The initial ICH E14 guidance described the thorough QT/QTc (TQT) study with the purpose of evaluating whether a new drug has effects on the QTc interval. Following its adoption, concentration-QTc (C-QTc) modeling was applied to data from TQT studies, and results were comparable with those based on a "by time point" analysis. In 2014, the IQ-CSRC study demonstrated that a small study in healthy subjects using C-QTc as the primary analysis could detect mild drug-induced QTc prolongation. The study led to the revision of the E14 guidance in 2015, allowing the use of C-QTc modeling to exclude a QTc effect at the threshold of concern, 10 ms. The 2015 revision was the starting point for the use of C-QTc modeling applied to data from first-in-human (FIH) studies with the intent to waive requests for a designated TQT study. The 2022 revision (S7B/E14 Q&A) brought non-clinical studies into the decision process for a "definitive" QT evaluation. In this manuscript, the emergence of C-QTc analysis applied to FIH studies with the intent to waive the TQT study is described, and a survey of FDA labels and reviews of approved drugs since 2015 is shared. The uptake has been modest, with only 30% of approved drugs for which a TQT study would be expected using this approach, while a TQT study has been conducted in ∼70% of development programs. It can be expected that the 2022 S7B/E14 revision will increase the number of programs for which a TQT study can be replaced.

e24005 Background: E7386 is a novel oral anticancer agent that inhibits the interaction between β-catenin and CREB-binding protein. Phase 1 studies provide an efficient approach to cardiac safety assessment by using data across a range of doses to model the concentration-QTc (C-QTc) relationship; such modeling enables early detection of cardiac risk. The analysis described herein was conducted to evaluate cardiac safety and assess the potential effect of E7386 on ECG parameters, including the QTcF interval. Methods: C-QTc analyses were performed using E7386 plasma concentrations and continuous Holter ECG data collected on C1D1 and C1D8 (at steady state) from two phase 1 monotherapy studies in patients (pts) with solid tumors: Study 101 (NCT03264664; data available from 25 pts treated with E7386 at doses ranging from 10-120 mg twice daily [BID]) and Study 103 (NCT03833700; data available from 18 pts treated at the E7386 monotherapy RP2D of 120 mg BID). The relationship between E7386 plasma concentrations and change-from-baseline QTcF (ΔQTcF) was investigated using a linear mixed-effects modeling approach. The concentration level at which the upper bound of the 2-sided 90% CI of model-predicted ΔQTcF exceeded 10 ms was determined. Results: E7386 showed no clinically significant impact on cardiac conduction parameters (PR and QRS intervals) or heart rate across the studied dose ranges. Observed changes on heart rate were minimal and unlikely to influence the C-QTc analysis. The absolute slopes of QTcF vs RR were minimal, indicating negligible effect on the C-QTc assessment. Consequently, additional heart rate correction methods were not warranted. Hysteresis was not present. Neither the fixed intercept nor the slope for the E7386 ─ C-QTc relationship were statistically significant. C-QTc analysis showed no clinically meaningful QTc effect (ΔQTcF >10 ms) for E7386 concentrations up to 2650 ng/mL in Study 103. Consistent results were seen in Study 101 with exclusion of a QTc effect up to E7386 concentrations of 2300 ng/mL. Results from the C-QTc analyses in Study 103 and 101 indicate substantial cardiac safety margins of ~5.70 and ~3.36‐fold, respectively, over corresponding clinical C max,ss values reported for the E7386 RP2D of 120 mg BID (Study 103, 464.8 ng/mL; Study 101, 684.0 ng/mL). Conclusions: Phase 1 C-QTc evaluations of E7386 offer critical insights on cardiac safety that inform dose selection and monitoring strategies for further clinical development. The predicted mean ΔQTcF and its 90% CI upper bound remained below 10 ms for concentrations up to 2650 ng/mL, based on C-QTc analysis of two phase 1 studies. No significant cardiac safety concerns were identified at the studied dose levels. Clinical trial information: NCT03264664 , NCT03833700 .

