EDG-7500 for Hypertrophic Cardiomyopathy
Recruiting in Palo Alto (17 mi)
+12 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Edgewise Therapeutics, Inc.
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This study is being conducted in order to understand the safety and effects of different doses of EDG-7500 as a single dose in adults with obstructive hypertrophic cardiomyopathy (oHCM) and as multiple doses in adults with obstructive or nonobstructive hypertrophic cardiomyopathy (nHCM).
Is the drug EDG-7500 a promising treatment for hypertrophic cardiomyopathy?Yes, EDG-7500 is a promising drug for hypertrophic cardiomyopathy. It is part of a new group of treatments that target the disease more precisely, showing encouraging results in improving symptoms and quality of life for patients.39111314
What safety data exists for EDG-7500 in treating Hypertrophic Cardiomyopathy?The provided research does not specifically mention EDG-7500 or its safety data. However, it discusses general cardiac safety pharmacology, including the prediction of drug-related cardiac adverse effects, the importance of assessing cardiac safety through electrocardiography, and the evaluation of drug-induced arrhythmia risks. These studies emphasize the need for thorough cardiac safety assessments in drug development, which may be relevant to EDG-7500 if it undergoes similar evaluations.456810
What data supports the idea that EDG-7500 for Hypertrophic Cardiomyopathy is an effective drug?The available research does not provide specific data on the effectiveness of EDG-7500 for Hypertrophic Cardiomyopathy. However, it mentions other treatments like Verapamil, which showed improvement in heart size and symptoms for patients with this condition. Verapamil treatment resulted in a significant reduction in heart size for many patients and a low death rate of 1% per year. This suggests that certain drugs can be effective in managing the condition, but specific data on EDG-7500 is not available in the provided information.1271213
Do I have to stop taking my current medications for this trial?The trial protocol does not specify if you need to stop taking your current medications. However, it does exclude participants with current or prior use of any cardiac myosin inhibitors, so you may need to stop those if applicable.
Eligibility Criteria
This trial is for adults with obstructive hypertrophic cardiomyopathy, a condition where the heart muscle becomes abnormally thick. Participants should not have other serious medical conditions and must be able to follow the study procedures.Participant Groups
The study tests different doses of EDG-7500, administered either once or multiple times, to see how safe it is and what effects it has on patients with obstructive hypertrophic cardiomyopathy.
4Treatment groups
Experimental Treatment
Group I: Part D: EDG-7500 Multiple Dose in Adults with Hypertrophic CardiomyopathyExperimental Treatment1 Intervention
EDG-7500 daily for up to 48 weeks in participants who have completed Part B or C.
Group II: Part C: EDG-7500 Multiple Dose in Adults with Nonobstructive Hypertrophic CardiomyopathyExperimental Treatment1 Intervention
EDG-7500 once daily for up to 28 days.
Group III: Part B: EDG-7500 Multiple Dose in Adults with Obstructive Hypertrophic CardiomyopathyExperimental Treatment1 Intervention
EDG-7500 once daily for up to 28 days.
Group IV: Part A: EDG-7500 Single DoseExperimental Treatment1 Intervention
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Hospital of the University of Pennsylvania (University of Pennsylvania School of Medicine)Philadelphia, PA
The Lindner Research Center at Christ HospitalCincinnati, OH
Massachusetts General HospitalBoston, MA
Lahey Hospital and Medical CenterBurlington, MA
More Trial Locations
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Who is running the clinical trial?
Edgewise Therapeutics, Inc.Lead Sponsor
References
[Long-term course of hypertrophic cardiomyopathy: drug versus surgical therapy]. [2013]139 patients with hypertrophic cardiomyopathy (HCM) have been followed up for 1-28 years (mean 8.9 years). Group 1 consisted of 60 patients (mean age 38 years) without indication for septal myectomy (SM) (no pressure gradient at rest in 8, pressure gradient less than 50 mm Hg in 52 cases); group 2 consisted of 79 patients (mean age 36 years) who had SM (pressure gradient at rest 70 mm Hg). Management in group 1 was the following: (1a) propranolol (n = 20) (160 mg/d), (1b) verapamil (n = 18) (360 mg/d) and (1c) no therapy (n = 22). 19 patients died in group 1 (mortality 3.6% year); 17 died in group 2 (mortality 2.4%/year). 10 year survival in group 1b was 80% and in groups 1a und 1c 67% and 65% respectively. Patients of group 1b had a higher survival rate (p less than 0.05) than the other subgroups. Surgery patients treated with verapamil (120-360 mg/d) (n = 17) had a 10-year survival rate of 100% compared to 78% for surgery patients (n = 34) without such treatment (p less than 0.05). In summary, it can be said that the overall survival rate after SM is better than that with medical treatment. Under verapamil, however, survival is not different from that after surgery. The most favorable outcome was observed in surgery patients under long-term therapy with verapamil, probably due to the reduction of systolic pressure overload (SM) and improvement in diastolic function (verapamil).
