LQT-1213 for Long QT Syndrome

Overseen by Jan Matousek, DO

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Waitlist Available

Sponsor: Thryv Therapeutics, Inc.

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a new medication, LQT-1213, to help with heart rhythm problems. It involves healthy adults and patients with specific heart rhythm disorders (LQT2 or LQT3). The medication aims to keep the heart's electrical signals normal, preventing irregular heartbeats.

Do I have to stop taking my current medications for the trial?

Yes, participants must stop taking certain medications. For Part 1, you must refrain from using any drugs, including prescription and nonprescription medications, herbal remedies, or vitamin supplements, starting 14 days before the first dose and until the end of the study. For Part 2, you cannot take antiarrhythmic medications or drugs known to affect the QT interval within 7 days before admission or 5 half-lives (whichever is longer), unless approved by the sponsor and principal investigator.

What data supports the idea that LQT-1213 for Long QT Syndrome is an effective drug?

The available research does not provide specific data on the effectiveness of LQT-1213 for Long QT Syndrome. Instead, it discusses other treatments and approaches for managing the condition. For example, one study focuses on the drug flecainide for a specific type of Long QT Syndrome, while another explores a different compound, NS1643, in rabbit models. Additionally, there is mention of personalized care and the use of automated external defibrillators as part of a comprehensive treatment program. However, none of these studies directly address LQT-1213. ^{1 2 3 4 5}

What safety data is available for the treatment LQT-1213 for Long QT Syndrome?

The provided research does not contain specific safety data for LQT-1213 or its other names like Dofetilide or Tikosyn. The studies focus on other treatments and aspects of Long QT Syndrome, such as flecainide, sevoflurane, and 4-phenylbutyric acid, but do not mention LQT-1213. Therefore, no safety data for LQT-1213 is available in the provided research. ^{1 4 6 7 8}

Is the drug LQT-1213 a promising treatment for Long QT Syndrome?

The information provided does not directly mention LQT-1213, so we cannot determine if it is a promising treatment for Long QT Syndrome based on the given research articles. ^{1 2 4 9 10}

Research Team

Jan Matousek, DO

Principal Investigator

Spaulding Clinical Research LLC

Eligibility Criteria

Healthy adults and patients with Type 2 or 3 Long QT Syndrome (LQT2 or LQT3) can join this trial. Healthy participants must be 19-60 years old, have a BMI of 18-35 kg/m^2, not have used tobacco recently, and agree to use effective contraception. Patients with LQT need an ICD implanted and a specific QTcF interval. People with certain health conditions, recent blood donations, drug abuse history, or those on conflicting medications cannot participate.

Inclusion Criteria

I understand the study's requirements and agree to participate.

I am a woman who cannot have children because I am either surgically sterile or postmenopausal.

Not previously enrolled in a clinical study with LQT-1213

Exclusion Criteria

Known sensitivity to kinase inhibitors

My liver tests are not normal.

Allergy to band aids, adhesive dressing, or medical tape

Treatment Details

Interventions

• Dofetilide (Antiarrhythmic Agent)
• LQT-1213 (Potassium Channel Modulator)
• Placebo (Other)

Trial Overview The study tests the effects of LQT-1213 on heart rhythm prolongation caused by Dofetilide in healthy subjects (Part1), followed by its safety in patients with congenital Long QT syndrome types LQT2 or LQT3 (Part2). Part1 is a crossover study where subjects receive both treatments at different times; Part2 involves multiple doses for safety evaluation.

Participant Groups

Group I: Part 2: TID dosing of Placebo Experimental Treatment 1 Intervention

Placebo matched to LQT-1213 (Day 1)TID

Group II: Part 2: TID dosing of LQT-1213 Experimental Treatment 1 Intervention

LQT-1213 2.24 mg/kg/day TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4 at time 0, though these time points may be adjusted based upon emerging data.

Group III: Part 1: Arm A: 500 μg of Dofetilide BID in combination with dose-escalating LQT-1213 TID, orally Experimental Treatment 2 Interventions

Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and LQT-1213 3 times a day (TID) low dose (Days 3 and 4), mid dose (Days 5 and 6), and high dose (not to exceed 0.747 mg/kg TID, daily dose 2.24 mg/kg/day) on Days 7 and 8. The specific doses will be determined before administration of the first dose of LQT-1213, but the high dose will not exceed 0.747 mg/kg TID or 2.24 mg/kg/day. Only 1 dose of dofetilide and LQT-1213 will be administered on Day 8.

Group IV: Part 1: Arm B: 500 μg of Dofetilide BID in combination with placebo Placebo Group 2 Interventions

Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and placebo matched to LQT-1213 TID (Days 3-8). Only 1 dose of dofetilide and placebo matched to LQT-1213 will be administered on Day 8.

Who Is Running the Clinical Trial?

Thryv Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

150+

Findings from Research

Chronic low-dose flecainide therapy significantly reduced the QTc interval in six male LQT-3 patients with the DeltaKPQ deletion, achieving an average reduction of -27.1 ms compared to placebo, indicating its efficacy in this genetic disorder.

The study found minimal prolongation in QRS duration and no major adverse cardiac effects, suggesting that flecainide is safe for use in this small patient group, although the limited sample size means further research is needed to fully assess its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of flecainide in subjects with Long QT-3 syndrome (DeltaKPQ mutation): a randomized, double-blind, placebo-controlled clinical trial. Moss, AJ., Windle, JR., Hall, WJ., et al.[2020]

Long QT Syndrome (LQTS) is a serious inherited heart condition that can be effectively treated, but management must be personalized based on individual and genetic factors.

