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

This is a single-center, randomized, double-blind, placebo-controlled study to be conducted in 2 parts: single ascending dose (SAD) incorporating a food effect arm and multiple ascending dose (MAD). Potential participants for each part will undergo screening procedures within 28 days of enrollment.

开始日期2024-06-06

申办/合作机构

Thryv Therapeutics, Inc.初创企业

NCT05906732 / Recruiting临床1/2期

A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 1, 2 or 3 Long QT Syndrome

Part 1: This is a Phase 1b, randomized, double-blind, crossover, dose escalation, placebo-controlled study to evaluate the effect of oral LQT-1213 on dofetilide-induced QTc prolongation in healthy adult subjects. This is a 2-treatment, 2-period crossover study with approximately up to 28 healthy subjects, with screening procedures within 28 days of enrolment.
Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT1, LQT2 or LQT3. Up to 12 participants with LQT1, up to 20 participants with LQT2 and up to 12 participants with LQT3 will be recruited.

开始日期2023-03-12

申办/合作机构

Thryv Therapeutics, Inc.初创企业

NCT05759962 / Completed临床1期

A Phase 1, Randomized, Double-blinded, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluated the Safety, Tolerability, Pharmacokinetics, Food Effect, and Pharmacodynamics of LQT-1213 in Healthy Adult Participants

开始日期2022-09-14

申办/合作机构

Thryv Therapeutics, Inc.初创企业

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项与 Thryv Therapeutics, Inc. 相关的文献（医药）

2023-11-07·Circulation

Abstract 15963: A Novel SGK1 Inhibitor (SGK1-I), Prevents Obesity-Related Atrial Fibrillation

作者: Sager, Philip ; Srinivasan, Dinesh ; Ellinor, Patrick T ; Bapat, Aneesh ; Pradhananga, Sabindra

Introduction: Obesity is an important risk factor for atrial fibrillation. We have previously demonstrated the protective effect of genetic SGK1 inhibition in a mouse model of obesity-related atrial fibrillation (AF). SGK1-I is a novel and potent SGK1 inhibitor that has been shown to reduce late sodium current and has currently entered clinical trials as a potential treatment of long QT syndrome. Hypothesis: We sought to assess the efficacy of pharmacologic SGK1 inhibition in a mouse model of obesity-related AF. Methods: Wild type C57/Bl6 mice were fed a high fat diet containing 60% cholesterol (by calories) compounded with (HFD-SGK1i) or without (HFD) SGK1-I for 10 weeks. After feeding, the mice were assayed with invasive electrophysiology studies (EPS), optical mapping, and biochemical assays. Results: There were no significant differences in rate of weight gain, final body weight, fasting glucose, glucose tolerance, or tail-cuff blood pressure between the two groups of mice throughout the study. During EPS, there were no differences in nodal (sinus and atrio-ventricular) function or tissue (atrial/ventricular) refractory periods. However, HFD-SGK1i mice were significantly protected from obesity-related inducible AF during EPS, with a lower rate of AF inducibility (5.7% versus 1.5%, p<0.0001) and a lower total AF burden (35±54 versus 5.5±10.7 s, p=0.04). Optical mapping revealed abbreviated right (RA), but not left (LA), atrial action potential duration (APD) and attenuated inter-atrial APD differences in HFD-SGK1i mice as compared to HFD mice. In this context, Western blotting data demonstrated greater RA (versus LA) SGK1 activity/expression resulting from HFD, suggesting that SGK1 signaling may contribute to inter-atrial heterogeneity caused by HFD. Finally, protein expression of NLRP3 inflammasome components, Caspase-1 and ASC, as well as TGF-β expression were decreased in the SGK1-1 group; consistent with anti-inflammatory and anti-fibrotic signaling resulting from SGK1-I treatment. Conclusion: SGK1-I protects mice from obesity-related AF. These data further highlight SGK1 and its inhibition as a compelling target in cardiac arrhythmogenesis.

