Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by thickening of the ventricular wall. As a chronic, mostly progressive heart disease, HCM can lead to acute and chronic complications such as heart failure, stroke, and sudden cardiac death (SCD), which seriously affects the prognosis and quality of life of patients1. However, there is a lack of drugs that target the root cause of the occurrence and progression of HCM, and patients are in urgent need of innovative treatments2.
Recently, the results of the Kansas City Cardiomyopathy Questionnaire (KCCQ) for patient-reported health conditions in the Mavacantas EXPLORER-CN study were unveiled at the 2024 American College of Cardiology (ACC) Annual Meeting. The results of the study showed that Mavacaitai can effectively improve the health of patients with obstructive hypertrophic cardiomyopathy (oHCM) in China. After the meeting, Yimaitong was honored to invite Professor Tian Zhuang, an EXPLORER-CN researcher and director of the International Medical Department of Peking Union Medical College Hospital, to interpret the results of KCCQ in depth and discuss the treatment prospects of HCM.
Expert Profile
Professor Grange
Chief physician, doctoral supervisor
Director of the International Medical Department of Peking Union Medical College Hospital
- He graduated from Peking Union Medical College in July 1999 with a doctorate degree, and then joined Peking Union Medical College Hospital.
- He presided over the 14th Five-Year Plan of National Key R&D, the special task of scientific and technological innovation in Xiong'an New Area of the Ministry of Science and Technology, and the Beijing Natural Science Foundation. Undertake a number of national key R&D programs.
- Social positions: Member of the Heart Failure Group of the Cardiovascular Disease Branch of the Chinese Medical Association, Member of the Rare Disease Branch of the Chinese Medical Association, Member of the Clinical Pharmacy Branch of the Chinese Medical Association, Vice Chairman of the Clinical Pharmacy Branch of the Beijing Medical Association, Deputy Head of the Cardiovascular Precision Medicine and Rare Disease Group of the Cardiovascular Physician Branch of the Chinese Medical Doctor Association, etc.
There is an important unmet need in patients with nonspecific HCM for existing therapies
At present, oHCM is treated with medication and invasive treatments such as surgery or interventional therapy. "Based on the left ventricular outflow tract (LVOT) gradient, HCM is divided into obstructive hypertrophic cardiomyopathy and non-obstructive hypertrophic cardiomyopathy. Compared with patients with non-obstructive hypertrophic cardiomyopathy, patients with obstructive hypertrophic cardiomyopathy have more severe clinical symptoms and a higher risk of complications such as heart failure and arrhythmias, as well as sudden death. However, the current treatment of obstructive hypertrophic cardiomyopathy can only reduce the symptoms and cannot change the progression of the disease. ”
Drugs are the preferred treatment for HCM, and the current clinical use in mainland China are all non-specific therapeutic drugs, including β receptor blockers, non-dihydropyridine calcium channel blockers, etc. Although these drugs can bring varying degrees of obstructive relief, they cannot prevent disease progression and have limited effect on oHCM. Professor Tian Zhuang said, "The current HCM drug treatment mainly reduces cardiac output by slowing down the heart rate and inhibiting myocardial contractility, and these treatments have the problem of patient tolerance, which cannot well alleviate patients' symptoms and improve patients' exercise tolerance, and it is difficult to improve patients' quality of life. ”
In addition, Professor Tian Zhuang emphasized, "In addition to drug treatments, although we have some non-drug invasive treatments for HCM, invasive treatments such as surgery or interventional therapy are difficult and have the risk of surgical complications, and the acceptance of patients is not high, which limits their accessibility." ”
Explore the never-ending pathophysiology of Marvacaitech targeting HCM
For a long time, there has been an important unmet need for treatment of HCM patients worldwide. It was not until April 2022 that Mavacite was officially approved by the U.S. Food and Drug Administration (FDA) for marketing, and the drug treatment of HCM ushered in a revolutionary breakthrough. "Mechanistically, HCM has an over-formation of actin-myosin cross-bridges, which leads to changes in cardiomyocyte hypercontraction, limited diastolic and abnormal energy metabolism. By selectively decreasing the ATPase activity of the cardiac myosin heavy chain, Avacaitech targets the core pathophysiology of this HCM disease, reversibly inhibits the overformation of myosin-actin transverse bridges, and promotes the entire myosin population to shift to an energy-efficient hyperflaccid state, thereby inhibiting myocardial hypercontraction and improving diastolic function and energy metabolism. This fundamentally treats the cause of obstruction in HCM patients, so it can effectively reduce the left ventricular outflow tract pressure difference without affecting the physiological contraction of the heart, thereby effectively improving the patient's exercise tolerance and health status. ”
As the first cardiac myosin allosteric inhibitor targeting the core pathophysiology of HCM, in recent years, there have been a number of high-quality phase III clinical studies of Mavacaitech for the treatment of oHCM. Among them, the EXPLORER-CN study 3 is a multicenter, double-blind, randomized, placebo-controlled phase III clinical registration study led by Professor Shuyang Zhang of Peking Union Medical College Hospital, which included 81 symptomatic oHCM patients from 12 centers in mainland China, and all patients were randomized into the mavacytai group (n=54) and the placebo group (n=27) in a 2:1 ratio through the interactive response system (IxRS) After 30 weeks of treatment, the efficacy and safety of Mavakaitai in the treatment of Chinese adult patients with oHCM were evaluated.
