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 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 LQT2 or LQT3. Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be recruited.

Start Date12 Mar 2023

Sponsor / Collaborator

Thryv Therapeutics, Inc.Startup

NCT04128878 / CompletedNot ApplicableIIT

Improvement in Endothelial Dysfunction After Initiation of Anti-arrhythmic Therapy in Atrial Fibrillation Patients

This is a prospective, observational study that will examine endothelial dysfunction in atrial fibrillation before and after treatment with anti-arrhythmic agents and the extent to which baseline endothelial dysfunction improves after treatment.

Start Date01 May 2019

Sponsor / Collaborator

University of Pittsburgh

ACTRN12617000777392 / CompletedPhase 1

A single dose, randomized, blinded, bioequivalence study of a test formulation of dofetilide capsule in a 2 way crossover comparison against the innovator dofetilide capsule conducted under fed conditions in healthy male and female volunteers.

Start Date23 Jun 2017

Sponsor / Collaborator

Zenith Technology Corp. Ltd.

100 Clinical Results associated with Dofetilide

100 Translational Medicine associated with Dofetilide

100 Patents (Medical) associated with Dofetilide

983

Literatures (Medical) associated with Dofetilide

01 Jan 2024·Journal of cardiovascular pharmacology and therapeutics

Assessment of Dofetilide or Sotalol Tolerability in the Elderly

Article

Author: Mara, Kristin ; Moreland-Head, Lindsay ; Macielak, Shea ; Yagnala, Nikitha ; Zieminski, Joseph J

Background: Dofetilide and sotalol are potassium channel antagonists that require inpatient QTc monitoring during initiation, due to increased risk of fatal arrhythmias. Elderly patients are especially subject to an increased risk of fatal arrhythmias due to polypharmacy, comorbidities, and physiologic cardiac changes with aging. This study will describe the tolerability and risk factors associated with the initiation of sotalol or dofetilide in patients ≥80 years of age. Methodology: This is a multicenter, retrospective, descriptive study of patients ≥80 years old who were initiated on either dofetilide or sotalol between May 8, 2018 and July 31, 2021 at institutions within the Mayo Clinic Health System. The percentage of patients who received nonpackage insert recommended doses was identified. Incidence of and reasons for dose reductions or discontinuations due to safety-related events or clinical concerns during the initial loading period were collected. Results: The final analysis included 104 patients. The majority of patients (75%) received nonstandard initial doses of dofetilide or sotalol based on baseline estimated creatinine clearance or QTc. Overall, 39% ( N = 41) of patients experienced a dose reduction or discontinuation due to a safety-related event or concern. Patients who received nonstandard initial doses of dofetilide or sotalol had 4.7 times greater odds of experiencing a safety-related event requiring dose reduction or discontinuation. Conclusion: Following package insert dosing in elderly patients increases safety and tolerability relative to more aggressive dosing of dofetilide or sotalol.

01 Dec 2023·Computer methods and programs in biomedicine

Combining pharmacokinetic and electrophysiological models for early prediction of drug-induced arrhythmogenicity

Review

Author: Baroudi, Samuel ; Dayan, Frederic ; Koloskoff, Kévin ; Trenor, Beatriz ; Benito, Sylvain ; Basset, Matthieu ; Romero, Lucía ; Mora, Maria Teresa ; Saiz, Javier ; Llopis-Lorente, Jordi

BACKGROUND AND OBJECTIVE:

In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods.

METHODS:

Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels.

RESULTS:

Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K⁺]_o = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values.

CONCLUSIONS:

This study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients.

17 Oct 2023·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

Pairwise biosynthesis of ion channels stabilizes excitability and mitigates arrhythmias.