[Conservative medical treatment of hypertrophic myocardiopathies]. [2013]50 patients with hypertrophic cardiomyopathy were treated with 480 mg Verapamil per day over a period of 47 months (11-82 months beginning in 1973). Subjective improvement was seen in 37 of 50, 6 were unchanged, 1 worsened, 6 were symptom-free from the beginning and remained so during treatment. Heart size (heart volume determined from chest x-rays in supine position) showed a reduction in 35 of 50. On average of all 50 patients a significant reduction of 8.6% was seen; in 26 patients treated for more than 2 years the average reduction was 11%. 26 patients on no medication or betablockers were followed over 24 months and revealed an average increase in heart volume of 11.9%. The ECG showed during Verapamil treatment a reduction in QRS amplitude and a tendency towards normalization of ST/T segments . . . On echocardiography a small but significant reduction in septal and free wall thickness as well as in left atrial diameter was seen. Recatheterization was performed in 19 patients while all 50 had right and left heart catheters before entering the study. Recatheterization showed on average of the 19 patients a reduction in left ventricular filling pressure, pressure gradient, left ventricular muscle mass and coronary artery diameter. It is concluded that subjective improvement, noninvasive and invasive parameters as well as the low death rate of 1% per year during a total of 200 treatment years point towards a beneficial influence of Verapamil treatment superior to other types of therapy.
Sudden death and hypertrophic cardiomyopathy: a review. [2013]Hypertrophic cardiomyopathy is a genetic disease that affects the cardiac sarcomere, resulting in myocardial hypertrophy and disarray. Affected patients have a predisposition for malignant ventricular tachyarrhythmias and, consequently, sudden cardiac death. With the availability of therapeutic measures that prevent sudden death, the identification of high-risk patients is now of greater importance. Clinical risk factors for sudden death (ie, age, syncope, family history of sudden cardiac death, cardiac arrest survivor, nonsustained ventricular tachycardia and abnormal blood pressure response to exercise) have been identified. The clinical electrophysiological study is of limited use for stratifying these patients. More recently, increased attention has been given to the degree of echocardiographically documented left ventricular hypertrophy and prognostically significant genetic mutations. Once a high-risk patient is identified, prophylactic treatment is warranted. For this purpose, amiodarone has been supplanted by the implantable cardioverter-defibrillator. Implantable cardioverter-defibrillator treatment appears to reduce the risk of sudden cardiac death in both primary and secondary prevention settings. Thus, tools are now available to identify and treat high-risk patients with hypertrophic cardiomyopathy.
Cardiac repolarization and the safety of new drugs defined by electrocardiography. [2018]A compelling assessment of both short- and long-term cardiac safety is increasingly emphasized before regulatory marketing approval. In that context, cardiac adverse effects that were otherwise unexpected become manifest when large numbers of subjects are treated after market approval, many of whom take multiple medications, have co-morbidities, and are subject to other conditions that were not represented in the original clinical trial population. Since 2005, dedicated, robust, and well-controlled electrocardiogram (ECG) trials are required, usually conducted in Phase II, to define the cardiac risk of a new therapy before large-scale Phase III trials are conducted or marketing is approved.
Prediction of drug-related cardiac adverse effects in humans--A: creation of a database of effects and identification of factors affecting their occurrence. [2013]This is the first of two reports that describes the compilation of a database of drug-related cardiac adverse effects (AEs) that was used to construct quantitative structure-activity relationship (QSAR) models to predict these AEs, to identify properties of pharmaceuticals correlated with the AEs, and to identify plausible mechanisms of action (MOAs) causing the AEs. This database of 396,985 cardiac AE reports was linked to 1632 approved drugs and their chemical structures, 1851 clinical indications (CIs), 997 therapeutic targets (TTs), 432 pharmacological MOAs, and 21,180 affinity coefficients (ACs) for the MOA receptors. AEs were obtained from the Food and Drug Administration's (FDA's) Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) and publicly available medical literature. Drug TTs were obtained from Integrity; drug MOAs and ACs were predicted by BioEpisteme. Significant cardiac AEs and patient exposures were estimated based on the proportional reporting ratios (PRRs) for each drug and each AE endpoint as a percentage of the total AEs. Cardiac AE endpoints were bundled based on toxicological mechanism and concordance of drug-related findings. Results revealed that significant cardiac AEs formed 9 clusters affecting Purkinje nerve fibers (arrhythmia, bradycardia, conduction disorder, electrocardiogram, palpitations, QT prolongation, rate rhythm composite, tachycardia, and Torsades de pointes), and 5 clusters affecting the heart muscle (coronary artery disorders, heart failure, myocardial disorders, myocardial infarction, and valve disorders). Based on the observation that each drug had one TT and up to 9 off-target MOAs, cardiac AEs were highly correlated with drugs affecting cardiovascular and cardioneurological functions and certain MOAs (e.g., alpha- and beta-adeno, dopamine, and hydroxytryptomine receptors).
