BAF312 (Siponimod) : 2.7.2 Summary of Clinical Pharmacology Studies in Multiple Sclerosis
BAF312 (Siponimod) : 2.7.2 Summary of Clinical Pharmacology Studies in Multiple Sclerosis
BAF312 (Siponimod) : 2.7.2 Summary of Clinical Pharmacology Studies in Multiple Sclerosis
BAF312 (siponimod)
BAF312A
Property of Novartis
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May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Table of Contents
Table of Contents................................................................................................................... 2
Abbreviations......................................................................................................................... 8
1 Background and Overview ................................................................................................. 12
1.1 General overview ........................................................................................................ 12
1.2 Summary of overall conclusions ................................................................................. 14
1.2.1 Pharmacokinetics ............................................................................................. 14
1.2.2 Drug interactions ............................................................................................. 17
1.2.3 Pharmacodynamics .......................................................................................... 19
2 Summary of Results of Individual Studies ......................................................................... 22
2.1 In vitro, ex vivo, and in silico studies using human biomaterials ............................... 22
2.1.1 Plasma protein binding .................................................................................... 22
2.1.2 Hepatic metabolism and drug interaction studies ............................................ 23
2.1.3 Studies using other human biomaterials .......................................................... 23
2.2 Studies in healthy subjects .......................................................................................... 24
2.2.1 Single ascending dose study ............................................................................ 24
2.2.2 Multiple ascending dose studies ...................................................................... 25
2.2.3 Dose titration study .......................................................................................... 26
Table 2-1 Study A2107 Dose Titration Schedule ..................................... 27
Figure 2-1 Mean daily minimum heart rate after once daily
dosing administered over 12 days as a fixed
dose or uptitration to 10 mg ................................................. 28
2.2.4 Treatment interruption and re- initiation .......................................................... 29
2.2.5 Human ADME study ....................................................................................... 30
2.2.6 Bioequivalence and relative bioavailability..................................................... 30
2.2.7 Drug-drug interaction studies .......................................................................... 31
Figure 2-2 Emax heart rate (bpm) by time (0 to 24 hours)
and treatment group for co‑ administration of
siponimod and beta blocker propranolol .............................. 34
2.2.8 Absolute bioavailability and pharmacodynamic/cardiac safety of
intravenous formulations ....................................................................... 35
2.2.9 Thorough QT/QTc study ................................................................................. 36
Figure 2-3 Estimated mean difference and 2-sided 90
percent CI for change from placebo-adjusted
time-matched Baseline in QTcF (msec) by
time point and siponimod treatment (2 and 10
36
mg) .......................................................................................
2.2.10 Studies in special populations........................................................................ 37
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Abbreviations
ABCB1 ATP-binding cassette sub-family B member 1/P-glycoprotein
ABCG2 breast cancer resistant protein
ABPM ambulatory blood pressure monitoring
ADME absorption distribution metabolism excretion
AE adverse event
ALC absolute lymphocyte count
ALT alanine aminotransferase
AP alkaline phosphatase
AST aspartate aminotransferase
AUC area under the curve
AUC0-t area under the curve to a defined point in time
AUCinf area under the plasma (or serum or blood) concentration-time curve extrapolated to
infinity
AUClast area under the curve calculated to the last quantifiable concentration point
AUCMABP area under the mean-arterial-blood-pressure curve
AUCtau area under the curve calculated to the end of the dosing interval, tau
AUCtau,ss area under the curve calculated to the end of the dosing interval, tau, at steady state
AUEC area under the effect curve
AV atrioventricular
BCRP breast cancer resistant protein
bid twice a day
BMI body mass index
BP blood pressure
BSEP bile salt export pump
Cav,ss average steady state concentration during multiple dosing
Cb/Cp ratio of blood-to-plasma concentrations
CM central memory T cells
CI confidence interval
Clast last observed quantifiable concentration
CL systemic (or total body) clearance from plasma (or serum or blood) following
intravenous administration
CL/F apparent systemic (or total body) clearance from plasma (or serum or blood) following
extravascular administration
CLr renal clearance from plasma (or serum or blood)
Cmax observed maximum plasma (or serum or blood) concentration following administration
Cmax,ss observed maximum plasma (or serum or blood) concentration following administration
at steady state
Cmin,ss observed lowest plasma (or serum or blood) concentration during a dosing interval at
steady state
CNS central nervous system
CSF clinical service formulation (capsule)
CUAL combined unique active [MRI] lesion
CV coefficient of variation
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SE standard error
SHBG sex hormone binding globulin
SLC solute-carrier
SOC system organ class
SNP single nucleotide polymorphism
SPMS secondary progressive multiple sclerosis
SVE supraventricular ectopy
T1/2 half-life
TEmax time to maximum effect
Tlag lag time
Tmax time to reach peak or maximum concentration
Tmax,ss time to reach peak or maximum concentration following drug administration at steady
state
ULN upper limit of normal
UPLC ultra performance liquid chromatography
WHO World Health Organization
Vc/F apparent volume of central compartment
VE ventricular ectopy
Vp/F apparent volume of peripheral compartment
Vz apparent volume of distribution during the terminal elimination phase following
intravenous administration
Vz/F apparent volume of distribution during the terminal elimination phase following
extravascular administration
Vss apparent volume of distribution at steady state following intravenous administration
Vss/F apparent volume of distribution at steady state following extravascular administration
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modulators (Subei and Cohen 2015). The maximum tolerated dose (MTD) for a single dose of
siponimod was determined to be 25 mg based upon the occurrence of symptomatic bradycardia
after a single dose of 75 mg. Safety and tolerability of the highest investigated multiple dose of
20 mg for 28 days was satisfactory, so that the MTD in the multiple dose setting could not be
established.
