Siponimod, through S1PR modulation, targets MS by inhibiting auto-reactive lymphocyte migration to the CNS and may have direct neurobiological effects.2,3 ... (2 mg) and supratherapeutic (10 mg) doses of siponimod versus placebo.
P 626
Placebo-like occurrence of atrioventricular blocks and sinus pauses: results from a siponimod QT/QTc study 1
1
1
1
2
3
4
P517
1
K. Shakeri-Nejad, B. Brendani, N. Pezous, L. Mooney, A. Juan, M. Allison, R.G. Perry, and E. Legangneux 1
Novartis Pharma AG, Basel, Switzerland; 2SeaView Research Inc., Miami, FL, United States; 3Celerion, Tempe, AZ, United States; 4Elite Research Institute, Miami, FL, United States
CONCLUSIONS • The limited effect of siponimod on PR, QRS and heart rate (HR) supports the benefit of the up-titration regimen in mitigating bradyarrhythmic effects. • Atrioventricular blocks (AVBs) and sinus pauses (SPs) were less frequent under siponimod than under placebo conditions. • All detected AVBs and the majority of SPs were observed during resting hours, associated with increased vagal tone. • These results are consistent with the physiological diurnal distribution pattern and should be taken into consideration to differentiate physiological versus drug-induced effects.
INTRODUCTION
Concentration-response analysis
• Siponimod, through S1PR modulation, targets MS by inhibiting auto-reactive lymphocyte migration to the CNS and may have direct neurobiological effects.2,3 • S1PR modulators including siponimod cause transient, dose-dependent decreases in HR and occasional asymptomatic first and second degree AVBs.4,5
• A weak positive correlation was observed between the siponimod plasma concentration and ΔHR (slope: 0.022; Figure 2C).
(A)
Siponimod 2 mg
Siponimod 10 mg
Regression
Figure 4. ΔΔHR by time point and treatment (A) DAY 10 (Therapeutic profile day; 2 mg) 2.5
90% of Confidence Limits
40
∆PR (ms)
• Dose titration with siponimod starting at 0.25 mg has shown to attenuate the bradyarrhythmia typically observed at treatment onset with S1PR modulators.6
OBJECTIVE
20
0
−10.0
0
(B)
50
100
150
200
250
Concentation (ng/mL)
∆∆HR (bpm)
∆QRS (ms)
20
(C)
2.0
2.0
2.0
2.0 + M-P
3.0
5.0
8.0 10.0 10.0 10.0 10.0
0 50
100
150
200
Concentation (ng/mL)
20
25
10.0 + M-P
–– Second degree AVBs (Mobitz 1) which were not already present at baseline were detected in 2 subjects — 1 receiving 2 mg of siponimod on Day 10 (3 episodes) and 1 receiving placebo on Day 18 (2 episodes).
0
−20 50
S-P
S-P
S-P
S-P + M-P
S-P
S-P
S-P
S-P
S-P
S-P
S-P
S-P + M-P
S-P
3
S-P
4
150
200
250
Figure 5. Summary of AVBs
S-P
5
S-P
6
S-P
7
R H *Moxifloxacin group was not included in the current analysis. A
S-P
8
S-P
9
S-P S-P + M 400 10 H
11
S-P
12
S-P
13
S-P
14
S-P
15
S-P
16
S-P
17
Time of event set up arbitrarily as precise time was not collected
Mean actual HR
Type of AVB
• Mean actual HR showed a similar pattern on Day ‐1 and Day 18 for both the treatments, whereas the increase in mean HR values with siponimod on Day 10 was less pronounced versus placebo.
S-P + M 400 18
19
H
D
32-39 End of Study Visit
A, admission to clinic for in-subject stay; D, discharge from clinic; H, Holter ECG assessment; M, moxifloxacin; M-P, moxifloxacin placebo; R, randomization, S-P, siponimod placebo. An up-titration regimen was employed for siponimod to stepwise establish steady state conditions for the clinical therapeutic dose of 2 mg. This was followed by further up-titration to establish steady state conditions for a supratherapeutic dose of 10 mg.