The authors emphasize the need to move away from a 'one-size-fits-all' approach to treatment, advocating for tailored strategies that consider the specific genotype of each patient to improve care outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized Care in Long QT Syndrome: Better Management, More Sports, and Fewer Devices. MacIntyre, CJ., Ackerman, MJ.[2023]

The novel compound NS1643 effectively activates the rapid delayed-rectifier K+ current (I(Kr)), significantly reducing QT interval prolongation and suppressing arrhythmic activity in two rabbit models of long QT syndrome (LQTS).

In both models, NS1643 not only reversed the effects of I(Kr) inhibition but also increased I(Kr) in cardiac myocytes, suggesting that pharmacological activation of I(Kr) could be a promising new treatment strategy for LQTS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome. Diness, TG., Yeh, YH., Qi, XY., et al.[2019]

4-Phenylbutyric acid (4-PBA) has been shown to correct transport defects in the hERG channel associated with Long QT syndrome type 2 (LQT2) by inhibiting excessive endoplasmic reticulum stress and enhancing channel function, based on experiments conducted in HEK293 cells.

The study demonstrated that 4-PBA not only increased the current of the mutated hERG channel (G572R) but also reversed its gating kinetics, suggesting its potential as a new therapeutic option for patients with LQT2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene. Tang, W., Cai, D., Fu, Y., et al.[2023]

In a study of 1665 patients evaluated for Long QT syndrome (LQTS) at a specialty center, only 3 out of 291 children managed without an implantable cardioverter-defibrillator (ICD) required an automated external defibrillator (AED) rescue, indicating that AEDs are rarely needed in well-managed cases.

The AED rescues occurred in a small number of cases (1%) during follow-up, highlighting that while AEDs can be lifesaving, they are not typically necessary for children receiving appropriate treatment for LQTS, which includes beta-blockers and other interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome. Pundi, KN., Bos, JM., Cannon, BC., et al.[2018]

Long QT syndrome (LQTS) is a serious heart condition that can lead to fainting, seizures, and even sudden death, often linked to the prolongation of the QT interval on an electrocardiogram due to slowed heart repolarization.

Certain medications, including anti-arrhythmics and psychiatric drugs, can cause acquired LQTS by blocking the IKr potassium current, which is crucial for heart rhythm; thus, understanding these risks is essential for safe prescribing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current. Witchel, HJ., Hancox, JC.[2022]

A 14-year-old girl with Long QT Syndrome (LQTS) experienced a life-threatening cardiac arrhythmia called Torsade de Pointes (TdP) during sevoflurane inhalational induction, highlighting potential risks of this anesthetic in LQTS patients.

While sevoflurane is generally considered safe for healthy individuals, this case suggests that caution is needed when using it in patients with LQTS, prompting the need for a tailored anesthetic plan for such patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SEVOFLURANE AS A CAUSE OF TORSADE DE POINTES IN PATIENT WITH THE LONG QT SYNDROME: Case Report. Choromanski, DW., Amin, S., Zestos, MM.[2018]

Long QT syndrome (LQTS) is a serious genetic heart condition that can be effectively treated with therapies like beta-blockers, left cardiac sympathetic denervation, and implantable cardioverter defibrillators.

Optimal treatment for LQTS varies significantly among patients, highlighting the importance of personalized and genotype-specific management strategies rather than a standard approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision therapy in congenital long QT syndrome. Neves, R., Bains, S., Bos, JM., et al.[2022]

The new hERG channel activator, ITP-2, effectively increases the activity of hERG1a channels, showing a half-maximal effective concentration (EC50) of 1.0 μM, which suggests its potential utility in treating long QT syndrome.

ITP-2 not only activates hERG1a channels but also demonstrates the ability to activate certain arrhythmia-associated LQT2 mutant channels, indicating its promise as a therapeutic option for specific long QT syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Kv 11.1 (hERG) channels by 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), a novel small molecule activator. Sale, H., Roy, S., Warrier, J., et al.[2021]

Inhibition of SGK1 significantly shortens the action potential duration (APD) in induced pluripotent stem cell-derived cardiomyocyte models of Long QT Syndrome (LQTS), demonstrating a potential new therapeutic approach for this condition.

The SGK1 inhibitor SGK1-I1 showed greater efficacy in reducing APD compared to the standard treatment mexiletine across multiple LQTS genotypes, indicating its promise as a first-in-class therapy for congenital LQTS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome. Kim, M., Das, S., Tester, DJ., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of flecainide in subjects with Long QT-3 syndrome (DeltaKPQ mutation): a randomized, double-blind, placebo-controlled clinical trial. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Personalized Care in Long QT Syndrome: Better Management, More Sports, and Fewer Devices. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome. [2019]

4. China pubmed.ncbi.nlm.nih.gov

4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Automated external defibrillator rescues among children with diagnosed and treated long QT syndrome. [2018]

6. Australia pubmed.ncbi.nlm.nih.gov

Familial and acquired long qt syndrome and the cardiac rapid delayed rectifier potassium current. [2022]

7. Lebanon pubmed.ncbi.nlm.nih.gov

SEVOFLURANE AS A CAUSE OF TORSADE DE POINTES IN PATIENT WITH THE LONG QT SYNDROME: Case Report. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Precision therapy in congenital long QT syndrome. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Modulation of Kv 11.1 (hERG) channels by 5-(((1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (ITP-2), a novel small molecule activator. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

SGK1 inhibition attenuated the action potential duration in patient- and genotype-specific re-engineered heart cells with congenital long QT syndrome. [2023]