The effects of siponimod cease more rapidly after discontinuation in comparison to fingolimod
(recovery of ALC within days, compared to months) due to its short half-life (T1/2: 30 hours).
The short T1/2 has particular relevance in clinical situations requiring a fast wash-out and re-
establishment of normal immune function, including patients in need of vaccinations, surgical
interventions, becoming pregnant or with specific (infectious) adverse events (AEs) requiring
treatment discontinuation.
Similar to other S1P modulators acting through S1P1, negative chronotropic effects were
common at treatment initiation of siponimod. In the single ascending dose (SAD) and multiple
ascending dose (MAD) studies, a transient, dose-dependent decrease in heart rate (HR) was
observed during the initial dosing phase that plateaued at doses ≥ 5 mg.
Occasional asymptomatic bradyarrhythmic events (atrioventricular (AV) blocks and sinus
pauses) were detected at a higher incidence under siponimod treatment compared to placebo
and were typically evident after the first dose. A specifically designed dose titration (DT)
[Study A2107] demonstrated that the effects on HR and AV conduction observed under non-
titrated conditions could be attenuated by DT. A DT regimen was employed in subsequent
multiple dose Clinical Pharmacology studies and in the Phase 2 and 3 studies in MS patients,
in which it efficiently mitigated the known effects on HR and AV conduction.
During the US FDA End-of-Phase 2 (EoP2) consultation in September 2011, Novartis agreed
with the agency on a panel of 19 Clinical Pharmacology studies which were considered to
constitute a complete package that supports the submission of the siponimod NDA (Table 5-1).
In addition, [Study A2126] was conducted to evaluate the absolute bioavailability of a single
oral dose of siponimod.
At the time of conduct of the DT study the highest anticipated therapeutic dose in the ongoing
Phase 2 [Study A2201] in MS patients was 10 mg, which was also investigated as the highest
dose in [Studies A1101, A2104 and A2107] conducted after the SAD/MAD studies (N = 3).
During the course of clinical development, the doses investigated in the Clinical Pharmacology
program were adjusted to the highest predicted therapeutic maintenance dose level as
determined by pharmacokinetic (PK)/pharmcodynamic (PD) analyses on magnetic resonance
imaging (MRI) assessments (combined unique active lesion; CUAL) in the Phase 2 dose
selection (Study A2201) in relapsing-remitting MS (RRMS) patients ([SCE-Section 4.1]). The
highest therapeutic dose was adjusted to 4 mg, as investigated in the Clinical Pharmacology
[Studies A2119, A2108, A2110, A2111 and A2121] and finally to a therapeutic maintenance
dose of 2 mg qd, as investigated in the Phase 3 [Study A2304] in SPMS patients and in the
subsequent 9 PK or PD Clinical Pharmacology [Studies A2118, A2116, A2122, A2129, A2130,
A2128, A2126, A2125 and A2124].
The clinical benefit (efficacy), safety and tolerability of siponimod have been mainly
investigated in patients with RRMS and SPMS. Siponimod was also investigated in 3 clinical
studies in patients with PM and DM (Table 5-1). PM and DM comprise a heterogeneous group
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1.2.1 Pharmacokinetics
An overview of intrinsic and extrinsic factors with and without influence on the PK of
siponimod is provided in Figure 3-1 (Section 3.1).
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1.2.1.2.1 Absorption
In vitro, siponimod was classified as a highly permeable compound. Luminal membrane
permeability most likely occurs by a passive permeation process (Section 3.1.1).
Across clinical studies of single oral administration of various solid oral dosage forms, the
median time to reach maximum concentration (Tmax) ranged between 2 and 6 hours
(Section 3.1.1). At equivalent doses, exposure to siponimod is generally similar between oral
formulations. The absolute oral bioavailability of siponimod (0.25-mg dose) was 84%.
