An interim look at the EXPLORER-LTE study showed no safety signals but retained benefits in LVOT and LVEF improvements.
WASHINGTON, DC – Mavacamten continues to deliver benefits to patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) beyond 48 weeks, according to interim results from the ongoing long-term extension study (LTE) EXPLORER-H LTE. The drug is a new class I heart myosin inhibitor (Bristol Myers Squibb) currently under review by the US Food and Drug Administration, with a decision date of April 28. Florian Rader (ACC Source) As previously reported by TCTMD, the main EXPLORER-HCM study, published in 2020, showed that 37% of patients receiving mavacamten achieved the primary endpoint of the study, defined by maximal VO2 gains and improvement or stabilization of the NYHA functional class, compared with 17% of placebo-treated patients. A subsequent quality of life study presented at last year’s meeting of the American College of Cardiology (ACC) showed large gains in the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores within weeks of treatment. Whether these improvements would be viable over time or whether a worrying LVEF reduction signal (below 50%) would continue beyond the 7% affected in the previous trial were factors investigated in the follow-up study. So far, so good, suggested Florian Rader, MD (Cedars-Sinai Medical Center, Los Angeles, CA), who presented the findings here at the ACC 2022 Scientific Conference today. “This data is very consistent with the initial test results,” he said in a statement. “The heart block was relieved, two-thirds of the patients felt better and the severity of the disease improved.” Intermediate results of EXPLORER-LTE The EXPLORER-LTE trial included 231 of the original 244 patients in the EXPLORER-HCM trial. A total of 206 patients could be evaluated at 48 weeks and 67 patients at week 84, with a median follow-up of 62 weeks for the entire cohort. By week 48, the rapid improvements in the left ventricular outflow tract (LVOT) and Valsalva outflow ratios observed in the first weeks of the initial test were maintained, decreasing by 35.6 mm Hg and 45.3 mm Hg, as measured by individual seats. By week 84, with fewer patients included, these values remained relatively stable at -32.8 mm Hg and -46.4 mm Hg. Decreases in serum NT-proBNP were observed at week 48 and persisted until week 84. More than two-thirds of patients had improved by at least one NYHA functional class by week 48. LVEF reductions were -7% per week 48 and -9% per week 84. In total, 26 patients (11%) had to discontinue mavacamten due to treatment-related adverse reactions, including 12 (5.2%) due to LVEF drops <50%, but most could start again at a lower dose and only 10 could not start again with the drug. In all, five patients discontinued the drug permanently for low LVEF, although one eventually resumed the study. “Treatment with mavacamten showed clinically significant improvements in LVOT, NYHA, and NT-proBNP levels at and after 48 weeks in patients with symptomatic obstructive HCM,” Rader told ACC participants, comparable to what was seen. in the original EXPLORER study. No new safety signals were observed and the drug was well tolerated, with the number of patients whose LVEF dropped before 50% not being more common in patients with extension than before. “This extension test shows that dose titration and monitoring as a security guard, guided by a position measurement echocardiogram, instead of a central echocardiogram – which is obviously going to happen in clinical practice – is also very safe and feasible,” he concluded. additional information Kyle Klarich, MD (Mayo Clinic, Rochester, MN), commenting on the long-term results following Rader’s presentation, noted: for the disease treatment that was not invasive, non-surgical or non-invasive and was specifically related to the underlying pathophysiology of the disease, so I think this is very exciting for all of us. “I’m excited to see that security continues in long-term monitoring, and that efficiency remains so high.” Klarich had questions about translating test endpoints into clinical practice, noting that LVOT gradients are not commonly used to guide dose titration of standard therapies – beta-blockers, calcium channel blockers and disopyramine – out of the box. . In response, Rader suggested that monitoring the echo would probably only be necessary after dose adjustments, not a regular schedule. Patients would be suitable for dose adjustment if LVOT was elevated but the ejection fraction was normal. If a patient was asymptomatic and “felt great,” then “no dose increase is required,” he said. He also noted that the LVEF measures taken by the sites themselves were slightly although consistently lower than those measured at the central laboratory. This in itself shows that it is feasible and safe to monitor patients in individual positions, with these somewhat lower LVEF scores offering “a light, safety buffer”, as lowering LVEF is a known drug effect. Klarich also asked how this agent might be compared to disopyramide, which tends to bring about similar improvements in symptoms and functional order. In response, Rader said disopyramide would likely remain an option in practice. “If [patients] “They are doing well with disopyramide, then there may be no reason to switch to a myosin inhibitor,” he said. “I think for what we have a little more data. . . targeting pathophysiological mechanisms with myosin inhibitors. There are actually structural changes that occur with treatment with this new class of drugs, therefore reducing LV mass decline, improving diastolic function, reducing sinus size and so on, along with very significant drops in BNP levels, and I think There is no such convincing data on disopyramide at this point. In addition, he added, “we have no frontal comparisons” at the moment. During a press conference after today’s presentation, Maya Guglin, MD PhD (Indiana University School of Medicine, IN) described the emergence of myosin inhibitors as an “almost revolutionary change” in the management of this disease, offering patients the ability to choose between open heart surgery and or a lifelong drug. While the data so far show benefits in terms of heart function and symptoms, it is hoped that it may also help reduce the risk of sudden cardiac death among, for example, young athletes with HCM underlying. “This changes the whole landscape and will change the instructions:. . . “No question about that,” he said. These intermediate results represent the second positive report in 2 days for mavacamten. Yesterday, as reported by TCTMD, the VALOR-HCM results showed that, over a 16-week period, the drug significantly reduced the need for surgical or invasive septum treatment in patients with obstructive HCM who were candidates for treatment, despite fact that he was on with the maximum tolerated medical treatment. EXPLORER-LTE is part of the larger MAVA-LTE test.