Q1 · CROSS-FIELD

Article

Author: Ríos-Pérez, Erick B ; Robertson, Gail A ; Eichel, Catherine A ; Liu, Fang ; Jameson, Margaret B

Coordinated expression of ion channels is crucial for cardiac rhythms, neural signaling, and cell cycle progression. Perturbation of this balance results in many disorders including cardiac arrhythmias. Prior work revealed association of mRNAs encoding cardiac Na_V1.5 (SCN5A) and hERG1 (KCNH2), but the functional significance of this association was not established. Here, we provide a more comprehensive picture of KCNH2, SCN5A, CACNA1C, and KCNQ1 transcripts collectively copurifying with nascent hERG1, Na_V1.5, Ca_V1.2, or KCNQ1 channel proteins. Single-molecule fluorescence in situ hybridization (smFISH) combined with immunofluorescence reveals that the channel proteins are synthesized predominantly as heterotypic pairs from discrete molecules of mRNA, not as larger cotranslational complexes. Puromycin disrupted colocalization of mRNA with its encoded protein, as expected, but remarkably also pairwise mRNA association, suggesting that transcript association relies on intact translational machinery or the presence of the nascent protein. Targeted depletion of KCHN2 by specific shRNA resulted in concomitant reduction of all associated mRNAs, with a corresponding reduction in the encoded channel currents. This co-knockdown effect, originally described for KCNH2 and SCN5A, thus appears to be a general phenomenon among transcripts encoding functionally related proteins. In multielectrode array recordings, proarrhythmic behavior arose when I_Kr was reduced by the selective blocker dofetilide at IC₅₀ concentrations, but not when equivalent reductions were mediated by shRNA, suggesting that co-knockdown mitigates proarrhythmic behavior expected from the selective reduction of a single channel species. We propose that coordinated, cotranslational association of functionally related ion channel mRNAs confers electrical stability by co-regulating complementary ion channels in macromolecular complexes.

News (Medical) associated with Dofetilide

26 Apr 2024

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FDA Approves Biktarvy® Label Update With Data for Pregnant Adults With HIV