Cardiac safety pharmacology: from human ether-a-gogo related gene channel block towards induced pluripotent stem cell based disease models. [2016]The field of cardiac safety pharmacology has been experiencing exciting changes over the recent years. Drug induced arrhythmia of the torsade des pointes types has been the reason for the denial of approval of novel drug candidates. The aim of cardiac safety pharmacology is to detect undesirable pharmacodynamic drug effects within and above the therapeutic range. A special focus is on the identification of potential arrhythmogenic effects within the drug discovery chain.
Insights and challenges in hypertrophic cardiomyopathy, 2012. [2021]We present a contemporary overview of hypertrophic cardiomyopathy (HCM), incorporating recent thinking on disease mechanisms and advances in therapy. Clinical, pathological, genetic, and mechanistic definitions of HCM are discussed. The genetic profile of HCM in both adults and children is explored to the extent of present knowledge. The spectrum of morphological and histological abnormalities in HCM is reviewed, including involvement of the right ventricle, which is less widely recognised. Morbidity and mortality from HCM may result from diastolic dysfunction, ischaemia, left ventricular outflow tract obstruction, mitral regurgitation, supraventricular and ventricular arrhythmia, or--less commonly--progression to "burnt out" disease or sudden cardiac death (SCD). Defibrillators offer an efficacious means of averting SCD, but are not without their complications, underscoring the importance of identifying at-risk cases. We address the strengths and weaknesses of prognostication based on readily obtainable clinical markers, and discuss the integration of auxiliary approaches such as genotyping, cardiovascular magnetic resonance, and fractionation analysis into existing risk stratification guidelines. Finally, we provide an update on the pharmacological and interventional management of HCM, including the advent of disease-modifying therapy.
[Effect of single doses of HX0507 on QTc intervals in healthy people: a phase I safety and tolerability study]. [2018]To assess the effect of HX0507 on QTc interval in healthy people in a phase I safety and tolerability study.
[Diagnosis and treatment of hypertrophic cardiomyopathies]. [2013]Hypertrophic cardiomyopathy is the most common inherited disease of the heart with a prevalence of 0.2 %. One third of patients show no obstruction of the left ventricular outflow tract, whereas two third develop a significant gradient under resting conditions and/or on exertion. Angina pectoris, dyspnea, syncope, heart failure und atrial fibrillation are typical clinical features. Apart from ECG and echocardiography, holter ECG and exercise testing via ergospirometry should be routinely used to identify an adverse clinical course and potential risk factors. Cardiac MRI is a complementary and comprehensive imaging modality and further aids in risk stratification for sudden cardiac death and ICD-implantation for primary prophylaxis. Mainstay of conservative therapy are betablockers, and novel pharmacological approaches are to be expected in the near future. Symptomatic patients with outflow tract obstruction benefit from septum-reducting therapy either by surgical myectomy or catheter-based septum ablation (TASH/PTSMA) with ethanol injection.
How in vitro influences in silico utilized for the prediction of in vivo - pilot study of the drug-induced pro-arrhythmic potency prediction. [2016]The current drug cardiac safety risk assessment paradigm is about to be changed. The discussed modifications cover clinical as well as pre-clinical sides. As for the latter, the pre-clinical assessment, it is planned to be based on the analysis of the drug-triggered multiple ion currents inhibition. Considering the variability in the in vitro patch clamp studies results, it would be of benefit to assess how these apparatus- and protocol-dependent differences influence the risk prediction and, eventually, the decision making. Four compounds, namely dextromethorphan, ketoconazole, terfenadine, and quinidine were screened for hERG inhibition with an automated patch clamp apparatus (CytoPatch(TM)2). The results were then compared against the literature published data, and after being complemented with information about other current inhibitions and effective therapeutic plasma concentration, utilized for the in silico based safety assessment. Two endpoints were used: (1) the concentration dependent potential to induce early afterdepolarizations in the simulated action potential and (2) the arrhythmia-like disruption in the simulated pseudo-ECG signals. Data analysis results prove that IC50 values, describing the inhibition potential, significantly differ among studies, and the choice of input data can greatly influence the in silico based safety assessment and thus the decision making process.
