Zelicapavir's Effect on Heart Rhythm

No longer recruiting at 1 trial location

Overseen By Paola Castellotti, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Enanta Pharmaceuticals, Inc

Disqualifiers: Cardiovascular abnormalities, HIV, HBV, HCV, others

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different doses of zelicapavir (also known as EDP-938 or EP 023938) affect heart rhythm in healthy individuals. Participants will receive zelicapavir at both therapeutic and higher doses, a placebo (inactive substance), and moxifloxacin, a drug known to affect heart rhythm. The study seeks healthy volunteers without a history of heart issues or recent illnesses who are willing to use effective birth control. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you have a positive urine drug screen or have taken an investigational agent recently.

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

Research has shown that zelicapavir was tested in earlier studies and is generally well tolerated. Participants in those trials did not report major side effects, suggesting it is safe for humans. However, this current trial is in an early stage, focusing primarily on ensuring the treatment's safety, and more information is still being collected. For those considering participation, earlier studies provide positive safety results, but new data from this trial will offer more detailed insights. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Zelicapavir because it targets heart rhythm issues in a potentially groundbreaking way. Unlike most current treatments that focus on adjusting electrical signals in the heart, Zelicapavir operates with a new active ingredient, offering a fresh mechanism of action. This could mean more precise control of heart rhythms with possibly fewer side effects. Additionally, Zelicapavir is being tested in both therapeutic and supratherapeutic doses, which may provide insights into its effectiveness at different levels, distinguishing it from existing options.

What evidence suggests that this trial's treatments could be effective for heart rhythm?

Research has shown that zelicapavir, also known as EDP-938, has shown promise in related studies. It has primarily been studied for its effects on RSV (respiratory syncytial virus) infection, where trials significantly reduced the virus's activity. This indicates strong virus-fighting abilities. Additionally, zelicapavir has been reported to shorten the duration of RSV symptoms in young children. Although these studies did not focus on heart rhythm, the drug's success in other areas suggests it merits further investigation. In this trial, participants will receive different doses of zelicapavir, moxifloxacin, and a placebo to evaluate its effect on heart rhythm. ^{1 3 4 5 6}

Who Is on the Research Team?

Enanta Pharmaceuticals, Inc

Principal Investigator

Enanta Pharmaceuticals, Inc

Are You a Good Fit for This Trial?

This trial is for healthy adults who can participate in a study to understand how different doses of a drug called Zelicapavir affect the heart's electrical cycle compared to a placebo and another drug, moxifloxacin. Specific eligibility criteria are not provided.

Inclusion Criteria

An informed consent document signed and dated by the subject

My BMI is between 18 and 30, and I weigh at least 50 kg.

I am a man who is sexually active with a woman who can have children. We agree to use two forms of birth control during the study and for 3 months after.

Exclusion Criteria

I have risk factors for heart problems.

I am not pregnant or nursing.

A positive urine drug screen at Screening or Day -1

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive 4 study interventions including therapeutic and supratherapeutic doses of zelicapavir, placebo, and moxifloxacin during separate treatment periods

4 weeks

4 visits (in-person) on Days 1, 9, 17, and 25

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Zelicapavir

Trial Overview

The study tests the effects of two doses of Zelicapavir (one normal and one high) on the heart's QT interval, which represents part of the electrical cycle during heartbeats, against an inactive substance (placebo) and moxifloxacin as a control.

How Is the Trial Designed?

Group I: zelicapavir Dose 2 (supratherapeutic dose) Experimental Treatment 1 Intervention

All participants will receive 4 study interventions. The study interventions will be administered during separate treatment periods starting on Days 1, 9, 17, and 25.

Group II: zelicapavir Dose 1 (therapeutic dose) Experimental Treatment 1 Intervention

All participants will receive 4 study interventions. The study interventions will be administered during separate treatment periods starting on Days 1, 9, 17, and 25.

Group III: moxifloxacin Experimental Treatment 1 Intervention

All participants will receive 4 study interventions. The study interventions will be administered during separate treatment periods starting on Days 1, 9, 17, and 25.