– Additional Data in Pregnant Adults Who Are Virologically Suppressed Reinforce Safety and Tolerability Pro Biktarvy in Broad Range of People With HIV – – Perinatal Guidelines Recognize Biktarvy as Alternative Regimen for Use During Pregnancy and for Those Trying to Conceive – FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc., (Nasdaq: GILD) today announced the U.S. Food and Drug Administration (FDA) approved an updated label with additional data reinforcing the safety and efficacy pro Biktarvy® (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, B/F/TAF) to treat pregnant people with HIV-1 (PWH) with suppressed viral loads. These additional data stem from Study 5310, which evaluated the pharmacokinetics, safety and efficacy of Biktarvy in pregnant PWH who have suppressed viral loads and no known resistance to any components of Biktarvy in their second and third trimesters and through a median of 16 weeks postpartum. This update makes Biktarvy the only second-generation integrase strand transfer inhibitor (INSTI)-based single-tablet regimen (STR) with in-label clinical trial data and FDA approval in virologically suppressed adults who are pregnant. The U.S. Department of Health and Human Services (DHHS) perinatal guidelines recognize Biktarvy as having sufficient data to support being recommended as an alternative complete regimen for use in pregnancy and for people who are trying to conceive. Additionally, guidelines recommend continuing Biktarvy for PWH already on treatment who are virologically suppressed and tolerating treatment well who may become pregnant. “This label update marks an important milestone for Biktarvy, reinforcing its efficacy pro pregnant PWH, an often understudied and most vulnerable community in clinical research,” said Jared Baeten, MD, PhD, Vice President, HIV Clinical Development, Gilead Sciences. “Not only is Biktarvy an alternative regimen for use in pregnancy, but people of childbearing potential can also remain on Biktarvy if they become pregnant. We continue to keep people at the center of our tireless commitment to HIV treatment research and development so that our medicines address the needs of the broad range of communities that we serve.” The updated label now includes additional data from Study 5310, a Phase 1b, open-label, single-arm, multicenter clinical trial evaluating the pharmacokinetics, safety and efficacy of Biktarvy in pregnant PWH who were virologically suppressed (HIV-1 RNA < 50 copies/mL) and had no known resistance to the components of Biktarvy. Participants were administered Biktarvy once daily from the second or third trimester through postpartum. Lower plasma exposures of Biktarvy were observed during pregnancy as compared to postpartum; all 32 participants who completed the study maintained viral suppression during pregnancy, at delivery and through week 18 postpartum. The median CD4+ cell count at baseline was 558 cells/μL, and the median change in CD4+ cell count from baseline to week 12 postpartum was 159 cells/μL. All 29 newborn participants had negative/nondetectable HIV-1 PCR results at birth and/or at four to eight weeks post birth. Further, the study did not identify any new safety or tolerability concerns for people who use Biktarvy during pregnancy and postpartum as the overall incidence and types of adverse events observed were consistent with those expected for the population studied. This label update marks a significant milestone in Gilead’s efforts to address the individual needs of all people impacted by HIV, as these data can help to provide assurance for people of childbearing potential to remain on Biktarvy if they were to become pregnant. The Biktarvy label was also updated in February 2024 to align with Centers for Disease Control and Prevention (CDC) guidance on breastfeeding, which encourages a dialogue between a person and their healthcare provider regarding breastfeeding. “As an OB-GYN and a longtime women’s health advocate, I’m incredibly passionate about helping end health disparities among women, and especially Black women who are disproportionately impacted by HIV,” said Yolanda M. Lawson, MD, President, National Medical Association. “I’m encouraged by the tremendous progress made in personalizing HIV treatment over the years, including this milestone that further supports the safety pro Biktarvy use during pregnancy. Together, we can help bring all PWH the care they need, including those who are or may become pregnant, so they can continue to live longer, healthier lives while on HIV treatment.” “These additional data can help to better inform treatment decisions between pregnant PWH and their providers and mark an incredible step forward in addressing the unique needs PWH have when they are pregnant or planning to become pregnant,” said William R. Short, MD, Associate Professor of Medicine, Perelman School of Medicine at the University of Pennsylvania. “As experts in perinatal care, we will continue to recommend ways pregnant PWH can maintain undetectable viral loads so they can stay healthy and prevent transmission to their baby.” Please see below for U.S. Indications and Important Safety Information for Biktarvy, including Boxed Warning. There is no cure for HIV or