Hypertrophy, Left Ventricular

SOUTH SAN FRANCISCO, Calif., Sept. 27, 2024 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that additional data from SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), were presented at the Hypertrophic Cardiomyopathy Medical Society (HCMS) Scientific Sessions by Anjali T. Owens, M.D., Medical Director of the Center for Inherited Cardiac Disease and Assistant Professor of Medicine at the University of Pennsylvania. A new analysis from SEQUOIA-HCM showed that treatment with aficamten was associated with beneficial changes in five indices reflecting structural, electrophysiologic and biomarker changes in patients from SEQUOIA-HCM. This analysis was performed in patients treated with aficamten and compared to placebo, at 24 weeks as follows: Improvement in maximal wall thickness by ≥1.5 mm (n = 282; 47.9% vs 30.7%; p=0.003)Improvement in left atrial volume index (LAVI) category in those with mild, moderate, or severe enlargement at baseline (n = 185; 46.8% vs. 18.7%; p<0.001)Resolution of ECG changes consistent with left ventricular hypertrophy (n = 282; 19.0% vs. 4.3%; p<0.001)Normalization of hyperdynamic left ventricular ejection fraction (defined as ≥72%) into the normal range (n = 282; 35.2% vs 20.7%; p<0.007)Reduction in NT-proBNP by ≥50% from baseline (n = 282; 81.7% vs. 7.1%; p<0.001). Overall, 83.8% of patients treated with aficamten experienced favorable effects in at least one of the five domains, compared to 39.3% of patients on placebo (p<0.001, NNT = 2.2). “This new analysis evaluated clinical data from SEQUOIA-HCM through the lens of remodeling to characterize the impact of treatment with aficamten in patients with obstructive HCM in terms of structural and functional changes. The results demonstrated favorable remodeling across multiple domains, including cardiac structure and function, electrophysiology and biochemistry,” said Stephen Heitner, M.D., Vice President, Head of Clinical Research. “We are encouraged by these findings, and we look forward to further expanding our understanding of the long-term clinical outcomes of treatment with aficamten through our continued conduct of FOREST-HCM, the open-label extension clinical study.” Poster Abstract Presentation Update Due to Hurricane Helene and its expected impact to the Atlanta, GA area, the HCMS Scientific Sessions have converted from in person to virtual presentations. As such, the Company has decided to withdraw the poster entitled “Efficacy and Safety of Aficamten in Patients with Obstructive Hypertrophic Cardiomyopathy and Very High Left Ventricular Outflow Tract Gradients” from the sessions. The Company plans to submit the poster for presentation at a future medical meeting where it can be presented in person. About Aficamten Aficamten is an investigational selective, small molecule cardiac myosin inhibitor discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties and as may translate into next-in-class potential in clinical development. Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduced myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. The development program for aficamten is assessing its potential as a treatment that improves exercise capacity and relieves symptoms in patients with HCM as well as its potential long-term effects on cardiac structure and function. Aficamten was evaluated in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), a positive pivotal Phase 3 clinical trial in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic obstructive HCM from the U.S. Food & Drug Administration (FDA) as well as the National Medical Products Administration (NMPA) in China. Aficamten is also currently being evaluated in MAPLE-HCM, a Phase 3 clinical trial of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients with non-obstructive HCM, and CEDAR-HCM, a clinical trial of aficamten in a pediatric population with obstructive HCM, and FOREST-HCM, an open-label extension clinical study of aficamten in patients with HCM. About Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. This ultimately limits the heart’s pumping function, resulting in reduced exercise capacity and symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity. HCM is the most common monogenic inherited cardiovascular disorder, with approximately 280,000 patients diagnosed, however, there are an estimated 400,000-800,000 additional patients who remain undiagnosed in the U.S.1,2,3 Two-thirds of patients with HCM have obstructive HCM (oHCM), where the thickening of the cardiac muscle leads to left ventricular outflow tract (LVOT) obstruction, while one-third have non-obstructive HCM (nHCM), where blood flow isn’t impacted, but the heart muscle is still thickened. People with HCM are at high risk of also developing cardiovascular complications including atrial fibrillation, stroke and mitral valve disease.4 People with HCM are at risk for potentially fatal ventricular arrhythmias and it is one of the leading causes of sudden cardiac death in younger people or athletes.5 A subset of patients with HCM are at high risk of progressive disease leading to dilated cardiomyopathy and heart failure necessitating cardiac transplantation. About Cytokinetics Cytokinetics is a late-stage, specialty cardiovascular biopharmaceutical company focused on discovering, developing and commercializing muscle biology-directed drug candidates as potential treatments for debilitating diseases in which cardiac muscle performance is compromised. As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to impact myocardial muscle function and contractility. Cytokinetics is preparing for regulatory submissions for aficamten, its next-in-class cardiac myosin inhibitor, following positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial in obstructive hypertrophic cardiomyopathy which were published in the New England Journal of Medicine. Aficamten is also currently being evaluated in MAPLE-HCM, a Phase 3 clinical trial of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients with non-obstructive HCM, CEDAR-HCM, a clinical trial of aficamten in a pediatric population with obstructive HCM, and FOREST-HCM, an open-label extension clinical study of aficamten in patients with HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac muscle activator, in patients with heart failure. Additionally, Cytokinetics is developing CK-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten for the potential treatment of HFpEF. For additional information about Cytokinetics, visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube. Forward-Looking Statements This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”). Cytokinetics disclaims any intent or obligation to update these forward-looking statements and claims the protection of the Act’s Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements express or implied relating to the properties or potential benefits of aficamten or any of our other drug candidates, our ability to obtain regulatory approval for aficamten for the treatment of obstructive hypertrophic cardiomyopathy or any other indication from FDA or any other regulatory body in the United States or abroad, and the labeling or post-marketing conditions that FDA or another regulatory body may require in connection with the approval of aficamten. Such statements are based on management’s current expectations, but actual results may differ materially due to various risks and uncertainties, including, but not limited to the risks related to Cytokinetics’ business outlines in Cytokinetics’ filings with the Securities and Exchange Commission. Forward-looking statements are not guarantees of future performance, and Cytokinetics’ actual results of operations, financial condition and liquidity, and the development of the industry in which it operates, may differ materially from the forward-looking statements contained in this press release. Any forward-looking statements that Cytokinetics makes in this press release speak only as of the date of this press release. Cytokinetics assumes no obligation to update its forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. CYTOKINETICS® and the C-shaped logo are registered trademarks of Cytokinetics in the U.S. and certain other countries. Contact:Cytokinetics Diane WeiserSenior Vice President, Corporate Affairs(415) 290-7757 References: CVrg: Heart Failure 2020-2029, p 44; Maron et al. 2013 DOI: 10.1016/S0140-6736(12)60397-3; Maron et al 2018 10.1056/NEJMra1710575Symphony Health 2016-2021 Patient Claims Data DoF;Maron MS, Hellawell JL, Lucove JC, Farzaneh-Far R, Olivotto I. Occurrence of Clinically Diagnosed Hypertrophic Cardiomyopathy in the United States. Am J Cardiol. 2016; 15;117(10):1651-1654.Gersh, B.J., Maron, B.J., Bonow, R.O., Dearani, J.A., Fifer, M.A., Link, M.S., et al. 2011 ACCF/AHA guidelines for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Journal of the American College of Cardiology and Circulation, 58, e212-260.Hong Y, Su WW, Li X. Risk factors of sudden cardiac death in hypertrophic cardiomyopathy. Current Opinion in Cardiology. 2022 Jan 1;37(1):15-21

Lexeo Therapeutics’ investigational gene therapy has shown promise as a treatment for Friedreich’s ataxia (FA) cardiomyopathy, according to new phase 1/2 data shared by the company. Affecting approximately one in every 40,000 people, FA is a neurodegenerative movement disorder and the most common form of inherited ataxia. The typical age of disease onset is between ten and 15 years, with initial symptoms including unsteady posture, frequent falling, fatigue and progressive difficulty walking due to an impaired ability to coordinate voluntary movements. Administered intravenously, Lexeo’s LX2006 is designed to treat FA cardiomyopathy, the most common cause of death in this patient population. Clinically meaningful improvements in cardiac biomarkers were observed in patients receiving the therapy across the Lexeo SUNRISE-FA phase 1/2 trial and the Weill Cornell Medicine investigator-initiated phase 1A study, with increasing improvements seen over time. A mean reduction in left ventricular mass index (LVMI) of 11.4% was observed at 12 months among patients with elevated LVMI at baseline, increasing to 18.3% at 18 months. Left ventricular lateral wall thickness, an early indicator of left ventricular hypertrophy, was reduced by 13.6% and troponin I, a biomarker of myocardial injury, dropped by 53.3% on average in all patients at 12 months. An increase in levels of the protein which is deficient in FA, frataxin, was also observed in all patients and LX2006 was well tolerated. Dr Sandi See Tai, chief development officer at Lexeo, said: “Together with the increases in frataxin protein expression observed in SUNRISE-FA cardiac biopsies to date, these results further highlight the potential of LX2006 to positively impact outcomes for people with FA cardiomyopathy.” LX2006 has already received rare paediatric disease, fast track and orphan drug designations from the US Food and Drug Administration to treat FA cardiomyopathy. Dr Eric Adler, chief medical officer and head of research at Lexeo, said: “We are very encouraged by this data and the potential of LX2006 to treat FA cardiomyopathy, a devastating and fatal condition with no currently approved therapies. “Based on the favourable safety profile and clinical benefits observed to date, we are excited to explore expedited clinical development of LX2006, including potential for accelerated approval of this possibly life-saving treatment.”