In the EXPLORER-CN study, compared with placebo, Mavacaitech significantly improved clinical symptoms, relieved LVOT obstruction, improved ventricular wall stress and biomarkers of cardiac injury, and improved cardiac structure in adult patients with oHCM in China, and was generally well tolerated by patients. "At week 30, the Valsalva LVOT peak differential was reduced by more than 50 mmHg from baseline, with a between-group difference of −70.29 mmHg (P < 0.001) compared to placebo, which is a considerable improvement," Professor Tian Zhuang noted. In addition, the ventricular wall stress and myocardial injury related indexes in the Mavacaitai group were also effectively reduced. At the same time, the left ventricular ejection fraction (LVEF) of the patients in the Mavacaitai group remained stable during the study period, and no patients experienced a decrease in LVEF to less than 50%. These findings support the efficacy and safety of Mavachem in the Chinese patient population. ”
To improve overall health outcomes, the future of MVACHEM in HCM treatment is promising
At the 2024 American College of Cardiology (ACC) Annual Meeting held recently, detailed data from the Kansas City Cardiomyopathy Questionnaire Scale (KCCQ) for patient-reported health status in the EXPLORER-CN study were officially announced. The results of this study further enrich the evidence-based evidence for the use of Mavakaitai for the treatment of oHCM in mainland China.
The results of the 23-item KCCQ score (KCCQ-23, including symptoms, physical function, social functioning, and quality of life) of patient-reported health status were presented at the conference to evaluate the impact of Mavacaitai on the health status of Chinese oHCM patients, including the change from baseline in the KCCQ-23 global symptom score (TSS), clinical summary score (CSS) and global summary score (OSS) at 30 weeks. The results showed a significant improvement in KCCQ-23 scores in patients treated with Mavakatai compared with placebo at week 30, with a difference of 10.2 least squares mean (LSM) between CSS groups (95% CI: 4.4-16.1; P <0.001), TSS 10.3 (95%CI: 3.1-17.5; P=0.006), OSS was 9.8 (95%CI: 3.4-16.2; P=0.003) (Table 1).
Table 1. Change from baseline in KCCQ-23 score at 30 weeks
In addition, the study also compared the proportions of patients in different groups based on previously reported thresholds of clinically meaningful changes with varying degrees (5-, 10-, and 15-point increases). It was found that at week 30, a higher proportion of patients treated with Mavacetech reached thresholds with varying degrees of clinically meaningful change in all KCCQ-23 scores (TSS, CSS, and OSS) compared with placebo (Figure 1).
Figure 1. Proportion of patients with previously reported thresholds of varying degrees of clinically meaningful change at 30 weeks
Commenting on the results of the KCCQ analysis of the EXPLORER-CN study, Professor Tian Zhuang said, "The main treatment goals of oHCM include improving symptoms, physical function and quality of life, so that patients can live longer and better, so it is important for HCM patients to effectively improve their health and quality of life through treatment. The results presented in this (KCCQ) confirm that Mavacantas treatment can significantly improve the health status and health-related quality of life of oHCM patients, which is consistent with the significant improvement in physiological measures such as LVOT differential pressure in the EXPLORER-CN master study. Although there is still a lack of data on cardiovascular events and mortality, the results and mechanisms of existing studies on reducing LVOT differential pressure and improving patients' health status and health-related quality of life are likely to reduce the risk of adverse cardiovascular events and even death in the future, and bring more improvement to the long-term prognosis of oHCM patients. ”
Mavacaitech is the first innovative drug targeting the core pathophysiology of HCM, and the results of the EXPLORER-CN study and the latest KCCQ data have confirmed that it has good efficacy in the Chinese oHCM population, which can effectively reduce the left ventricular outflow tract pressure difference, alleviate the clinical symptoms of patients, and improve the quality of life and cardiac function of patients. Based on its clinical research data and unique mechanism of action, Mavachem is expected to bring new treatment options to more Chinese HCM patients.
Bibliography:
1. Heart Failure Professional Committee of the National Cardiovascular Disease Expert Committee, et al.Chinese Journal of Heart Failure and Cardiomyopathy.2022; 6(2):80-105.
2. Maron BJ, Desai MY, et al. J Am Coll Cardiol. 2022 Feb 1; 79(4):372-389.
3. Tian Z,Li L,Li X,et al. JAMA Cardiol. 2023 Oct 1; 8(10):957-965.