SGK1 inhibitors(Sanofi)

Treatment with LQT-1213 demonstrated statistically significant and clinically meaningful reductions in dofetilide-induced QTc prolongation. Larger treatment effects seen in pre-defined subgroups of individuals with largest increases in QTc from baseline and longest QTc intervals. No meaningful safety findings, including no effects on ECG morphology. MONTREAL, March 26, 2024 /PRNewswire/ - Thryv Therapeutics is pleased to announce the presentation of its poster: SGK1 inhibitor LQT-1213 significantly attenuates dofetilide-induced QT prolongation in humans: Results of the WAVE I Clinical Study at the American College of Cardiology Conference. Thryv's poster presentation will be presented on Sunday, April 7th from 12:15 p.m. - 1:00 p.m. in Hall B4-5. Representatives from Thryv will also be present throughout the weekend to meet with cardiologists and electrophysiologists to gain insights into various elements of their development program strategies. To learn more about this initiative, please contact admin@thryvtrx.com. The WAVE I proof of concept clinical study evaluated LQT-1213 for the reduction of QTcF in individuals with dofetilide-induced long QT Syndrome ("LQTS"). LQT-1213 is a potent and selective inhibitor of Serum Glucocorticoid inducible Kinase 1 (SGK1), which is implicated in QTc prolongation. In the WAVE I study, following two days of treatment with dofetilide (baseline) – an agent known to prolong QTc – individuals with meaningful increases in their QTc interval received six days of increasing LQT-1213 doses with a consistent dose of dofetilide. Individuals were continuously monitored and received regular ECGs to assess the safety and efficacy of LQT-1213. Mean reductions of QTcF from baseline (measured as QTcF) were statistically significant beginning with the first evaluable time point of the primary analysis and were sustained during the peak dofetilide-induced prolongation. In a predefined subset of individuals who experienced larger dofetilide-induced prolongation of QTcF, individuals treated with LQT-1213 achieved more robust, clinically meaningful reductions of QT consistent with scientific evidence of SGK1 activation in LQTS. LQT-1213 was well tolerated with no serious adverse events or treatment-related study discontinuations. No QTcF over-shortening was observed in the study. There were no observed changes in ECG morphology, heart rate or blood pressure. Part 2 of the WAVE I clinical study is currently enrolling a small cohort of individuals with genetically confirmed congenital Long QT Syndrome Type 2 and Type 3. This study will provide information about the safety of LQT-1213 before initiation of Phase 3 clinical studies in congenital LQTS patients. Data from this study is expected in the second quarter of 2024. More about the WAVE I (Parts 1 and 2) can be found at . Long QT Syndrome, or LQTS, is a disorder of the heart's electrical system causing the lower chambers of the heart to contract and release too slowly. LQTS can be either congenital or acquired. Congenital LQTS is a set of rare orphan diseases in which people are genetically predisposed to chronic prolongation of their QTc interval (commonly more than 480 milliseconds), leading to increased risk of torsades de pointes, a lethal cardiac arrhythmia that causes sudden cardiac death. Acquired Long QT may develop from the administration of therapies which block electrical pathways in the heart, leading to a similar mechanistic prolongation of QT and risk of sudden cardiac death. 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 treat indications including Congenital Long QT Syndromes (LQTS), atrial fibrillation and heart failure, with potent and selective inhibitors of Serum Glucocorticoid inducible Kinase (SGK1).

