Electrophysiological Effects of Potential QT Prolonging Drugs

Since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence.

To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach.

This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals.

The risk of drug-induced Torsades de Pointes (TdP), a potentially fatal ventricular arrhythmia, has resulted in multiple drugs worldwide being removed from the market, as well as over 150 drugs being listed on CredibleMeds.org for QT prolongation or TdP association. In response, since 2005, FDA has required almost all new drugs be tested for their ability to prolong the QT interval through clinical studies. This requirement stems from the increased TdP risk QT interval prolongation can cause. However, the QT interval is an imperfect biomarker, as there are multiple drugs that can prolong the QT interval, without causing increased TdP occurrence. As such, numerous drugs labeled as causing QT prolongation, may in fact have no impact on TdP occurrence. While this labeling affects physician prescribing, it also has the potential to limit effective therapeutic options for patients.

To address this problem, FDA, in collaboration with multiple external partners, has led an initiative to combine novel preclinical in vitro experiments within silico modeling and simulation followed by pharmacodynamic electrocardiographic (ECG) biomarkers. The goal is to use these novel computational and analytical tools to better predict TdP risk (beyond just the QT interval) by focusing on understanding the underlying mechanisms and applying an integrated biological systems approach.

Recently, the International Council on Harmonization (ICH) released a new Guideline with updated Questions and Answers (Q\&As) to the clinical (ICH E14) and nonclinical (ICH S7B) Guidelines for assessing the QT prolongation and proarrhythmic risk of non-antiarrhythmic drugs. The Q\&A provides more guidance on the use of an integrated nonclinical analysis to support clinical QT assessment. This includes the comparison of the hERG safety margin of the investigational product to the safety margin of predominant hERG (the human Ether-à-go-go-Related Gene) blockers with a characterization of the concentration-QTc relationship based on a limited set of example drugs, i.e., ondansetron, moxifloxacin and dofetilide.

This clinical study consists of 2 parts: a 3-arm, 22-subject crossover study (Part 1) and a 4-arm, 22-subject crossover study (Part 2). These parts are included in the same protocol and study due to the similarity of the inclusion and exclusion criteria, similar procedures, and similar primary goals.

Part 1: Intermediate risk predominant hERG blocking drugs The FDA performed a literature review and identified 28 proarrhythmic drugs from available in vitro studies of cardiac ion channel IC50 (using HEK293 cells and the hERG 1a subunit). Two of these drugs, classified as intermediate risk "predominant hERG blocking" (pimozide and clarithromycin), have been identified as candidates for evaluation in Part 1. An aim of this study will be generating higher quality QT data on "intermediate risk" "predominant hERG" blocking drugs' effect on both electrocardiographic biomarkers, QTc and J-Tpeakc interval prolongation, at therapeutic and supratherapeutic exposures. These data will also be used to support assessment of the hERG safety margin threshold together with moxifloxacin, dofetilide, and ondansetron as described in the recently released ICH Q\&A's.

Part 2: Combination of hERG and multi-ion channel block Part 2 of this study will assess the effects of a mixed ion channel blocking drug, cobicistat, on the QTc and J-Tpeakc interval alone and in combination with a predominant hERG blocking drug (moxifloxacin). Clinical data with cobicistat, a structural analog of ritonavir used as a pharmacokinetic enhancer in various anti-viral regimens, has demonstrated QTc shortening and PR prolongation with supratherapeutic doses. Whether this is a results of late sodium block, calcium channel block, or other features is unclear. Additional clinical data with cobicistat alone or in combination with moxifloxacin will enhance our understanding of the effects of mixed ion channel blocking on electrocardiographic biomarkers (QTc and J-Tpeakc interval).

