analysis also pointed out that “the current standard of care for HCM patients is inadequate, with many patients remaining symptomatic and requiring surgical intervention. If approved, mavacamten will be the first disease-specific drug for these patients, and therefore will likely experience rapid market adoption.”
MyoKardia chief commercial officer William Fairey also said that the LVOT results showing that nearly three-quarters of patients fell below the threshold that would make them candidates for surgery should be compelling to payers, along with the exploratory endpoint that showed more than a quarter of patients could be classified as complete responders.
“If you're a payer [and] you're looking to manage this disease, putting people into this complete response bucket and having to avoid kind of downstream costs associated with surgery is something you're going to be thinking about,” Fairey said. “But I'll also say that some of the stuff we saw on quality of life and, of course, the overall improvement in NYHA are also going to catch their attention.”
Efficacy Enhanced By Safety Profile
Whether patients could improve enough that they no longer qualified for invasive open-heart surgery was one of the big questions that MyoKardia CEO Gianakakos said the company hoped to answer with EXPLORER. Also, “could mavacamten achieve this level of efficacy with safety results comparable to placebo? The answer is yes,” he said.
MyoKardia reported that mavacamten’s safety and tolerability was comparable to placebo. Only 2% of patients dropped out of EXPLORER-HCM due to adverse events or other issues – three patients treated with mavacamten and two who got a placebo – and 95% of the trial participants opted to enroll in the long-term extension study.
Treatment-emergent adverse event rates were 87.8% for mavacamten and 78.9% for placebo, but serious adverse event (SAE) rates were higher for placebo at 8.6% (11 patients) versus 8.1% (10 patients) for the study drug, including 20 SAEs associated with placebo and 12 with mavacamten.
There were four cardiac SAEs in each arm of the study, including one sudden death in the placebo group. Atrial fibrillation was observed in eight patients treated with mavacamten (6.5%) and nine treated with placebo (7%) with AFib SAEs observed in two mavacamten patients (1.6%) and four placebo patients (3.1%).
Importantly, LVEF outcomes were similar for both groups of patients with limited treatment disruptions due to reduced ejection fraction (EF) – three patients in the mavacamten arm of EXPLORER and two in the placebo arm. All five patients resumed treatment and completed the study.
Wedbush analyst David Nierengarten concluded in an 11 May note that the “safety profile was better than expected.” He pointed out that adverse event rates “were balanced or favored [mavacamten], including lower rates of atrial fibrillation, SAEs and cardiac SAEs” and that none of the patients who withdrew from the study experienced reduced ejection fraction or symptoms of heart failure, “which we believe is supportive of Myokardia’s implementation of echocardiographic-based dosing, and which, in our view, will greatly enhance physician comfortability with [mavacamten] and its real-world adoption.”
Wedbush raised its sales forecast of mavacamten to more than $4bn by 2027, but noted that its prediction is higher than analyst consensus. The mavacamten opportunity makes MyoKardia a more attractive acquisition target, Neirengarten commented, naming cardiovascular disease players Novartis AG, Amgen Inc. and Bayer AG as potential bidders for the company.
Credit Suisse analyst Martin Auster has described mavacamten as a blockbuster product, but said in an 11 May note that “the entirety of [mavacamten]’s commercial opportunity remains to be written with its value in the HFpEF and nHCM settings to be clarified with additional data.”
Gianakakos noted that MyoKardia is working to bring mavacamten to patients as soon as possible and will meet with the FDA in the third quarter to discuss submission, which is planned for the first quarter of 2021. When asked about potential impacts of the novel coronavirus on the regulatory process, the CEO said he does not expect COVID-19 concerns to impact the timing of mavacamten’s approval. (Also see "As US FDA Settles Into Teleworking, Will Application Reviews Be Affected?" - Pink Sheet, 24 Mar, 2020.)
“The FDA has been engaged. This division has recently approved a therapy – the cardiorenal division,” Gianakakos said, referring to approval of AstraZeneca PLC’s Farxiga for heart failure. (Also see "AZ To Adopt Indication-Based Pricing For Farxiga In Heart Failure" - Scrip, 6 May, 2020.)
“These are important data today that we think are going to help a lot of patients and I think the whole community is going to be eager to work with us to find a way to appropriately get this to folks around the world,” he noted.
MyoKardia plans to file for approval in Europe by the end of 2021. The company already has built a team in Amsterdam to work with the European Medicines Agency.
While MyoKardia is pursuing development, approval and commercialization of mavacamten on its own in the US, Fairey said the company is speaking to multiple potential partners for Europe and other markets.
MyoKardia partnered with Sanofi outside the US in 2014, but MyoKardia said in January 2019 that Sanofi handed back its rights to the drug after the Brisbane, CA-based company declined to take the French big pharma up on its offer to partner in the US as well. (Also see "MyoKardia Frames End Of Sanofi Partnership As A Bet On Itself" - Scrip, 2 Jan, 2019.)