AIDS. About Biktarvy Biktarvy is a complete HIV treatment that combines three powerful medicines to form the smallest 3-drug, integrase strand transfer inhibitor (INSTI)-based single-tablet regimen (STR) available, offering simple once-daily dosing with or without food, with a limited drug interaction potential and a high barrier to resistance. Biktarvy combines the novel, unboosted INSTI bictegravir, with the Descovy® (emtricitabine 200 mg/tenofovir alafenamide 25 mg tablets, F/TAF) backbone. Biktarvy is a complete STR and should not be taken with other HIV medicines. U.S. Indication for Biktarvy Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 14 kg who have no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically-suppressed (HIV-1 RNA <50 copies per mL) on a stable ARV regimen with no known or suspected substitutions associated with resistance to bictegravir or tenofovir. U.S. Important Safety Information for Biktarvy BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue BIKTARVY. If appropriate, anti-hepatitis B therapy may be warranted. Contraindications Coadministration: Do not use BIKTARVY with dofetilide or rifampin. Warnings and precautions Drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during BIKTARVY therapy and monitor for adverse reactions. Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported. New onset or worsening renal impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)–containing products. Do not initiate BIKTARVY in patients with estimated creatinine clearance (CrCl) <30 mL/min except in virologically suppressed adults <15 mL/min who are receiving chronic hemodialysis. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue BIKTARVY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Renal monitoring: Prior to or when initiating BIKTARVY and during therapy, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, assess serum phosphorus. Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including FTC and TDF. Discontinue BIKTARVY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse reactions Most common adverse reactions (incidence ≥5%; all grades) in clinical studies through week 144 were diarrhea (6%), nausea (6%), and headache (5%). Drug interactions Prescribing information: Consult the full prescribing information for BIKTARVY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments. Enzymes/transporters: Drugs that induce P-gp or induce both CYP3A and UGT1A1 can substantially decrease the concentration of components of BIKTARVY. Drugs that inhibit P-gp, BCRP, or inhibit both CYP3A and UGT1A1 may significantly increase the concentrations of components of BIKTARVY. BIKTARVY can increase the concentration of drugs that are substrates of OCT2 or MATE1. Drugs affecting renal function: Coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC and tenofovir and the risk of adverse reactions. Dosage and administration Dosage: Adult and pediatric patients weighing ≥25 kg: 1 tablet containing 50 mg bictegravir (BIC), 200 mg emtricitabine (FTC), and 25 mg tenofovir alafenamide (TAF) taken once daily with or without food. Pediatric patients weighing ≥14 kg to <25 kg: 1 tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. Renal impairment: For patients weighing ≥25 kg, not recommended in patients with CrCl 15 to <30 mL/min, or <15 mL/min who are not receiving chronic hemodialysis, or <15 mL/min who are receiving chronic hemodialysis and have no antiretroviral treatment history. For patients weighing ≥14 kg to <25 kg, not recommended in patients with CrCl <30 mL/min. Hepatic impairment: Not recommended in patients with severe hepatic impairment. Prior to or when initiating: Test patients for HBV infection. Prior to or when initiating, and during treatment: As clinically appropriate, assess serum creatinine, CrCl, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, assess serum phosphorus. Pregnancy and lactation Pregnancy: BIKTARVY is recommended in pregnant individuals who are virologically suppressed on a stable ARV regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Lower plasma exposures of BIKTARVY were observed during pregnancy; therefore, viral load should be monitored closely during pregnancy. Lactation: Individuals infected with HIV-1 should be informed of the potential risks of breastfeeding. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, Calif. For 35 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 12 HIV medications, including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce new HIV infections, and the first long-acting injectable HIV treatment medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Forward-Looking Statement This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving Biktarvy; the risk that physicians may not see the benefits of prescribing Biktarvy to treat pregnant people with HIV with suppressed viral loads; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Biktarvy, Descovy, Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies. U.S. Prescribing Information for Biktarvy, including BOXED WARNING, is available at . For more information about Gilead, please visit the company’s website at , follow Gilead on X/Twitter (@Gilead Sciences) and LinkedIn (@Gilead-Sciences).