Eligibility Criteria:
Inclusion Criteria:

1. Subject has signed an IRB approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
2. Subject is a healthy non-smoker who weighs at least 50 kg (110 lbs) and has a body mass index of 18.5 to 33.0 kg/m2, inclusive, at Screening.
3. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, pulse oximetry, 12-lead ECG results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
4. Subject must have a negative test result for alcohol and drugs of abuse at screening and check-in days.
5. Subject must test negative for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by a rapid antigen test at check-in for all study periods.
6. Female subjects must be of non-childbearing potential (confirmed with follicle-stimulating hormone levels \> 40 mIU/mL) or, if they are of childbearing potential, they must: 1) have negative serum HCG at screening and check-in 2) have been strictly abstinent for 1 month before check-in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 3) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before check-in (Day -1) until at least 1 month after the end of the study.
7. Male subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee) from at least 1 month before check-in (Day -1) until at least 3 months after the last dose of study drug.
8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

Exclusion Criteria:

1. Subject has a 12-lead safety ECG result at Screening or check-in (Day -1) with evidence of any of the following abnormalities:

   * QT corrected interval (QTc) using Fridericia correction (QTcF) \>430 milliseconds (ms)
   * PR interval \>220 ms or \<120 ms
   * QRS duration \>110 ms
   * Second- or third-degree atrioventricular block
   * Complete left or right bundle branch block or incomplete right bundle branch block
   * Heart rate \<50 or \>90 beats per minute
   * Pathological Q-waves (defined as Q wave \>40 ms)
   * Ventricular pre-excitation
2. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsade de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects shall also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.
3. Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug. This includes prescription or nonprescription ophthalmic drugs. Note the only two drugs permitted are oral contraceptives and acetaminophen.
4. Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of dosing for this study.
5. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, electronic cigarettes) within 6 weeks of Screening. Subjects must refrain from using these throughout the study.
6. Subject has consumed alcohol, xanthine-containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 24 hrs of check-in. Subjects must refrain from ingesting these throughout the study.
7. Subject is unable to tolerate a controlled, quiet study conduct environment, including avoidance of music, television, movies, games, and activities that may cause excitement, emotional tension, or arousal during the prespecified time points (e.g., before and during ECG extraction windows).
8. Subject is unwilling to comply with study rules, including the study-specific diet, attempting to void at specified times (e.g., before ECG extraction windows), remaining quiet, awake, undistracted, motionless, and supine during specified times, and avoiding vigorous exercise as directed.
9. Subject has a history of consuming more than 14 units of alcoholic beverages per week within 6 months before Screening, has a history of alcoholism or drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine, or 1 ounce of spirits/hard liquor), or has a positive test result for alcohol or drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) at Screening or Check-in of each period.
10. Subject has a history or evidence of a clinically significant disorder, condition, or disease (e.g., cancer, human immunodeficiency virus \[HIV\], hepatic or renal impairment) that, in the opinion of the investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion. This includes subjects with any underlying medical conditions that the Investigator believes would put subjects at increased risk of severe illness from COVID-19 based on the Centers for Disease Control and Prevention (CDC) guidelines. The CDC lists cancer, chronic kidney disease, chronic obstructive pulmonary disease, immunocompromised state from solid organ transplant, severe obesity, serious heart conditions, sickle cell disease, pregnancy, smoking and type 2 diabetes mellitus as conditions that put subjects at increased risk. Additionally, the CDC lists asthma (moderate-to-severe), cerebrovascular disease, cystic fibrosis, hypertension, immunocompromised state or immune deficiencies, neurologic conditions such as dementia, liver disease, pulmonary fibrosis, thalassemia, BMI \> 25.0, and type 1 diabetes mellitus as conditions that might put subjects at increased risk.
11. Subject has any signs or symptoms that are consistent with COVID-19 per CDC recommendations. These include subjects with fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, or diarrhea may have COVID-19. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
12. Subject has known or suspected allergies or sensitivities to the study drug.
13. Subject has a history of thoracic surgery.
14. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
15. Subject has a skin condition likely to compromise ECG electrode placement.
16. Any individual with breast implants.
17. Subject has clinical laboratory test results (hematology, serum chemistry and urinalysis) at Screening or Check-In that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. Tests may be repeated once for confirmation.
18. Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
19. Subject has a mean systolic blood pressure \<90 or \>140 mmHg or a mean diastolic blood pressure \<50 or \>90 mmHg at either Screening or Check-in of Period 1.
20. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or is unlikely to complete the study due to poor venous access.
21. Female subject is currently pregnant or lactating or was within 3 months of the study.
22. Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days, or donated plasma within 7 days before Check-in of Period 1.
23. Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).
24. Subject undergoes genetic testing for CYP2D6 phenotype and is a "poor metabolizer" (only for Part 1).