Sepiapterin and its major metabolite 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) bind to distinct variants of phenylalanine hydroxylase (PAH), which converts excess phenylalanine to tyrosine, thereby stabilizing, enhancing, and prolonging PAH activity. Sepiapterin was recently approved in Europe and the USA for the treatment of hyperphenylalaninemia patients with phenylketonuria, an inherent metabolic disease caused by PAH deficiency. A thorough QT study of sepiapterin in healthy volunteers at therapeutic (60 mg/kg) and supratherapeutic (120 mg/kg) doses was conducted to assess potential cardiovascular risks. Thirty-two participants were randomized into one of 12 sequences and received single doses of sepiapterin (60 or 120 mg/kg), moxifloxacin 400 mg, or placebo in separate periods. Sepiapterin had no effect on heart rate or cardiac conduction (PR/QRS interval). Saturable sepiapterin absorption was observed, which resulted in less than dose-proportional increase of sepiapterin and BH4 and limited the maximum plasma concentrations clinically achievable. Using concentration-QT analysis, the placebo-corrected change from baseline in QT interval corrected using Fridericia's formula (ΔΔQTcF) was -2.11 (90% CI: -3.44, -0.79) ms at geometric mean baseline-corrected BH4 Cmax (728 ng/mL) and -1.9 (-3.25, -0.56) ms at sepiapterin Cmax (2.08 ng/mL) at the supratherapeutic dose of 120 mg/kg. An effect on ΔΔQTcF exceeding 10 ms was excluded within the observed concentration range of baseline-corrected BH4 up to 1088 ng/mL and sepiapterin up to 5.77 ng/mL. The consistency of results from this study and the previous concentration-QTc analysis based on pooled data from multiple clinical studies demonstrated the reliability of using concentration-QTc for assessing cardiovascular risks in early clinical development.

CIN-102 is a deuterated form of domperidone in development for the treatment of acute, recurrent gastroparesis. This thorough QT study assessed the effects of CIN-102 on cardiac repolarization in 62 healthy volunteers. In this 4-period randomized crossover study, participants were administered single doses of 30-mg CIN-102 (representing therapeutic exposures), 100-mg CIN-102 (representing supratherapeutic exposures), placebo, and moxifloxacin (positive control). Continuous 12-lead electrocardiograms (ECGs) and time-matched blood samples were collected to determine plasma levels of deuterated domperidone and its major metabolites. The primary endpoint was placebo-corrected change-from-baseline QTc corrected by Fridericia's formula (ΔΔQTcF). By-time-point and concentration-QTc analyses excluded an effect on ΔΔQTcF exceeding 10 ms for both doses of CIN-102 at all time points up to deuterated domperidone plasma concentrations of ≈92  ng/mL (≈6 times the therapeutic steady-state concentration). There were no clinically relevant effects of CIN-102 on heart rate or cardiac conduction, and no deaths or serious adverse events occurred. This thorough QT study demonstrated that at doses producing therapeutic and supratherapeutic exposures, CIN-102 does not have a clinically meaningful effect on ECG parameters, including QT interval. This modified formulation of domperidone provides a potential gastroparesis treatment while decreasing the risk of QT prolongation associated with the traditional formulation of domperidone.

Givinostat is a class I/II histone deacetylase inhibitor indicated for Duchenne muscular dystrophy (DMD). The study evaluated the effect of therapeutic and supratherapeutic givinostat doses on the QT/QTc interval. Healthy volunteers received each treatment-givinostat hydrochloride monohydrate oral suspension as a therapeutic (100 mg) or supratherapeutic (300 mg) dose, placebo oral suspension, or moxifloxacin oral tablet (positive control, 400 mg)-according to a block randomization scheme. Cardiodynamic assessments were paired with pharmacokinetic samples. A small, clinically non-relevant effect on mean placebo-corrected, change-from-baseline QTcF (∆∆QTcF) of 5.5 ms was seen after givinostat 100-mg dose. Clinically relevant QTc prolongation was observed with the supratherapeutic dose, with a mild ∆∆QTcF increase of 13.6 ms. A delay of ≈3 h between Tmax and the largest effect on the QTc interval was seen for both doses. In the concentration-QTc analysis, an Emax model captured the data better than the prespecified linear model and showed that an effect on ∆∆QTcF exceeding 10 ms could be excluded within the full range of observed givinostat concentrations in this study and up to ≈745 ng/mL. Givinostat at the maximum labeled dose (up to 53.2 mg twice daily for DMD) is not expected to pose a QT prolongation risk.