Assessments • 12-lead Holter recording for ECG measurement was performed starting from 1 h pre dose until 24 h post dose on Day -1 (baseline), and at the therapeutic (Day 10) and supratherapeutic (Day 18) doses on-treatment assessment days. • Chronotropic/dromotropic effects were analysed based on timematched changes from baseline for ECG variables PR, QRS and HR (i.e. ΔPR, ΔQRS and ΔHR, respectively) on Days 10 and 18 (Time-points: 0.5, 1, 2, 3, 4, 6, 12 and 24 h post dose) supported by categorical outlier and concentration-response analyses. • For the categorical outlier analysis the following criteria were defined: – PR change from baseline: more than 25% increase leading to PR > 200 ms. – QRS change from baseline: more than 25% increase leading to QRS > 120 ms. – HR changes from baseline: more than 25% decrease from baseline to a HR < 50 beats per minute (bpm) or a more than 25% increase from baseline reflecting a HR > 100 bpm. • The frequency of the SPs (defined by RR > 2 s) and second or third degree AVBs was determined by treatment group, treatment day and diurnal distribution, i.e. resting hours (11:00 PM–07:00 AM [8 h]) and non-resting hours (07:00 AM and 11:00 PM [16 h]). • Each second degree AVB was characterized for type and the conduction ratio.
• The study groups were well balanced with regards to age, gender, race and BMI.
Effects on ECG variables
5193 a) : Placebo/Day -1
Siponimod
(A) DAY -1 (Baseline)
Placebo
75
• The overall incidence of treatment-emergent HR increases > 25% to values > 100 bpm was low and observed only in 2 subjects in the placebo group (Day 18). The observed episodes in the placebo group were asymptomatic.
5391 c) : Placebo/Day 18
5411 d) : Placebo/Day -1
5424 e) : Siponimod 2 mg/Day 10 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7
70
Clock Time (24 h)
Patient 5391 and 5424 did not have AVBs at baseline. AVBs, atrioventricular blocks. ‡
65
• SPs (RR > 2s) were detected in 11 subjects — 10 in placebo group and 1 in siponimod group (Day 10); predominantly during nocturnal hours (Figure 6).
60 0
5
10
Time (h)
15
20
–– SPs (RR > 2s) which were not already present at baseline were detected in 3 subjects — 1 receiving 2 mg of siponimod on Day 10 and 2 receiving placebo.
25
(B) DAY 10 (Therapeutic profile day; 2 mg)
Figure 6. Summary of SPs (RR > 2s)
75
5121 : Siponimod/Day 10 (Long. RR = 2.25)
07:41
70
65
08:08
5193 : Placebo/Day -1 (Long. RR = 2.07)
08:10
5227 : Placebo/Day -1 (Long. RR = 2.01)
08:12
5228 : Placebo/Day -1 (Long. RR = 2.16)
10
Time (h)
15
20
25
2
1
5346 : Placebo/Day -1 (Long. RR = 2.19)
08:03
5
1
1
60 0
6
2
1
‡‡
1
5391 : Placebo/Day 18 (Long. RR = 2.17)
08:08
1
‡‡
(C) DAY 18 (Supratherapeutic profile day; 10 mg) 75
08:33
5398 : Placebo/Day -1 (Long. RR = 2.62)
08:33
5398 : Placebo/Day 10 (Long. RR = 2.5)
1 1
08:33
5398 : Placebo/Day 18 (Long. RR = 2.51)
08:12
5432 : Placebo/Day -1 (Long. RR = 2.15)
65
08:13
5433 : Placebo/Day -1 (Long. RR = 2.34)
08:18
5438 : Placebo/Day -1 (Long. RR = 2.13)
1 2
1 1
70
1
1
1
1 1
60
6230 : Placebo/Day 10 (Long. RR = 2.22)
08:16
1
‡‡
0
5
10
Time (h)
15
20
25
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23
0
1
2
3
4
5
6
Clock Time (24 h) Patient 5121, 5391 and 6230 did not have SPs at baseline. SPs, sinus pauses.
‡‡
Time-matched change from baseline in HR (ΔHR) • Day 10: ΔHR in siponimod group differ significantly (range: −2.24 to 2.28 bpm; mean reduction was highest at 6 h post dose) versus placebo group (range: 3.33 to 5.84 bpm). • Day 18: ΔHR ranged from 6.68 to 8.05 bpm with siponimod versus 5.45 to 7.86 bpm with placebo.
References
Disclosures
1. 2. 3. 4. 5. 6.
K. Shakeri-Nejad, B. Brendani, N. Pezous, L. Mooney and E. Legangneux are employees of Novartis.
Selmaj K, et al. Lancet Neurol. 2013;doi: 10.1016/S1474–4422(13)70102-9. Choi JW, et al. Proc Natl Acad Sci U S A. 2011;108:751– 56. Jackson SJ, et al. J Neuroinflammation. 2011;8:76. Gergely P, et al. Br J Clin Pharmacol. 2012;167(5):1035–47. Kappos L, et al. N Engl J Med. 2010; 362(5): 387–401. Legangneux E, et al. Br J Clin Pharmacol. 2013;75(3):831–41.
