Evaluation of Efficacy and Safety of THRV-1268 in Long QT Syndrome Type 2 (LQTS 2)

Inclusion criteria

• Male and female participants over 15 years of age at Screening (at least the first 5 participants enrolled in Part A must be 18 years of age or older).
• LQTS 2 genotype: Demonstration of KCNH2 mutation by clinical laboratory test result that is autosomal dominant (heterozygous) and considered to be pathologic or likely pathologic can be included after approval from the sponsor medical monitor or qualified delegate.
• QTcF interval >480 ms and ≤600 ms based on Screening ECG.
• Body weight of at least 45 kg with body mass index between 18.0 and 40.0 kg/m2, inclusively at Screening.
• Male and female participants of childbearing potential must agree to use highly effective contraception throughout the duration of the study.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Participants age 15 to <18 years capable of providing signed assent.

Exclusion criteria

• Within 2 months prior to Screening, Participant has a history of an aborted cardiac arrest, ICD implantation, or syncopal episode due to a ventricular arrhythmia. Participants can be enrolled after the 2-month period has lapsed.
• History of structural or functional cardiovascular disease, myocardial infarction or stroke or transient ischemic attack (TIA), atrial fibrillation or atrial flutter, heart failure, bundle branch block, angina pectoris, or hemodynamically significant ventricular tachycardia not due to TdP
• Active or known liver disease.
• Active or past oncologic disease, except for non-melanoma skin cancer.
• Advanced pulmonary disease that requires more than a steroid inhaler.
• Pulmonary artery hypertension.
• Is pregnant, lactating, or breastfeeding, or planning to become pregnant.
• Has a positive result for the urine pregnancy test at the Screening Visit or the serum pregnancy test at the Day -7 Visit.
• Clinically significant abnormal findings on the physical examination or medical history during Screening or Day -21 as deemed by the investigator.
• Has experienced an acute illness that has resolved in less than 14 days before the first study drug dose or has had a major illness or hospitalization within 1 month before the first study drug dose.
• Has a recent history of alcohol or substance abuse that would pose a risk for the participant's safety and compliance with the study protocol, in the opinion of the investigator.
• Has a pacemaker or ICD that is actively used for ventricular pacing.
• Is currently taking or anticipates the use of any restricted drugs
• Is considering or scheduled to undergo any elective surgical procedure during the study.
• Current participation or recent within 1 month of participating in another interventional clinical study.
• Screening Visit diastolic blood pressure >95 mm Hg, systolic blood pressure <90 or >150 mm Hg.
• At Screening, if the 12-lead triplicate ECG demonstrates any of the following: PR >280 ms; QRS >110 ms, or QTcF >600 ms or ≤480 ms; bundle branch block or significant ST-T wave abnormalities or flat T waves that could interfere with QT analysis. HR <50 bpm, unless receiving a beta-blocker in which case <40 bpm, or HR >100 bpm at rest.
• Atrial pacing rate set to >80 bpm in those participants with atrial pacing.
• Abnormal renal function with an eGFR of <70 mL/min/1.73 m2 (with eGFR calculated by the CKD-EPI formula at Screening). One retest of the exclusionary eGFR value is allowed at the discretion of the investigator.
• Has abnormal liver function tests:

• ALT, AST, GGT, ALP > 1.5 the ULN.
• Total bilirubin >ULN.
• INR >1.2 ULN (requires measurement of prothrombin time (PT)).
• Has clinically significant abnormality in serum chemistry values at Screening for hemoglobin, potassium, magnesium, or calcium levels as determined by the investigator. A single repeat test and/or correction of abnormal values (e.g., electrolyte repletion) is permitted at the investigator's discretion prior to enrollment.
• Any participant, who, for any reason, is deemed by the investigator to be inappropriate for this study or has any condition which would confound or interfere with the evaluation of the safety, tolerability, or efficacy of the investigational medicinal product (IMP) or prevent compliance with the study protocol.
• Consumes on average more than 21 standard alcoholic drinks per week in men and 14 standard drinks per week in women over the last 2 years.