Lack of ECG effects of BMS-986165, an oral, selective tyrosine kinase 2 (TYK2) inhibitor: results from a thorough QT study in healthy subjects Fall Clinical Dermatology Conference • October 17–20, 2019 • Las Vegas, NV, USA IG Girgis,1 A Chimalakonda,1 JP Jones III,2 R Dockens,1 D Marchisin,1 R Darbenzio,1 S Singhal,1 J Throup,1 S Banerjee1 1Bristol-Myers Squibb, Princeton, NJ, USA; 2PRA Health Sciences, Blue Bell, PA, USA • TYK2, an intracellular signaling enzyme, activates signal transducer and activator of transcription (STAT)–dependent gene expression and the functional responses of interleukin (IL)-12, IL-23, and Type I interferons, which are involved in the pathogenesis of psoriasis and other immune-mediated disorders.1–6 • BMS-986165 is an oral, selective inhibitor of TYK2. • In a 12-week, placebo-controlled, Phase 2 trial in patients with moderate to severe plaque psoriasis, BMS-986165 demonstrated an acceptable safety profile, and 67–75% of patients achieved Psoriasis Area and Severity Index 75 at Week 12 (primary endpoint) at doses 3 mg twice daily versus 7% with placebo (P0.001).7 • In patients treated with the highest dose (12 mg once daily), the predicted mean maximum concentration (Cmax) at steady state was 93.9 ng/mL, and no cardiovascular (including electrocardiogram [ECG]) abnormalities were reported.7 INTRODUCTION • To determine the effect of BMS-986165 plasma concentrations on the QT interval corrected for heart rate (HR) using Fridericia’s method (QTcF), and on other 12-lead ECG-derived endpoints, in healthy subjects. OBJECTIVE Study design • This study used a randomized, double-blind, positive- and placebo-controlled, 4-period crossover design (Figure 1). • Eligible subjects were randomized according to a 4-sequence Williams Design to receive 1 sequence of 4 treatments (all oral single doses): ○ placebo BMS-986165 ○ 12 mg BMS-986165 (a potential therapeutic dose) ○ 36 mg BMS-986165 (supratherapeutic dose) ○ 400 mg moxifloxacin (positive control). • Subjects fasted for approximately 10 hours prior to and 4 hours after study drug was administered on Day 1 of each of the 4 treatment periods (Days 1, 6, 11, and 16); there was a 5-day washout between each period. Study population • Key inclusion criteria: ○ healthy male and female subjects ○ age 18–50 years at screening ○ body mass index 18.0–32.0 kg/m2 and body weight 50 kg at screening ○ normal renal function (estimated glomerular filtration rate 80 mL/min/1.73 m2) at screening. • Key exclusion criteria: ○ a personal history of clinically relevant cardiac disease ○ history of hypokalemia, personal history or family history of prolonged QT interval, or family history of sudden cardiac death at a young age ○ use of concomitant medications that prolong the QT/QTc interval within 4 weeks (or 5 half-lives) prior to study drug administration ○ second- or third-degree heart block at screening or baseline (Day -1) ○ any history or risk of tuberculosis ○ a known or suspected autoimmune disorder. Study assessments • On Day 1 of each treatment period, following a 10-minute supine or semi-recumbent rest period, serial 12-lead ECG measurements were extracted from 24-hour continuous recordings using Holter monitors in up to 10 replicates at 3 time points prior to dosing and at time points paired with pharmacokinetic sampling up to 24 hours post-dose. • Physical examination, vital sign measurements, clinical laboratory evaluations, and safety ECGs were performed at selected times throughout the dosing interval. • Safety was assessed by adverse event (AE) reporting throughout the study. Study endpoints • The primary endpoint was placebo-adjusted change from baseline (i.e. pre-dose on Day 1 per treatment period) in QTcF (QTcF). METHODS Study population • A total of 40 subjects were screened and randomized and 38 subjects completed the study; 2 subjects were discontinued (1 due to an AE and 1 for other reasons). • Demographic and other baseline characteristics are summarized in Table 1. • Baseline mean ECG parameters were within ranges for a healthy population (HR 61.7–63.5 beats per minute [bpm], QTcF 399.3–400.4 msec, PR 147.5–149.6 msec, QRS 104.0–104.6 msec). Change from baseline in QTcF • The pattern of mean QTcF observed for BMS-986165 closely followed that of placebo and did not suggest an effect on cardiac repolarization (Figure 2). • The largest mean QTcF with BMS-986165 at 2 hours post-dose was 0.8 msec (90% CI: -0.86 to 2.49) for the 12-mg dose and 3.0 msec (90% CI: 1.32 to 4.68) for the 36-mg dose. • The relationship between BMS-986165 plasma concentration and QTcF was adequately described by a linear mixed-effects model (Figure 3). ○ Concentration–QTcF analysis predicted the exclusion of QTcF 10 msec for BMS-986165 plasma concentrations of at least 500 ng/mL, which is 5× higher than Cmax at the highest dose studied in Phase 2 (12 mg once daily). • Assay sensitivity was demonstrated by the effects of moxifloxacin. ○ A clear increase in mean QTcF was observed (peak at 2 hours post-dose: 12.9 msec [90% CI: 11.24 to 14.56]) (Figure 2). ○ The lower bound of the 2-sided 90% CI of the predicted effect at the observed geometric mean Cmax was 5 msec and the slope of the concentration–QTcF relationship was statistically significant (Figure 4). RESULTS References 1. Watford WT et al. Immunol Rev. 2004;202:139-156. 