Sorfequiline (TBAJ-876) is a novel diarylquinoline under development for tuberculosis. In a first-in-human, multiple-ascending-dose study, electrocardiogram and pharmacokinetic data were analyzed to assess cardiac repolarization. Placebo-corrected change-from-baseline in QTcF (ΔΔQTcF) ranged from -11.4 to +2.4 ms without dose dependency. Concentration-QTc modeling showed a shallow, non-significant slope. The predicted mean effect on ΔΔQTcF at the maximum geometric mean Cmax of sorfequiline's M3 metabolite was -1.1 ms (90% CI -9.5 to 7.4).CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06058299.

PURPOSE:Rusfertide, a hepcidin mimetic, is in clinical development for the treatment of polycythemia vera. This study evaluated the effect of rusfertide on cardiac repolarization. METHODS:A positive-controlled, randomized, double-blind, crossover study was conducted in healthy adults. Subjects received subcutaneous rusfertide 90 mg, matching subcutaneous placebo, and oral moxifloxacin. Subjects underwent continuous 12-lead Holter recording during each period. A central laboratory extracted up to 10 replicate electrocardiograms (ECGs) at each time point prior to and following treatment, paired with pharmacokinetic sampling. The primary analysis for Fridericia corrected QT interval (QTcF) was a mixed model for repeated measures with change from baseline QTcF (ΔQTcF) as the dependent variable; period, sequence, time, treatment, and time-by-treatment interaction as fixed effects; and baseline QTcF as a covariate. The relationship between rusfertide and metabolite concentrations and change-from-baseline QTcF was quantified using linear mixed-effects modeling. FINDINGS:Mean age and body mass index were 40.1 years and 25.4 mg/m2, respectively, with a slight majority of female (57%) and White (60%) subjects. Mean rusfertide plasma concentrations increased rapidly, with median peak of 4 hours. The geometric mean rusfertide peak concentration (Cmax) was 1100 ng/mL. Rusfertide did not have a clinically relevant effect on heart rate (HR) or cardiac conduction (PR and QRS interval). The least squares (LS) mean ΔQTcF on rusfertide closely followed the placebo pattern, and LS mean placebo-corrected ΔQTcF (ΔΔQTcF) varied from -2.0 to 1.8 ms. After 400 mg oral moxifloxacin, an increase of LS mean ΔΔQTcF was observed with a peak of 12.4, 12.4, and 11.2 ms at 2, 3, and 4 hours, respectively, with all three lower bounds of the 2-sided 90% confidence interval greater than 5 ms. Estimated population slope of the rusfertide concentration-QTc relationship was not statistically significant: 0.00042 ms per ng/mL (90% confidence interval [CI]: -0.001172 to 0.002013; P = 0.6624). Predicted ΔΔQTcF at the geometric mean Cmax was 0.04 ms (90% CI: -1.21 to 1.29). Overall, 24 of 60 subjects (40.0%) experienced treatment-emergent adverse events (TEAEs). All TEAEs were mild. TEAEs noted in ≥5% subjects were headache, nausea, injection site erythema, injection site pain, and influenza-like illness. There were no clinically significant changes in clinical laboratory, vital signs, ECG, or physical examination findings. IMPLICATIONS:Rusfertide had no clinically relevant effect on HR, cardiac conduction, or QTc. Rusfertide was well tolerated. An effect on ΔΔQTcF exceeding 10 ms could be excluded within the observed rusfertide plasma concentrations up to approximately 2130 ng/mL.

Concentration-QTc (C-QTc) analysis was accepted to serve as an alternative to the by-time point analysis with intersection-union test (IUT) as the primary basis for decisions to classify the arrhythmogenic risk of a drug by ICH E14 Q As (R3) in December 2015. Since then, this analysis method has been widely applied by industry as it significantly reduces the sample size to achieve the same power as with IUT. There are many model-based power calculation approaches available for C-QTc through simulation in the literature, however, there is still no standard method with a clear formula to determine the sample size for C-QTc analysis to exclude a small effect on the QTc interval. The current model-based simulation approaches are too complicated to prevent them from being widely used, which is not commensurate with the popular status. We have developed a systematic method based on t-tests to determine the sample size for different study designs using the C-QTc analysis method and applied it to many studies. The results of the sample sizes utilizing this method are consistent with simulation studies and validated by real analyses.