MONTRÉAL, Dec. 19, 2023 /PRNewswire/ - As we bid farewell to 2023, it is with great enthusiasm that we share with you the accomplishments and progress that the Thryv team has achieved over the past year. Thryv has grown to include 17 full-time employees, and we are grateful for the dedication and talent that each team member brings to our mission. Long QT Syndrome In the realm of Long QT Syndrome, our progress has been substantial. The completion of our Phase 1 healthy volunteer study demonstrated that LQT-1213 was well tolerated, with good bioavailability and predictable pharmacokinetics. Furthermore, the data from our WAVE I Part 1 clinical proof of efficacy study was particularly encouraging. It showed that LQT-1213 rapidly and significantly reduces the QTc interval in individuals with prolonged QTc induced by dofetilide, mimicking the Long QT Syndrome Type 2. Thanks to the extraordinary efforts of our team, the WAVE I Part 2 study is underway, now focusing not only on evaluating safety, tolerability, and pharmacokinetics of LQT-1213, but providing a glimpse of efficacy in patients diagnosed with Long QT Syndrome Type 2 or Type 3. We would like to extend our appreciation to the teams at the Sudden Arrhythmia Death Syndromes Foundation (SADS), Mayo Clinic, and the University of Rochester for their pivotal roles in facilitating our efforts to provide patients with Long QT Syndrome a potential new therapeutic choice. In addition to these clinical developments, our team has made significant contributions to the scientific community this year. We have published three influential papers related to Long QT Syndrome research. The first, titled "SGK1 Inhibition Attenuates Action Potential Duration in Reengineered Heart Cell Models of Drug-Induced QT Prolongation," and second titled "SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome" were featured in the Heart Rhythm Society Journal. The first study demonstrated the efficacy of two novel SGK1 inhibitors in IPSC-CM models displaying dofetilide-induced action potential duration prolongation, and the second study sought to test the efficacy of novel, selective SGK1 inhibitors in induce pluripotent stem cell–derived cardiomyocyte (iPSC-CM) models of LQTS. Our third paper, "Gene- and Variant-Specific Efficacy of Serum/Glucocorticoid-Regulated Kinase 1 Inhibition in Long QT Syndrome Types 1 and 2," was published by the European Society of Cardiology. This study showed that SGK1 inhibition shortens action potential duration in individuals with Long QT Syndrome Types 2 and 1. Atrial Fibrillation and Heart Failure Our endeavors in atrial fibrillation and heart failure have been equally promising. We successfully demonstrated the preventive effect of an SGK1 inhibitor in an animal model of high-fat diet-induced atrial fibrillation and our abstract, A Novel SGK1 Inhibitor (SGK1-I), Prevents Obesity-Related Atrial Fibrillation, was selected for an oral presentation at the American Heart Association Annual Scientific Sessions. We would like to thank our collaborator, Dr. Aneesh Bapat, Cardiac Electrophysiologist at Massachusetts General Hospital and Instructor in Medicine, Harvard Medical School, who served as this study's investigator. In the realm of Heart Failure, to further understand the cardiometabolic benefit of SGK-1 inhibition, two new preclinical studies for heart failure with preserved ejection fraction (HFpEF) have been initiated, with data expected in early 2024. Furthermore, the preclinical studies required for human dosing are now completed and we are gearing up for a healthy volunteer Phase 1 study early next year for our third novel SGK1 inhibitor. Oncology In the field of oncology, we have made impressive strides. Our research team demonstrated the efficacy of THRV-1257 in delaying and reversing resistance to standard-of-care treatment in a mouse xenograft model of anaplastic thyroid cancer. Perhaps the most significant milestone was the FDA clearance we received for an Investigational New Drug (IND) application for THRV-1257 in anaplastic thyroid cancer (ATC). This achievement paves the way for clinical studies in humans, which we anticipate commencing in 2024. We attended the American Thyroid Cancer Annual meeting held in October and presented a poster titled "The SGK1 Inhibitor THRV-1257: Robust Tumor Regression and Overcoming Resistance to Standard of Care Dabrafenib Plus Trametinib in a Mouse Model of Anaplastic Thyroid Cancer (ATC) with BRAFV600E Mutation". This presentation demonstrated the ability of THRV-1257 to induce significant tumor regression and successfully combat resistance when combined with the standard of care treatment, dabrafenib + trametinib. These results provide support for the clinical evaluation of THRV-1257 in patients with Anaplastic Thyroid Cancer and the BRAFV600E mutation. THRV-1257 also promoted a significant increase in tumor growth inhibition when combined with the standard of care treatment in a mouse xenograft model of colorectal cancer, which could enable future study in this indication as well. The Thryv team would like to express its gratitude to the International Thyroid Oncology Group (ITOG) for their continuous support in providing guidance and recommendations for our clinical development. We would like also to thank our collaborator, Dr. Antonio Di Cristofano, at the NCI-designated Montefiore Einstein Comprehensive Cancer Center, for a great year of results that should culminate in the publication of two research papers highlighting the potential of SGK1 inhibition in ATC. Advisory Boards In 2023, Thryv convened three advisory board meetings featuring Key Opinion Leaders (KOLs) in their respective fields. The inaugural meeting was the Commercial Advisory Board Meeting, where participants engaged in discussions regarding our strategic commercial roadmap, encompassing all three of our programs. Additionally, we reconvened our Long QT Syndrome Advisory Board and organized dedicated advisory board meetings for oncology and atrial fibrillation, where attending physicians and KOLs provided guidance on our clinical pathways for all three programs. Thanks for a Great Year These achievements are the result of relentless dedication, rigorous research, and unwavering commitment to improving the lives of those affected by these conditions. We want to extend our gratitude to the entire Thryv community. A special thank you goes out to our Board of Directors and our Investors for their invaluable contributions. As we venture into 2024, we do so with optimism and determination. The past 12 months have been a whirlwind of activity, and we are excited about what's to come in the new year. Wishing all our supporters, patients, and families a healthy and happy new year! Sincerely, Debra Odink President & Chief Development Officer SOURCE Thryv Therapeutics Inc.