2. Tokarski JS et al. J Biol Chem. 2015;290:11061-11074. 3. Volpe E et al. Nat Immunol. 2008;9:650-657. 4. Geremia A et al. J Exp Med. 2011;208:1127-1133. 5. Tucci M et al. Clin Exp Immunol. 2008;154:247-254. 6. Lazear HM et al. Immunity. 2015;21:15-28. 7. Papp K et al. N Engl J Med. 2018;379:1313-1321. Acknowledgments This study was sponsored by Bristol-Myers Squibb. Professional medical writing and editorial assistance was provided by Catriona McKay, PhD, at Caudex and was funded by Bristol-Myers Squibb. Disclosures IGG, AC, RDo, DM, RDa, SS, JT, SB: employees, shareholders: Bristol-Myers Squibb. JPJ III: employee: PRA Health Sciences, which has a contract with Bristol-Myers Squibb on clinical development of BMS-986165. Previously presented at the European Academy of Dermatology and Venerology (EADV), held October 9–13, 2019. Change from baseline in HR • BMS-986165 at doses of 12 mg and 36 mg had no clinically relevant effect on HR or ECG parameters. ○ The greatest mean HR of 4.0 bpm (90% CI: 2.57 to 5.53) was observed 1 hour post-dose with the highest dose of BMS-986165 (36 mg; Figure 5). ○ BMS-986165 had no effect on PR and QRS intervals (data not shown). Overall safety • Most AEs were mild in intensity and all treatment-emergent AEs had resolved by the end of study (data not shown). • The most common AE related to BMS-986165 treatment was headache. • Key secondary endpoints: ○ QTcF for moxifloxacin (positive control) ○ change from baseline and placebo-corrected change from baseline for HR, QRS, and PR intervals (HR, QRS, and PR). Statistical analysis • A total of 40 subjects (10 per treatment sequence) were screened and randomized to ensure 32 subjects with data from all treatment periods. ○ A sample size of 32 provided 95% power to exclude that BMS-986165 caused more than a 10-msec QTc effect at clinically relevant plasma levels, as shown by the upper bound of the 2-sided 90% confidence interval (CI) of QTcF at the observed geometric mean Cmax of BMS-986165. ○ To demonstrate assay sensitivity with exposure–response analysis, it had to be shown that the QTcF of a single dose of 400 mg moxifloxacin exceeded 5 msec. • The primary analysis was based on exposure–response modeling of the relationship between BMS-986165 and its metabolites and QTcF with the intent to exclude an effect 10 msec at clinically relevant plasma concentrations. • Assay sensitivity was evaluated by an exposure–response analysis of the effect on QTcF of moxifloxacin using a similar model. • Secondary analyses of the effect of BMS-986165 on QTcF, HR, QRS, and PR were evaluated at each post-dose time point using the Intersection Union Test. • This study demonstrated that the oral, selective TYK2 inhibitor BMS-986165, at single doses of 12 mg (therapeutic) and 36 mg (supratherapeutic), did not have a clinically relevant effect on ECG parameters, including QTcF and HR, in healthy subjects. • Based on this analysis, a clinically meaningful QTcF prolongation 10 msec can be excluded for BMS-986165 plasma concentrations of at least 500 ng/mL. CONCLUSIONS 15 10 5 0 -5 � � Q Tc F (m se c) Time post-dose (hours) 2412106432.521.510.5 BMS-986165 12 mg BMS-986165 36 mg Moxifloxacin Figure 2: Placebo-corrected QTcF over time (QT/QTc set; N=40). Least squares mean and 90% CIs were based on a linear mixed-effects model: QTcF = period + sequence + time + treatment + time*treatment + baseline QTcF. An unstructured covariance structure was used to specify the repeated measures (time for subjects within period). Baseline was defined as the mean of the 4 pre-dose values on Days 1, 6, 11, and 16 in each corresponding treatment period. The black dotted line indicates the threshold of 10 msec. QT/QTc analysis set: all subjects in the safety set with measurements at baseline and on-treatment with at least 1 post-dose time point with a valid QTcF; all 40 subjects met the criteria to be included in the QT/QTc analysis set. QTcF=change in QTcF; QTcF=change from baseline in QTcF; CI=confidence interval. 