Hypertrophic cardiomyopathy: genetics and clinical perspectives. [2020]Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and defined by unexplained isolated progressive myocardial hypertrophy, systolic and diastolic ventricular dysfunction, arrhythmias, sudden cardiac death and histopathologic changes, such as myocyte disarray and myocardial fibrosis. Mutations in genes encoding for proteins of the contractile apparatus of the cardiomyocyte, such as β-myosin heavy chain and myosin binding protein C, have been identified as cause of the disease. Disease is caused by altered biophysical properties of the cardiomyocyte, disturbed calcium handling, and abnormal cellular metabolism. Mutations in sarcomere genes can also activate other signaling pathways via transcriptional activation and can influence non-cardiac cells, such as fibroblasts. Additional environmental, genetic and epigenetic factors result in heterogeneous disease expression. The clinical course of the disease varies greatly with some patients presenting during childhood while others remain asymptomatic until late in life. Patients can present with either heart failure symptoms or the first symptom can be sudden death due to malignant ventricular arrhythmias. The morphological and pathological heterogeneity results in prognosis uncertainty and makes patient management challenging. Current standard therapeutic measures include the prevention of sudden death by prohibition of competitive sport participation and the implantation of cardioverter-defibrillators if indicated, as well as symptomatic heart failure therapies or cardiac transplantation. There exists no causal therapy for this monogenic autosomal-dominant inherited disorder, so that the focus of current management is on early identification of asymptomatic patients at risk through molecular diagnostic and clinical cascade screening of family members, optimal sudden death risk stratification, and timely initiation of preventative therapies to avoid disease progression to the irreversible adverse myocardial remodeling stage. Genetic diagnosis allowing identification of asymptomatic affected patients prior to clinical disease onset, new imaging technologies, and the establishment of international guidelines have optimized treatment and sudden death risk stratification lowering mortality dramatically within the last decade. However, a thorough understanding of underlying disease pathogenesis, regular clinical follow-up, family counseling, and preventative treatment is required to minimize morbidity and mortality of affected patients. This review summarizes current knowledge about molecular genetics and pathogenesis of HCM secondary to mutations in the sarcomere and provides an overview about current evidence and guidelines in clinical patient management. The overview will focus on clinical staging based on disease mechanism allowing timely initiation of preventative measures. An outlook about so far experimental treatments and potential for future therapies will be provided.
Hypertrophic Cardiomyopathy: New Concepts and Therapies. [2022]Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited myocardial disorder, transformed over the last several years into a treatable condition with the emergence of effective management options that alter natural history at all ages. Now available are a matured risk stratification algorithm selecting patients for prophylactic implantable defibrillators that prevent arrhythmic sudden death; low-risk, high-benefit surgical myectomy to reverse progressive heart failure symptoms due to left ventricular outflow obstruction; anticoagulation prophylaxis to prevent atrial fibrillation-mediated embolic stroke; and heart transplant for refractory end-stage disease in the absence of obstruction. Those strategies have resulted in reduction of HCM-related morbidity and reduction of mortality to 0.5% per year.
Stage-specific therapy for hypertrophic cardiomyopathy. [2023]Hypertrophic cardiomyopathy (HCM) is the most common inherited myocardial disease and is defined by otherwise unexplained left ventricular hypertrophy. The main complications include heart failure and arrhythmias such as atrial fibrillation and ventricular arrhythmias. Current treatment rests on septal reduction therapies, prevention of sudden cardiac death through implantable cardioverter defibrillator, and use of drugs such as beta-blockers, calcium antagonists, or amiodarone. In the last years, new pharmacological agents specifically targeting the pathophysiology of the disease have been developed with encouraging results in terms of functional capacity and symptoms improvement from clinical trials. In this review, we summarize the possible treatment approaches for each phase of the natural history of the disease: pre-phenotype expression, classic phenotype, adverse remodelling, and overt dysfunction.
[Therapeutic approaches in hypertrophic cardiomyopathy: from symptom relief to precision therapy]. [2023]Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy. Main complications include the development of arrhythmias and heart failure, and the latter may be triggered by left ventricular outflow tract obstruction. The treatment of left ventricular outflow tract obstruction includes pharmacological therapies (beta-blockers, calcium channel blockers, disopyramide) and septal reduction therapies (alcohol septal ablation, surgical myectomy). Myosin inhibitors represent a new therapeutic opportunity and in recent clinical trials proved effective in symptom relief, improvement of functional capacity and quality of life in patients with obstructive hypertrophic cardiomyopathy. In this narrative review we will summarize the available and under development therapeutic approaches for hypertrophic cardiomyopathy.