2023-05-19·Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

Article

作者: Schwartz, Peter J ; Das, Saumya ; Sala, Luca ; Giannetti, Federica ; Brink, Paul ; Pradhananga, Sabindra ; Gepstein, Lior ; Casini, Simona ; Srinivasan, Dinesh ; Louradour, Julien ; Mura, Manuela ; Shiti, Assad ; Koren, Gideon ; Zehender, Manfred ; Wilde, Arthur A M ; Alerni, Nicolò ; Sager, Philip T ; Crotti, Lia ; Zaza, Antonio ; Gnecchi, Massimiliano ; Barbieri, Miriam ; Nimani, Saranda ; Remme, Carol Ann ; Odening, Katja E

AIMSCurrent long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2.METHODS AND RESULTSHuman-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM.CONCLUSIONA robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

2023-04-01·Heart Rhythm O2

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome

Article

作者: Srinivasan, Dinesh ; Das, Saumya ; Ackerman, Michael J ; Kim, Maengjo ; Pradhananga, Sabindra ; Hamrick, Samantha K ; Tester, David J ; Gao, Xiaozhi ; Sager, Philip T

BackgroundLong QT syndrome (LQTS) stems from pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS.ObjectiveThe study sought to test the efficacy of novel, selective SGK1 inhibitors in induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQTS.MethodsThe mexiletine (MEX)-sensitive SCN5A-P1332L iPSC-CMs were tested initially compared with a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 SCN5A-P1332L variant-corrected isogenic control (IC). The SGK1-I1 therapeutic efficacy, compared with MEX, was tested for APD at 90% repolarization (APD90) shortening in SCN5A-P1332L, SCN5A-R1623Q, KCNH2-G604S, and KCNQ1-V254M iPSC-CMs using FluoVolt.ResultsThe APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared with its IC (646 ± 7 ms vs 482 ± 23 ms; P < .0001). MEX shortened the APD90 to 560 ± 7 ms (52% attenuation, P < .0001). SGK1-I1 shortened the APD90 to 518 ± 5 ms (78% attenuation, P < .0001) but did not shorten the APD90 in the IC. SGK1-I1 shortened the APD90 of the SCN5A-R1623Q iPSC-CMs (753 ± 8 ms to 475 ± 19 ms compared with 558 ± 19 ms with MEX), the KCNH2-G604S iPSC-CMs (666 ± 10 ms to 574 ± 18 ms vs 538 ± 15 ms after MEX), and the KCNQ1-V254M iPSC-CMs (544 ± 10 ms to 475 ± 11ms; P = .0004).ConclusionsTherapeutically inhibiting SGK1 effectively shortens the APD in human iPSC-CM models of the 3 major LQTS genotypes. These preclinical data support development of SGK1 inhibitors as novel, first-in-class therapy for patients with congenital LQTS.

项与 Thryv Therapeutics, Inc. 相关的新闻（医药）

2024-10-01

·PRNewswire

Thryv Therapeutics Granted FDA Orphan Drug Designation for LQT-1213 in Long QT Syndrome Treatment