Clinical ResultPhase 1Drug Approval

08 Apr 2024

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ViiV Healthcare announces U.S. FDA approval of Dovato (dolutegravir/lamivudine) for adolescents living with HIV

Dovato is now the first and only oral, two-drug, single-tablet regimen available for people aged 12 and older living with HIV, a population in need of additional treatment options DURHAM, N.C.--(BUSINESS WIRE)-- ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer and Shionogi as shareholders, today announced the U.S. Food and Drug Administration (FDA) approved Dovato (dolutegravir/lamivudine) for the treatment of HIV-1 infection in adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of Dovato.1 In the U.S., 20 percent of new HIV diagnoses in 2020 were among young people aged 13-24.2 This expanded indication marks the first time an oral, two-drug, single-tablet regimen is available for adolescents between 12- and 18-years old living with HIV and underscores ViiV Healthcare’s ongoing commitment to bringing more therapeutic options to young people. Lynn Baxter, Head of North America at ViiV Healthcare, said: "This expanded indication for Dovato brings an oral, two-drug, single-tablet regimen to adolescents living with HIV, providing a complete HIV therapy with fewer ARV medicines – an important consideration for young people who will require lifelong treatment. As a leader in HIV, ViiV Healthcare is proud of our focused efforts to improve and expand care for children and adolescents and we remain committed to addressing the existing treatment gaps in these communities.” The approval is supported by data from the DANCE study which evaluated Dovato in treatment-naïve adolescents as well as evidence from well-controlled trials in adults living with HIV, GEMINI-1 and GEMINI-2 (treatment-naïve adults) and TANGO (treatment-experienced adults).1 Results from the DANCE study, which included adolescents between 12- and 18-years old weighing at least 25 kg with HIV-1 RNA 1000 to ≤500,000 c/mL, showed that 26/30 participants achieved and maintained viral suppression at Week 48.1 The safety and efficacy data in adolescents from the DANCE study were comparable to those observed in adults.1 Exposures for components of Dovato were higher but were not clinically significant.1 About Dovato (dolutegravir/lamivudine)1,3 Dovato is a once-daily, oral, two-drug, single-tablet regimen that combines the integrase strand transfer inhibitor (INSTI) dolutegravir (50 mg) with the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (300 mg). Dovato contains two medicines to inhibit the viral life cycle at two different sites. INSTIs, like dolutegravir inhibit HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. The principal mode of action of lamivudine, an NRTIs, is inhibition of reverse transcriptase via DNA chain termination. Dovato is approved in the U.S., Europe, Japan, Australia and other countries worldwide. Trademarks are owned by or licensed to the ViiV Healthcare group of companies. About the DANCE Study DANCE (NCT03682848) is an ongoing phase 3b, single-arm, multicenter, open-label study evaluating once-daily, fixed-dose combination of Dovato (50 mg/300 mg) as initial ARV therapy for adolescents aged ≥12 to <18 years and weighing ≥25 kg, with HIV-1 RNA 1000 to ≤500,000 c/mL. The primary endpoint assessed proportions achieving HIV-1 RNA <50 c/mL at Week 48. A total of 32 participants were enrolled across nine centers from Thailand, Kenya, and South Africa.1 DOVATO (dolutegravir and lamivudine) tablets INDICATION DOVATO is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. IMPORTANT SAFETY INFORMATION BOXED WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1: EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. Contraindications Do not use DOVATO in patients with previous hypersensitivity reaction to dolutegravir or lamivudine Do not use DOVATO in patients receiving dofetilide Warnings and precautions Hypersensitivity Reactions: Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury Discontinue DOVATO immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure), in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of DOVATO. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn Monitoring for hepatotoxicity is recommended Embryo Fetal Toxicity: Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects Pregnancy testing is recommended before initiation of DOVATO. Individuals of childbearing potential should be counseled on the consistent use of effective contraception Lactic Acidosis and Severe Hepatomegaly With Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including lamivudine. Discontinue DOVATO if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of DOVATO and other drugs may occur (see Contraindications and Drug interactions). Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of DOVATO. Adverse reactions The most common adverse reactions (incidence ≥2%, all grades) with DOVATO were headache (3%), nausea (2%), diarrhea (2%), insomnia (2%), fatigue (2%), and anxiety (2%). Drug interactions Consult full Prescribing Information for DOVATO for more information on potentially significant drug interactions DOVATO is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of dolutegravir Administer DOVATO 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, DOVATO and supplements containing calcium or iron can be taken with food Use in specific populations Pregnancy: There are insufficient human data on the use of DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Advise individuals of childbearing potential of the potential risk of neural tube defects. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant Females and Males of Reproductive Potential: Pregnancy testing is recommended before initiation of DOVATO. Counsel individuals of childbearing potential taking DOVATO on the consistent use of effective contraception Renal Impairment: DOVATO is not recommended for patients with creatinine clearance <30 mL/min. Patients with a sustained creatinine clearance between 30 and 49 mL/min should be monitored for hematologic toxicities, which may require a dosage adjustment of lamivudine as an individual component Hepatic Impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) About ViiV Healthcare ViiV Healthcare is a global specialist HIV company established in November 2009 by GSK (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of acquiring HIV. Shionogi became a ViiV shareholder in October 2012. The company’s aims are to take a deeper and broader interest in HIV and AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline, and commitment, please visit viivhealthcare.com. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. Cautionary statement regarding forward-looking statements GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D “Risk factors” in the company's Annual Report on Form 20-F for 2023. Registered in England & Wales: GSK plc No. 3888792 ViiV Healthcare Limited No. 06876960 Registered Office: GSK plc 980 Great West Road Brentford, Middlesex United Kingdom TW8 9GS ViiV Healthcare Limited GSK Medicines Research Centre Gunnels Wood Road, Stevenage United Kingdom SG1 2NY References Dovato US Prescribing Information. Available at: . Accessed April 2024. “HIV Information and Youth.” Centers for Disease Control and Prevention. . Accessed April 2024. Dovato EU Summary of Product Characteristics. February 2024. Available at: . Accessed April 2024.