10 5 0 -5 � � Q Tc F (m se c) 0 100 200 300 400 500 BMS-986165 concentration (ng/mL) Figure 3: Model-predicted and observed mean (90% CI) placebo-corrected QTcF across deciles of plasma concentrations for BMS-986165 (PK/QTc set; N=40). Prediction was based on the model QTcF = 0.19 + [concentrations of BMS-986165*0.0059]. The pink-filled circles with vertical bars denote the observed mean QTcF with 90% CI displayed at the median plasma concentration within each decile for BMS-986165. The solid black line with grey shaded area denotes the model-predicted QTcF with 90% CI. The horizontal pink line with notches shows the range of concentrations divided into deciles for BMS-986165. The black dotted line indicates the threshold of 10 msec. The distance between each decile represents the point at which 10% of the data are present; the first notch to second notch denotes the first 10% of the data; the second notch to third notch denotes 10–20% of the data; and so on. PK/QTc analysis set: all subjects in both the PK and QT/QTc sets with at least 1 pair of post-dose PK and QTcF data from the same time point (PK set: all randomized subjects who took at least 1 dose of BMS-986165 or moxifloxacin and had at least 1 evaluable PK concentration); all 40 subjects met the criteria to be included in the PK and PK/QTc analysis sets. QTcF=change from baseline in QTcF; CI=confidence interval; PK=pharmacokinetic. 20 15 10 5 0 � � Q Tc F (m se c) 0 500 1000 1500 2000 2500 Moxifloxacin concentration (ng/mL) 3000 Moxifloxacin Figure 4: Predicted placebo-corrected QTcF interval at geometric mean peak moxifloxacin concentrations (PK/QTc set; N=40). Prediction was based on the model ΔΔQTcF = 3.98 + concentrations of moxifloxacin*0.0045. The solid black line with grey shaded area denotes the model-predicted mean (90% CI) QTcF. The purple diamond with shaded bands denotes the estimated mean (90% CI) QTcF at the geometric mean (90% CI) Cmax of moxifloxacin. The black dotted line indicates the threshold of 10 msec. PK/QTc analysis set: all subjects in both the PK and QT/QTc sets with at least 1 pair of post-dose PK and QTcF data from the same time point (PK set: all randomized subjects who took at least 1 dose of BMS-986165 or moxifloxacin and had at least 1 evaluable PK concentration); all 40 subjects met the criteria to be included in the PK and PK/QTc analysis sets. QTcF=change from baseline in QTcF; CI=confidence interval; Cmax=maximum concentration; PK=pharmacokinetic. 5 0 -5 � � H R (b pm ) Time post-dose (hours) 2412106432.521.510.5 BMS-986165 12 mg BMS-986165 36 mg Moxifloxacin Figure 5: Placebo-corrected HR over time (QT/QTc set; N=40). Least squares mean and 90% CI based on a linear mixed-effects model: ΔHR = period + sequence + time + treatment + time*treatment + baseline HR. An unstructured covariance structure was used to specify the repeated measures (time for subjects within period). Baseline was defined as the mean of the 4 pre-dose values on Days 1, 6, 11, and 16 in each corresponding treatment period. The black dotted line indicates the reference line of 0 bpm. QT/QTc analysis set: all subjects in the safety set with measurements at baseline and on-treatment with at least 1 post-dose time point with a valid QTcF; all 40 subjects met the criteria to be included in the QT/QTc analysis set. HR=change in heart rate; HR=change from baseline in heart rate; QTcF=change from baseline in QTcF; bpm=beats per minute; CI=confidence interval; HR=heart rate. Screening (Days -28 to -1) Period 1 (Days 1–5) Period 2 (Days 6–10) Period 3 (Days 11–15) Period 4 (Days 16–20) Discharge (Day 21) Follow-up phone call (Day 26 ± 2) First study treatment Second study treatment Third study treatment Fourth study treatment Figure 1: Study design. Subjects were randomly assigned to 1 of 4 treatment sequences that included placebo, BMS-986165 12 mg, BMS-986165 36 mg, and moxifloxacin according to the Williams Design; 10 subjects were assigned to each treatment sequence. Table 1: Summary of demographics and baseline characteristics. Safety set (N=40) Sex, n (%) Male 28 (70.0) Female 12 (30.0) Race, n (%) White 12 (30.0) Black or African American 27 (67.5) Asian 1 (2.5) Age (years), mean (SD) 33.3 (8.9) BMI (kg/m2), mean (SD) 26.5 (3.1) The safety set included all randomized subjects who took at least 1 dose of a study treatment; all 40 subjects met the criteria to be included in the safety analysis set. BMI=body mass index. Scientific Content On-demand Copies of this poster obtained through Quick Response (QR) code are for personal use only and may not be reproduced without permission from Fall Clinical Dermatology Conference and the authors of this poster. Links are valid for 30 days after the congress presentation date. 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