Zelicapavir's Effect on Heart Rhythm

Recruiting at 1 trial location

Overseen By Paola Castellotti, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Enanta Pharmaceuticals, Inc

Trial Summary

What is the purpose of this trial?

The purpose of the study is to assess the effect of a therapeutic and supratherapeutic dose of zelicapavir on the corrected cardiac QT interval relative to a placebo and positive control in healthy participants.

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.

What data supports the idea that Zelicapavir's Effect on Heart Rhythm is an effective drug?

The available research does not provide any data on Zelicapavir's Effect on Heart Rhythm as an effective treatment. The studies mentioned focus on other drugs and their effects on HIV treatment, not on Zelicapavir or its impact on heart rhythm. ^{1 2 3 4 5}

What safety data exists for Zelicapavir regarding heart rhythm effects?

The provided research does not specifically mention Zelicapavir, EDP-938, or EP 023938. However, it discusses general cardiac adverse effects and safety assessments for drugs, including the creation of a database for predicting cardiac adverse effects, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) for evaluating proarrhythmic risk, and a study on drug-induced torsades de pointes. These resources may provide a framework for understanding potential cardiac risks associated with new drugs like Zelicapavir. ^{6 7 8 9 10}

Is the drug Zelicapavir a promising treatment for heart rhythm issues?

The provided research articles do not mention Zelicapavir or its effects on heart rhythm. Therefore, we cannot determine if Zelicapavir is a promising treatment for heart rhythm issues based on this information. ^{7 11 12 13 14}

Research Team

Enanta Pharmaceuticals, Inc

Principal Investigator

Enanta Pharmaceuticals, Inc

Eligibility Criteria

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 between 18 and 65 years old.

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

Treatment Details

Interventions

• Zelicapavir (Other)

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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 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]

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 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]

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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Are adverse events of nevirapine and efavirenz related to plasma concentrations? [2022]

2. Spain 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]. [2013]

3. England 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. [2013]

4. England pubmed.ncbi.nlm.nih.gov

The maraviroc expanded access program - safety and efficacy data from an open-label study. [2020]

5. England 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. [2020]

6. Netherlands 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. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

The anti-influenza drug oseltamivir reduces atrial fibrillation in an experimental whole-heart model. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Drug-induced torsades de pointes: Disproportionality analysis of the United States Food and Drug Administration adverse event reporting system. [2022]

9. England 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. [2014]

10. Switzerland 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. [2020]

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

Electrophysiologic Changes in the Human Heart Produced by Enalaprilat (Angiotensin-Converting Enzyme Inhibitor). [2019]

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

An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. [2022]

13. Belgium pubmed.ncbi.nlm.nih.gov

Electrophysiological effects of carocainide (770207) on the dog heart. [2014]

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

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