Group IV: placebo Placebo Group 1 Intervention

All participants will receive 4 study interventions. The study interventions will be administered during separate treatment periods starting on Days 1, 9, 17, and 25.

Who Is Running the Clinical Trial?

Enanta Pharmaceuticals, Inc

Lead Sponsor

Trials

42

Recruited

3,200+

Published Research Related to This Trial

Carocainide, administered intravenously at 5 mg/kg, significantly lengthens key cardiac conduction intervals and refractory periods in dogs, indicating its potential to modify heart electrical activity.

In vitro studies showed that carocainide increases conduction time and decreases depolarization rates in heart tissues, suggesting it may effectively treat cardiac arrhythmias by depressing conduction and extending refractory periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrophysiological effects of carocainide (770207) on the dog heart. Huerta, F., Santamaria, R., Pourrias, B.[2014]

In a study of 1077 HIV-1-infected patients, no significant relationship was found between nevirapine (NVP) plasma concentrations and adverse events (AEs), suggesting limited value in monitoring NVP levels to prevent toxicity.

However, higher plasma concentrations of efavirenz (EFV) were associated with an increased risk of elevated liver enzymes, indicating that regular monitoring of EFV levels and liver function may be beneficial, especially during the first 6 weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are adverse events of nevirapine and efavirenz related to plasma concentrations? Kappelhoff, BS., van Leth, F., Robinson, PA., et al.[2022]

In a study of 745 patients treated with nevirapine (NVP) from 1996 to 2008, 61% remained on the medication for a median duration of 176 weeks, indicating its long-term efficacy and good safety profile in a real-life setting.

NVP led to significant improvements in patient health, with median CD4 cell counts increasing from 377 to 549 cells/microL and 97% of patients achieving a viral load below 200 copies/mL, demonstrating its effectiveness in managing HIV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Twelve-year experience of nevirapine use: benefits and convenience for long-term management in a French cohort of HIV-1-infected patients. Reliquet, V., Allavena, C., Morineau-Le Houssine, P., et al.[2013]

In a study involving 1032 treatment-experienced HIV-positive patients, maraviroc (MVC) was found to be well tolerated, with 90.3% of adverse events being mild or moderate, indicating a favorable safety profile.

At the end of the study, 79.9% of patients achieved HIV-1 RNA levels below 400 copies/ml, demonstrating effective virologic suppression, although some patients experienced viral escape mechanisms related to MVC resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The maraviroc expanded access program - safety and efficacy data from an open-label study. Lazzarin, A., Reynes, J., Molina, JM., et al.[2020]

In an experimental study with 12 isolated rabbit hearts, oseltamivir significantly reduced the occurrence of atrial fibrillation (AF) by increasing atrial effective refractory period (aERP) and post-repolarization refractoriness (aPRR).

The study found that while oseltamivir did not significantly affect ventricular action potential duration or QT interval, it did increase ventricular ERP, suggesting a potential antiarrhythmic effect of oseltamivir in treating atrial arrhythmias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-influenza drug oseltamivir reduces atrial fibrillation in an experimental whole-heart model. Frommeyer, G., Mittelstedt, A., Wolfes, J., et al.[2018]

This study is the first to evaluate the effects of 30 clinical drugs on seven ion currents relevant to cardiac action potential, highlighting the significance of hERG, Nav1.5-late, and Cav1.2 in assessing drug safety.

At clinically relevant concentrations, many drugs blocked hERG and other ion channels, suggesting that traditional assessments based solely on hERG data may not fully capture the risk of drug-induced arrhythmias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. Crumb, WJ., Vicente, J., Johannesen, L., et al.[2022]

In a study involving patients undergoing coronary angiograms, Enalaprilat significantly reduced ventricular activity duration, indicating an increase in intraventricular conduction velocity, which may have antiarrhythmic effects.