Achieved mean reduction in left ventricular mass index (LVMI) of 11.4% at 12 months and 18.3% at 18 months in participants with elevated LVMI at baseline >10% reduction in LVMI at 12 months in 75% of participants with elevated LVMI at baseline Sustained and consistent improvements in other key measures of cardiac status, including left ventricular wall thickness and troponin I, in majority of participants at 12 months Increased post-treatment frataxin expression above baseline in all participants evaluated via myocardial biopsy to date LX2006 was well tolerated with no treatment-related serious adverse events to date; proceeding to Cohort 3 in SUNRISE-FA, with one participant dosed in this cohort to date Company to host webcast today at 8:00 AM ET NEW YORK, NY, USA I July 15, 2024 I Lexeo Therapeutics, Inc. (Nasdaq: LXEO), a clinical stage genetic medicine company dedicated to pioneering treatments for genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease, today announced positive interim data of LX2006 for the treatment of Friedreich ataxia (FA) cardiomyopathy. Across both the Lexeo SUNRISE-FA Phase 1/2 clinical trial ( NCT05445323 ) and the Weill Cornell Medicine investigator-initiated Phase 1A trial ( NCT05302271 ), LX2006 was well tolerated with no treatment-related serious adverse events, and clinically meaningful improvements in cardiac biomarkers were observed with increasing improvement over time. “We are very encouraged by these data and the potential of LX2006 to treat FA cardiomyopathy, a devastating and fatal condition with no currently approved therapies,” said Dr. Eric Adler, Chief Medical Officer and Head of Research at Lexeo Therapeutics. “Based on the favorable safety profile and clinical benefits observed to date, we are excited to explore expedited clinical development of LX2006, including potential for accelerated approval of this possibly life-saving treatment.” “The interim data shared today demonstrate clinically meaningful improvements across multiple cardiac biomarkers of hypertrophy, a hallmark of FA cardiomyopathy,” said Dr. Sandi See Tai, Chief Development Officer at Lexeo. “Together with the increases in frataxin protein expression observed in SUNRISE-FA cardiac biopsies to date, these results further highlight the potential of LX2006 to positively impact outcomes for people with FA cardiomyopathy. I would like to thank the participants, caregivers, and investigators participating in these trials who have helped to achieve this important milestone.” FA cardiomyopathy is a devastating, rare, and progressive disorder caused by loss of function mutations in the frataxin gene. Thus far in participants in the SUNRISE-FA trial with cardiac biopsies, low levels of frataxin have been found in the heart at baseline, estimated to be 2% or less of normal. In terms of clinical presentation, FA cardiomyopathy is typically characterized by left ventricular hypertrophy ultimately progressing to heart failure, and cardiac dysfunction is the cause of death in up to 80% of individuals with FA. A new natural history subset analysis conducted by Lexeo showed elevated left ventricular mass index (LVMI) in adults with FA cardiomyopathy, and LVMI remained stable or increased with age without spontaneous improvement. Elevated LVMI is an indicator of left ventricular hypertrophy and correlated with mortality in multiple cardiovascular conditions including FA cardiomyopathy. Interim Safety Results Interim Clinical Results (from 8 participants with > 6-months of follow-up) Dosing Update and Next Steps About the Clinical Studies SUNRISE-FA is a Lexeo-sponsored, multicenter, 52-week, open-label trial evaluating the safety and preliminary efficacy of LX2006 in people who have FA cardiomyopathy, with three ascending-dose cohorts. Investigators at Weill Cornell Medicine are conducting a Phase 1A study of AAVrh.10hFXN, known as LX2006 at Lexeo, in a single-site, 52-week, open-label trial evaluating the safety and preliminary efficacy in people who have FA cardiomyopathy, in two ascending-dose cohorts with five participants per cohort. About LX2006 LX2006 is an AAV-based gene therapy candidate delivered intravenously for the treatment of FA cardiomyopathy, the most common cause of mortality in individuals with FA affecting approximately 5,000 people in the United States. LX2006 is designed to target the cardiac manifestations of FA by delivering a functional frataxin gene to promote the expression of the frataxin protein and restore mitochondrial function in myocardial cells. In preclinical studies, LX2006 reversed the cardiac abnormalities in FA disease models and showed improvement in cardiac function and survival while demonstrating a favorable safety profile. The FDA has granted Rare Pediatric Disease designation, Fast Track designation, and Orphan Drug designation to LX2006 for the treatment of FA cardiomyopathy. About Lexeo Therapeutics Lexeo Therapeutics is a New York City-based, clinical stage genetic medicine company dedicated to transforming healthcare by applying pioneering science to fundamentally change how genetically defined cardiovascular diseases and APOE4-associated Alzheimer’s disease are treated. Using a stepwise development approach, Lexeo is leveraging early proof-of-concept functional and biomarker data to advance a pipeline of cardiovascular and APOE4-associated Alzheimer’s disease programs. SOURCE: Lexeo Therapeutics