‡
‡
Categorical analysis • No treatment-emergent increase in PR (PR of > 25% to a value > 200 ms) or QRS (QRS of > 25% to a value >120 ms) or decrease in HR (> 25% to a value < 50 bpm) from baseline in placebo and siponimod treatment groups was observed on the therapeutic (Day 10) and supratherapeutic (Day 18) on-treatment assessment days.
5346 b) : Placebo/Day -1
Figure 3. Mean actual HR values per treatment
HR (bpm)
• The mean age (SD) of the study population was 35.0 (7.6) years (range: 18 to 45 years). The proportion of male subjects was higher (89%) than females (11%). The majority of subjects were Caucasians (n=268 [88%]). Mean (SD) body mass index (BMI) of the population was 26.1 (2.6) kg/m2 (BMI range 18 to 30 kg/m2).
Second degree AVB, Type II or 2:1
–– Day ‐1 (Baseline): ~60 to 68 bpm (for both groups; Figure 3 A). –– Day 10 (Therapeutic profile day; 2 mg): ~61 to 67 bpm (siponimod group) versus ~65 to 74 bpm (placebo group; Figure 3 B). –– Day 18 (Supratherapeutic profile day; 10 mg): ~67 to 76 bpm (for both groups; Figure 3 C).
RESULTS Subject demographics and baseline characteristics
First degree AVB (PR > 200 ms) Second degree AVB, Type I
• Mean actual HR values between 0.5 and 4 h post dose to 6 h post dose were increased from:
HR (bpm)
S-P
HR (bpm)
S-P
*Moxifloxacin Group (dose in mg; N = 95)
S-P
100
Concentation (ng/mL)
S-P
Time (h)
Effects on AVBs and SPs
20
Placebo Group (N = 94)
S-P
10
• Second degree AVBs were detected in a total of 5 subjects — 4 in the placebo group and 1 in the siponimod group (Day 10); all during resting hours (Figure 5).
0
S-P
5
250
eqn: Y=3.954 + 0.022*X (R-Square = 0.0288)
2
15
−5.0 −7.5
40
∆HR (bpm)
0.25 0.25 0.5 0.75 1.25 2.0
1
25
−2.5
0
0
Siponimod Group (doses in mg; N = 92)
−1
20
0.0
eqn: Y=0.127 + −0.003*X (R-Square = 0.0058)
Figure 1. Study design
−2
Time (h)
15
2.5
−5
• Eligible subjects (N = 281) were randomized to three cohorts (Figure 1).
−44 Study Day
10
−10.0
• The QT/QTc study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin controlled multiple-dose study in healthy subjects.
S-P
5
(B) DAY 18 (Supratherapeutic profile day; 10 mg)
40
Study design and subjects
S-P
−5.0 −7.5
eqn: Y=1.366 + −0.004*X (R-Square = 0.0007)
METHODS
S-P
−2.5
−20
• Comparison with placebo was performed to better differentiate between treatment-related and physiological effects.
S-P
0.0
0
• To present the chronotropic/dromotropic effects and the frequency, type and diurnal distribution pattern of AVBs and SPs at therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod versus placebo.
S-P
• Day 18 : The highest effect of siponimod on ΔΔHR was observed at 1 h post dose with a maximum mean change of +2.55 bpm (Figure 4B).
Figure 2. Concentration response analysis for time-matched change from baseline in (A) PR, (B) QRS and (C) HR versus concentration for siponimod Placebo
• Day 10 : The highest effect of siponimod on ΔΔHR was observed at 6 h post dose with a maximum mean change of −8.08 bpm (Figure 4A).
∆∆HR (bpm)
• Siponimod (BAF312) is a next generation, once daily, orally administered, sphingosine 1–phosphate (S1P) receptor (S1PR) modulator with selectivity at the S1P1 and S1P5 receptors, currently in Phase III development for secondary progressive multiple sclerosis (MS).1
• No positive correlation was observed between the siponimod plasma concentration and the time-matched change from baseline in PR (ΔPR; slope: -0.004) or QRS (ΔQRS; slope: -0.003) (Figure 2, A and B).
Placebo corrected time-matched change from baseline in HR (ΔΔHR)
• Overall, no trend for the frequency or duration of SPs could be detected between the treatment groups and dose levels. • All observed second degree AVBs and SPs were asymptomatic and were not considered to be of clinical relevance.
Downloading data may incur costs which can vary depending on your service provider and may be high if you are using your smartphone abroad. Please check your phone tariff or contact your service provider for more details.
A. Juan, M. Allison and R.G. Perry received support from Novartis as employees of the Contract Research Organisations. Scan to download a reprint of this poster
This study was funded by Novartis Pharma AG, Basel, Switzerland | Poster presented at the European Committee for Treatment and Research in Multiple Sclerosis | 2 – 5 October 2013, Copenhagen, Denmark
7