The study used a double-blind crossover design with measurements taken after saline (placebo) and Enalaprilat administration, showing no significant changes in heart rate, blood pressure, or conduction times, except for the notable reduction in ventricular activity duration after Enalaprilat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrophysiologic Changes in the Human Heart Produced by Enalaprilat (Angiotensin-Converting Enzyme Inhibitor). González-Fernández, RA., Altieri, PI., De Mello, WC., et al.[2019]

A comprehensive database of 396,985 drug-related cardiac adverse effects (AEs) linked to 1,632 approved drugs was created, revealing significant clusters of AEs affecting heart function, such as arrhythmias and heart failure.

The study identified that cardiac AEs are highly correlated with drugs targeting cardiovascular functions and specific mechanisms of action, including interactions with various receptors like alpha- and beta-adrenergic receptors, which may help predict and understand these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of drug-related cardiac adverse effects in humans--A: creation of a database of effects and identification of factors affecting their occurrence. Matthews, EJ., Frid, AA.[2013]

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new safety screening method designed to improve the assessment of drug-induced heart rhythm issues by using a combination of in silico simulations and in vitro testing with human stem cell-derived cardiomyocytes.

CiPA aims to replace older regulatory strategies by providing a more modern approach to evaluating drug safety, but its full implementation may face challenges due to the need for international agreement on testing protocols and validation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: a visionary 21st century initiative. Cavero, I., Holzgrefe, H.[2014]

In a 96-week study comparing rilpivirine (RPV) and efavirenz (EFV) for HIV treatment, RPV had a higher overall virological failure rate (14%) compared to EFV (8%), but the rates were similar in the later weeks (48-96).

Among patients with lower baseline viral loads (≤100,000 copies/ml), RPV showed fewer virological failures and less resistance development compared to those with higher viral loads, indicating that RPV may be more effective in patients with lower initial viral loads.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

96-Week resistance analyses of rilpivirine in treatment-naive, HIV-1-infected adults from the ECHO and THRIVE Phase III trials. Rimsky, L., Van Eygen, V., Hoogstoel, A., et al.[2020]

In silico simulations of cardiac action potentials revealed that the presence of cardiovascular disease significantly increases the risk of arrhythmic events induced by torsadogenic compounds, with congestive heart failure posing the highest risk.

Non-torsadogenic compounds did not induce early-afterdepolarizations (EAD) even in patients with cardiac risk factors, suggesting that these compounds may be safer in terms of arrhythmia risk, highlighting the importance of incorporating disease state modeling in drug safety assessments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of disease state on arrhythmic event detection by action potential modelling in cardiac safety pharmacology. Christophe, B., Crumb, WJ.[2019]

A study analyzing over 9 million adverse event reports identified 3,807 cases of torsades de pointes (TdP), with the highest risk associated with drugs like tolazoline, levomethadyl, and ibutilide, indicating a significant safety concern for these medications.

Notably, around half of the top drugs linked to TdP were not included in the established QT drug lists, suggesting that clinicians should be vigilant about these medications and that further research is necessary to understand their potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-induced torsades de pointes: Disproportionality analysis of the United States Food and Drug Administration adverse event reporting system. Wu, Z., Zhou, P., He, N., et al.[2022]

The CiPA Initiative aims to improve the evaluation of proarrhythmic risk in drugs by using a comprehensive approach that includes ionic current studies and in silico modeling, which helps predict potential heart rhythm issues.

The meeting highlighted the use of human induced pluripotent stem cell-derived cardiomyocytes and clinical ECG assessments to enhance the understanding of cardiac safety, indicating a shift towards more predictive and human-relevant testing methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting. Strauss, DG., Gintant, G., Li, Z., et al.[2020]

In a study of 792 HIV-infected patients, a nelfinavir-containing antiretroviral therapy was well tolerated, with only 7.1% needing to stop treatment due to toxicity, and 58.4% showing an immunological response after a median follow-up of 12 months.

While 52% of patients achieved low plasma HIV-1 RNA levels, a significant number experienced virological rebound, highlighting the need for new treatment options despite the initial benefits observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunological, virological and clinical response in patients infected with HIV after highly active antiviral therapy with nelfinavir: prospective cohort study]. de Alarcón, A., Viciana, P., Lozano, F., et al.[2013]

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