Thryv Therapeutics Inc., a biotechnology company pioneering treatments for genetic and cardiometabolic conditions, including congenital Long QT Syndrome, heart failure, and atrial fibrillation, has completed phase 1 dosing of its second SGK1 inhibitor. This study was a first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending dose study to assess the safety, tolerability, pharmacokinetics, and food effect of THRV-1268 in healthy adult subjects. The completion of dosing marks a significant milestone in the development of THRV-1268, laying the groundwork for future clinical investigations in heart failure and atrial fibrillation.
“Completion of this first-in-human study is the initial clinical step with THRV-1268, providing a path towards addressing cardiometabolic diseases where both structural and electrical remodeling lead to adverse CV outcomes in patients with atrial fibrillation and heart failure,” stated Philip Sager, MD, Chief Medical Officer of Thryv Therapeutics. “Building on our initial clinical work with LQT-1213 for Long QT Syndrome, we now have an opportunity to address both the pro-arrhythmic and metabolic pathways of heart failure and atrial fibrillation in patients with underlying metabolic disease. We look forward to beginning our proof-of-concept studies next year.”
THRV-1268 is a novel and potent inhibitor of the Serum Glucocorticoid Kinase 1 (SGK1). SGK1 is a PI3-kinase-dependent kinase with its expression and activation regulated by several metabolic signaling pathways that are crucial in cardiometabolic diseases. Thryv Therapeutic’s first SGK1 inhibitor, LQT-1213, repeatedly demonstrated reductions in QTc interval in pre-clinical studies and in patients with the genetic and acquired Long QT Syndrome. SGK1 has been implicated in various pathological conditions, including QTc prolongation, arrhythmias, fibrosis, and heart failure. SGK1 dysfunction is also linked to cardiometabolic stressors such as obesity and hypertension, which are common comorbidities in heart failure.
Genetic and pharmacological inhibition of SGK1 has been demonstrated to have a protective effect in a mouse model of obesity-related atrial fibrillation. In several preclinical models of heart failure, THRV-1268 mitigated the development of heart failure and fibrosis, and reduced heart failure biomarkers associated with adverse changes in hemodynamic and functional cardiovascular outputs. These findings demonstrate the potential of SGK1 inhibition in addressing the pathogenesis of heart failure and related cardiometabolic conditions, including atrial fibrillation. Results from the THRV-1268 non-clinical efficacy program are to be presented at the American Heart Association meeting on November 16 – 18, 2024 in Chicago, Illinois.
Heart Failure
Heart failure is a complex clinical syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s needs. It can manifest in two primary forms: Heart Failure with Reduced Ejection Fraction (HFrEF), where the heart muscle is weakened and cannot contract effectively, leading to a reduced ejection fraction; and Heart Failure with Preserved Ejection Fraction (HFpEF), where the heart muscle contracts normally but is stiff and unable to relax properly, resulting in impaired filling and increased pressure in the heart. Often coexisting with atrial fibrillation, heart failure can result from various underlying conditions such as coronary artery disease, hypertension and previous heart attacks. If left untreated, heart failure leads to symptoms like fatigue and shortness of breath that profoundly impact a patient’s quality of life, and significantly increases the risk of severe complications and mortality.
Atrial Fibrillation
Atrial fibrillation (AF or AFib) is a prevalent cardiac arrhythmia characterized by irregular and often rapid heartbeats. Affecting nearly 40 million individuals worldwide, AF significantly diminishes quality of life and heightens the risk of stroke, heart failure and other cardiovascular complications. Obesity and metabolic disorders are key risk factors for AF, contributing to its rising prevalence. Effective treatment strategies aim to control heart rate, restore normal heart rhythm and mitigate complications.
About Thryv Therapeutics Inc.
Thryv Therapeutics Inc. is a privately owned company based in Montreal, Quebec, Canada. Thryv Therapeutics is pioneering a precision medicine approach to develop potent and highly selective inhibitors of serum glucocorticoid inducible kinase 1 (SGK1) to treat Long QT Syndrome, heart failure, and atrial fibrillation. For more information, please visit www.thryvtrx.com.