Phase 3Clinical ResultDrug Approval

26 Mar 2024

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Thryv Therapeutics to Present Results of Wave I Part 1 Clinical Study at American College of Cardiology Conference in Atlanta, Georgia on April 7th, 2024

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).

Clinical ResultPhase 1

100 Deals associated with Dofetilide

External Link

KEGG	Wiki	ATC	Drug Bank
D00647	Dofetilide	C01BD04	DB00204

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Atrial Fibrillation	US	Pfizer Inc.	01 Oct 1999
Atrial Flutter	US	Pfizer Inc.	01 Oct 1999

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03070470 (CTgov)	Phase 1	Long QT Syndrome	60	Ranolazine (Ranolazine)	xpkmsciatm(xcetxeuxyb) = itcwnthtln tulqdbmcyz (rzjxulgkkx, wscdjhdecz - vuvygirslt) View more	-	18 Jan 2020
				Verapamil (Verapamil)	xpkmsciatm(xcetxeuxyb) = rrkfneguws tulqdbmcyz (rzjxulgkkx, iudtznibnc - qeyqgfxmyp) View more
ESC2018	Not Applicable	Atrial Fibrillation	-	dofetilide	lrdammrbkg(qnwbjoazle) = zxjiqolmwg gtufyygdez (billvlmrau ) View more	-	28 Aug 2018
				dofetilide	lrdammrbkg(qnwbjoazle) = mmajcjpzkj gtufyygdez (billvlmrau ) View more
ESC2016	Not Applicable	-	-	dofetilide	jtwfxmmwka(rmcidzzteq) = iamzkxqmaw fobjzsxczw (vqzdmvkwxg, 1.27)	-	27 Aug 2016
NCT02308748 (CTgov)	Phase 1	Long QT Syndrome	22	Dofetilide+Mexiletine (Dofetilide + Mexiletine)	jcugrploac(jakegxrqdy) = wiqjfxpmsa ufjdzdosjv (sjvtnqcopr, qrlamscsdo - rlrqixicwj) View more	-	08 Jun 2016
				Lidocaine+Dofetilide (Dofetilide + Lidocaine)	jcugrploac(jakegxrqdy) = uefedesmly ufjdzdosjv (sjvtnqcopr, oerqxztkyl - vjvvrpkpde) View more
NCT01873950 (CTgov)	Phase 1	Abnormalities, Drug-Induced	22	Ranolazine (Ranolazine 1500mg)	vqijnrbvru(utpcamdzlv) = whwgnwovaw knspfotrll (kbsjasmolu, ecckgwjmnh - jvmvcqwmlb) View more	-	21 May 2015
				Dofetilide (Dofetilide 500mcg)	vqijnrbvru(utpcamdzlv) = vwwjxtluzf knspfotrll (kbsjasmolu, szataaxlgl - lhmhwrvgbo) View more
NCT00408200 (CTgov)	Not Applicable	Atrial Fibrillation \| Atrial arrhythmia	110	Radiofrequency catheter ablation (AAD:NO)	firowcbgop(dltrzbysul) = pkmeqplehs cinjodsabv (osifraqxhc, pdjpkwgxiy - otzszdoxpl) View more	-	07 Mar 2013
				Radiofrequency catheter ablation+propafenone+flecainide+dofetilide+sotalol (AAD:YES)	firowcbgop(dltrzbysul) = kkrpbbuigj cinjodsabv (osifraqxhc, iqbazxqwyl - osobunmwkt) View more
NCT00578617 (CTgov)	Not Applicable	Atrial Fibrillation	60	Ablation Therapy	ckbmwqkjle(eywjbtveuv) = jvsppuzagd utbuqkmazv (lbcmqohvbc, atyjysvknb - qnfhnfebox) View more	-	04 Jan 2013

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