MONTREAL, Oct. 1, 2024 /PRNewswire/ - Thryv Therapeutics, a clinical stage biotech company dedicated to developing treatments for rare and life-threatening cardiovascular indications, today announced that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to LQT-1213 for the treatment of Long QT Syndrome (LQTS). LQT-1213 is a novel, first-in-class SGK1 inhibitor specifically designed to treat congenital LQTS. Thryv has developed a series of SGK1 inhibitors for the treatment of cardiometabolic stress associated with various arrhythmic diseases including LQTS, atrial fibrillation, and heart failure. "We are pleased with the FDA's Orphan Drug Designation for LQT-1213 based partly on emerging positive clinical data from our Wave 1 clinical study in patients with Long QT Syndrome" said Debra Odink, PhD, President and Chief Development Officer of Thryv Therapeutics. "People with Long QT Syndrome deserve a properly studied and FDA-approved therapy to help in their battle against this potentially lethal genetic disease. There is currently no FDA-approved therapy for people with Long QT Syndrome. This designation reinforces the potential of LQT-1213 to fulfill this unmet need and provides critical incentives for Thryv to accelerate our efforts to deploy prospectively designed, pivotal efficacy studies in people with congenital Long QT Syndrome. We remain focused on bringing innovative treatments to adults and children with rare diseases who have limited options." Following a request from the FDA, clinical data from the ongoing Wave I clinical study in people with congenital LQTS was provided to the Office of Orphan Products Designation. Shortly thereafter, the company received notification that its request for Orphan Drug Designation was approved. The FDA Orphan Drug Designation is a special status granted to drugs and biologics targeting rare diseases, defined as those affecting fewer than 200,000 people in the United States. This designation offers numerous benefits to support the development of treatments for rare conditions, including tax credits for clinical trial costs, exemption from certain FDA fees, and up to seven years of market exclusivity following FDA approval. About LQT-1213 LQT-1213 is a potent and selective serum glucocorticoid regulated kinase 1 (SGK1) inhibitor being developed as an investigational therapeutic to treat Long QT Syndrome Type 1, 2, and 3. By targeting SGK1, LQT-1213 aims to reduce the prolonged QTc interval in people with LQTS, thereby decreasing the risk of life-threatening arrhythmias. Currently, LQT-1213 is being evaluated in clinical studies for its efficacy and safety in treating congenital LQTS. Additional information about the on-going Wave I clinical study is available at using identifier: NCT05906732. 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 highly selective SGK1 inhibitors to treat Long QT Syndrome, atrial fibrillation and heart failure, with potent and selective inhibitors of Serum Glucocorticoid inducible Kinase. For more information, please visit . SOURCE Thryv Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

孤儿药临床1期

2024-09-23

·PRNewswire

Thryv Therapeutics to Participate in Fireside Chat During 2024 RBC Capital Markets Biotechnology Private Company Virtual Conference

Thryv Therapeutics to participate in a fireside chat on Tuesday, October 1st, 2024, from 10:30 a.m. to 11:00 a.m. ET. MONTREAL, Sept. 23, 2024 /PRNewswire/ - Thryv Therapeutics announced today its participation in the upcoming 2024 RBC Capital Markets Private Company Virtual Conference. Thryv will attend on Tuesday, October 1st, 2024, and will sit for a fireside chat from 10:30 a.m. to 11:00 a.m. ET. Company management will also host and participate in one-on-one investor meetings at the conference. To schedule one-on-one meetings with the team, please contact [email protected]. About Thryv Therapeutics 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 Syndrome (LQTS), atrial fibrillation and heart failure, with potent and selective inhibitors of Serum Glucocorticoid inducible Kinase (SGK1). For more information, please visit . SOURCE Thryv Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2024-05-07

·PRNewswire

Thryv Therapeutics to Present Preclinical Data of SGK1 Inhibition in Models of Drug-Induced QT Prolongation at the 2024 Heart Rhythm Society Meeting

MONTREAL, May 7, 2024 /PRNewswire/ - Thryv Therapeutics Inc., a biotechnology company pioneering precision treatment to treat indications including Congenital Long QT Syndrome, atrial fibrillation, and heart failure, today announced a poster presentation of SGK1 inhibition in models of Drug-Induced QT prolongation at the 2024 Heart Rhythm Society meeting in Boston, MA. This presentation will take place on Friday, May 17th, from 10:30 a.m. to 12:30 p.m. ET. The meeting will commence with a presentation by Thryv co-founder and Principal Scientific Advisor, Dr. Saumya Das, at the Stanford Biodesign New Arrhythmia Technologies Retreat in Boston, where he will discuss Small Molecules for Arrhythmia Therapy. Heart Rhythm 2024 Poster Presentation Title: Attenuation of Drug-Induced QT Prolongation in Guinea Pig Isolated Heart and Anesthetized Dog Models by serum/glucocorticoid-regulated kinase 1 (SGK-1) Inhibitors. Date and Time: Friday, May 17th from 10:30 a.m. to 12:30 p.m. ET. 2024 Stanford BioDesign Arrhythmia Technologies Retreat Presentation Title: Small Molecules for Arrhythmia Therapy Presenter: Saumya Das, MD, PhD Date and Time: Wednesday, May 15th at 9:04 a.m. 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). For more information, please visit . SOURCE Thryv Therapeutics Inc.

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