LQT-1213 for Long QT Syndrome

Overseen By Doug Wight

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Thryv Therapeutics, Inc.

Must not be taking: Antiarrhythmics, QT-prolonging drugs

Disqualifiers: Cardiovascular disease, Renal impairment, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called LQT-1213 for individuals with Long QT Syndrome (LQTS), a heart condition that can cause irregular heartbeats. The first part of the trial involves healthy participants to observe how LQT-1213 affects a drug that temporarily changes heart rhythms. The second part involves participants with specific types of LQTS (LQT2 or LQT3) to assess safety and side effects. Individuals diagnosed with LQT2 or LQT3 may be a good fit for this trial. As a Phase 1 and Phase 2 trial, this research aims to understand how LQT-1213 works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking treatment development.

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.

Will I have to stop taking my current medications?

The trial requires participants to refrain from using any prescription or nonprescription medications, herbal remedies, or vitamin supplements starting 14 days before the first dose and until the end of the study, unless approved by the sponsor and principal investigator. This means you may need to stop taking your current medications, but you should discuss this with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that LQT-1213 is under investigation as a potential treatment for Long QT Syndrome, a condition affecting the heart's rhythm. Although not yet FDA-approved for this use, it has received "orphan drug" status, recognizing its potential to treat a rare condition.

The current trials are in the early stages, focusing primarily on understanding treatment tolerance. These early trials typically involve small groups to closely monitor any side effects. Researchers are testing the treatment on both healthy volunteers and individuals with Long QT Syndrome to assess tolerance and identify side effects.

While specific results from these studies are not yet available, the treatment's progression to this stage suggests some level of safety. Researchers will closely monitor participants for any reactions to ensure their safety as the research continues. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Long QT Syndrome?

Researchers are excited about LQT-1213 for Long QT Syndrome because it offers a novel approach to managing this heart condition. Unlike traditional treatments like beta-blockers or dofetilide, which focus on controlling heart rhythms, LQT-1213 may work by modulating cardiac ion channels, potentially reducing the risk of arrhythmias more effectively. Additionally, LQT-1213 is being tested in flexible dosing regimens, which could allow for personalized treatment plans based on a patient's specific needs. This innovative approach has the potential to improve patient outcomes where current options may fall short.

What evidence suggests that this trial's treatments could be effective for Long QT Syndrome?

Research has shown that LQT-1213 is designed to help people with Long QT Syndrome by targeting specific parts of the heart that control electrical signals. These signals are crucial for maintaining a steady heartbeat. Early results suggest that LQT-1213 might shorten the QT interval, which, if too long, can lead to dangerous heart rhythms. In this trial, participants will receive LQT-1213 in different dosing regimens to evaluate its effectiveness. Although detailed information from human studies is still being gathered, the treatment appears promising based on its mechanism of action. LQT-1213 is considered a potential treatment for congenital long QT syndrome, which is why researchers continue to study it. ^{1 2 3 4 5}

Who Is on the Research Team?

Jan Matousek, DO

Principal Investigator

Spaulding Clinical Research LLC

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Remote screening

Treatment Part 1

Randomized, double-blind, crossover, dose-escalation study with dofetilide and LQT-1213 in healthy subjects

8 days

Daily visits for dosing and monitoring

Treatment Part 2

Single-blind, multiple-dose safety study of LQT-1213 in patients with Long QT Syndrome

5 days

In-person visits for dosing and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

7 days

Remote follow-up via telephone

What Are the Treatments Tested in This Trial?

Interventions

• Dofetilide
• LQT-1213
• Placebo

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.

How Is the Trial Designed?

Group I: Part 2: TID dosing of LQT-1213 7mg (21 mg Daily) Experimental Treatment 2 Interventions

LQT-1213 7 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.

Group II: Part 2: TID dosing of LQT-1213 16 mg (48 mg Daily) Experimental Treatment 2 Interventions

LQT-1213 16 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.

Group III: Part 1: Arm B: Dofetilide with placebo followed by Dofetilide with LQT-1213 TID Experimental Treatment 3 Interventions

Sequence B : Dofetilide 500 μg BID, orally (Days 1-8) and placebo TID (Days 3-8). After adequate washout, Dofetilide 500 μg BID, orally (Days 1-8) and LQT-1213 3 times a day (TID) 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8.

Group IV: Part 1: Arm A: Dofetilide with dose-escalating LQT-1213 TID followed by Dofetilide with placebo Experimental Treatment 3 Interventions

Sequence A :Dofetilide 500 μg BID (Days 1-8) and LQT-1213 TID 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. After adequate washout, Dofetilide 500 μg BID (Days 1-8) and placebo (Days 3-8).

LQT-1213 is already approved in United States for the following indications:

Approved in United States as LQT-1213 for:

• Congenital Long QT Syndrome (Type 1, 2, and 3)

Who Is Running the Clinical Trial?

Thryv Therapeutics, Inc.

Lead Sponsor

Trials

3

Recruited

150+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

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]

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]

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]

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