Introduction and Objective: Pemvidutide is a GLP-1/glucagon dual receptor agonist in development for the treatment of obesity and metabolic dysfunction-associated steatohepatitis. Pemvidutide reduces cardiovascular (CV) disease risk factors (excess adiposity, total and LDL cholesterol, cardio-inflammatory lipids, visceral adipose tissue, liver fat content). In this study, its effects on parameters of CV safety were assessed. Methods: Systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) and rate pressure product (RPP) were assessed in integrated analyses across 5 clinical trials. In a separate QT study, healthy volunteers receiving single ascending doses (SAD) up to 4.8 mg and multiple ascending doses (MAD) up to 3.0 mg once weekly for 12 weeks underwent continuous ECG recordings, and Friderica-corrected QT intervals (QTcF) were assessed by linear time-matched concentration-QTc analysis. Results: In integrated analyses, reductions in SBP and DBP up to 13.0 mmHg and 6.5 mmHg, respectively, were observed without dose-related or clinically meaningful effects on RPP or HR or imbalances in cardiac adverse events. In QTc analyses, mean (90% CI) predicted placebo-corrected change in QTcF (∆∆QTcF) was <10 ms at all pemvidutide concentrations (Figure 1). Conclusion: Pemvidutide reduces SBP and DBP without clinically meaningful effects on QTc or HR and no imbalances in cardiac adverse events. S. Tomah: Employee; Altimmune Inc. Stock/Shareholder; Altimmune Inc. J. James: Consultant; Altimmune Inc. S.K. Browne: Employee; Altimmune Inc. B. Darpo: None. M.S. Roberts: Employee; Altimmune Inc. J.J. Suschak: Employee; Altimmune Inc. L. He: None. J. Yang: Employee; Altimmune Inc. M. Harris: Employee; Altimmune Inc.

Vatiquinone, a 15-lipoxygenase inhibitor, is in development for patients with Friedreich ataxia. The study determined the effect of vatiquinone on electrocardiogram parameters. This was a 2-part, single-center, randomized, double-blinded, and placebo-controlled study. Part 1 used an adaptive approach to identify a supratherapeutic dose, while Part 2 evaluated the effect of vatiquinone on Fridericia corrected QT interval (QTcF). A safe and tolerated supratherapeutic dose of 1400 mg was identified. Concentration-QTcF analysis confirmed there was no statistically significant relationship between vatiquinone concentration and QTcF. QTcF effect (ie, ΔΔQTcF) exceeding 10 milliseconds was excluded for concentrations up to approximately 11,500 ng/mL. By-time-point analysis confirmed that least-squares mean ΔΔQTcF was below 10 milliseconds. Largest least-squares mean ΔΔQTcF of 1.5 milliseconds was observed at 2 hours after dosing. Vatiquinone did not have a clinically relevant effect on heart rate nor on cardiac conduction (PR interval and QRS interval). No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: –0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be −1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and −5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean C max was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from –7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with –3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration–QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (Delta Delta QTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (<= 279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day -1 baseline (triangle triangle HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were -15.1, -8.5, and -6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (triangle triangle PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.

Nonracemic amisulpride (SEP-4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP-4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled-release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24-hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non-human primates produced significantly greater D2R occupancies during a gradual 6-hour administration compared with a single bolus; (iii) concentration-occupancy curves were left-shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model-informed drug development to continue in Phase III using the non-bioequivalent CR formulation with diminished QT prolongation as dose-equivalent to the immediate release (IR) formulation utilized in Phase II.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Aim: This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor. Methods: Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity). Results: Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild). Conclusion: There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.

Objective: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). Methods: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (AQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. Results: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, AQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected AQTc with relacorilant was small and negative, whereas placebo-corrected AQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. Conclusion: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant. (c) 2023 AACE. Published by Elsevier Inc. This is an open access article under the CC BY license (http://

Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day −1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were −15.1, −8.5, and −6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.

Abstract This phase I thorough QTc, double‐blind, randomized, placebo‐ and positive‐controlled, parallel group, multiple‐dose study evaluated avacopan's effect on cardiac repolarization using concentration‐QTc (C‐QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time‐matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (−5.5 to 3.5 ms) was similar to placebo (−6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (−0.17 to 3.09) and 0.8 ms (−2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C‐QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine’s activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine’s effect on the QT interval and investigated its cardiac safety profile. C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90