Despite a slight delay in Tmax, food intake had no effect on the systemic exposure (Cmax,
AUC) of siponimod (Section 3.1.2). Therefore, siponimod can be taken without regard to meals.
1.2.1.2.3 Metabolism
In vitro it was estimated that CYP2C9 and CYP3A4 contribute to 79.3% and 18.5%,
respectively, of the oxidative metabolism of siponimod (Section 3.1.7).
In human, no active or toxic siponimod metabolites were identified
([Toxicology Written Summary]). Consistent with in vitro findings, the primary phase I
metabolic pathway identified in the human ADME study was hydroxylation of siponimod to
form M5, M6 and M7; phase II glucuronidation of M5 yields M3, 1 of the 2 main circulating
metabolites of siponimod (M3 AUCinf amounted to 27.6% of siponimod exposure).
The cholesterol ester M17 was identified as the most prominent systemic metabolite in the
absolute bioavailability study (M17 AUCinf amounted to 81% to 97% of siponimod).
Additional metabolites detected in the human ADME study are described in Section 3.1.7.2.
Further details of the PK of the main metabolites M3 and M17 are discussed in Section 3.1.7.3.
Overall, unbound Cmax and EC50 values suggest that M3 and M17 systemic exposure are
unlikely to translate into a significant increase in pharmacological activity on S1P1 or S1P5
receptors.
1.2.1.2.4 Elimination/excretion
The apparent clearance of siponimod was low (typical CL/F value: 3.11 to 3.15 L/h).
The effective T1/2 ranged from 22 to 36 hours (Section 3.1.8). For M3, M5, M6 and M7 the
apparent terminal T1/2 ranged between 29.3 and 35.2 hours, compared to 150 to 155 hours for
M17. Fecal/biliary excretion was the major route of elimination (mean: up to 86.7% of
radioactive dose). Unchanged drug accounted for 9.2% of radioactive dose in feces. M5 and
M4 were the major metabolites in feces and M3 was the major metabolite in urine.
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1.2.3 Pharmacodynamics
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for 2 mg was 62% and was plateauing at doses ≥ 5 mg. At the therapeutic dose of 2 mg qd, it is
expected that for the majority of subjects siponimod treatment will not result in a reduction of
ALC values below 0.2 × 109/L. Among covariates that were tested (age, body weight, gender,
ethnicity (Chinese and Japanese) and disease status/population type), the only predictors of
lymphocyte response were population type (healthy subjects different from RRMS patients
different from SPMS patients), gender and Japanese ethnicity.
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Section 2.3) and based on pooled categorical analyses in healthy subjects (Section 3.4.2.2). In
addition, a dedicated [Study A2128] investigating DT in specific CYP2C9 genotypes (CYP2C9
*1*1 extensive metabolizers and CYP2C9 *2*3 and *3*3 poor metabolizers) showed that there
were no clinically-relevant bradyarrhythmic effects of siponimod in both genotypes. Average
of HR and arrhythmia analysis did not show any clinically relevant difference between CYP2C9
genotype groups (Section 2.2.10.3).
A dedicated treatment interruption and re-initiation [Study A2110] identified conditions
requiring siponimod re-titration after variable treatment interruption periods at different dose
levels (Section 2.2.4). In accordance with the results of this study, re-titration was only
warranted in patients missing 4 or more consecutive daily doses during maintenance dosing in
[Study A2304] in SPMS patients (Section 2.3.1.2). In addition, re-titration was required for
patients who missed 1 dose or more during the DT phase.
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phosphatase (AP) and bilirubin), elevations were mainly observed for ALT, AST and GGT
enzymes (Section 3.4.2.4.1). In healthy subjects these elevations were mainly increases < 3-fold
above the upper limit of normal (ULN) and mostly occurred at doses > 2 mg. Elevations in liver
enzymes in MS patients are described in [SCS–Section 3.4].
1.2.3.4.3 Infections
Considering the primary PD effect of siponimod on lymphocytes, potential translation to an
increased rate of infections was explored. Pooled analyses of AEs of healthy subjects revealed
a slightly higher incidence of upper respiratory tract infections in siponimod-treated subjects
(up to 2.0%) compared to placebo subjects (up to 1.0%); for uptitration to the therapeutic dose
of 2 mg qd, the incidence was 1.7% (Section 3.4.2.4.3). Other infection-related AEs reported
in > 1 subject were urinary tract infections (incidence rates up to 0.3% in siponimod-treated
healthy subjects, compared to no events for placebo treatment).
1.2.3.4.4 Abuse and dependence potential (8-factor drug abuse liability assessment)
Chemistry, nonclinical and clinical data with siponimod did not indicate any signals of abuse,
misuse or dependence potential in animals or humans or demonstrate any potential
pharmacological similarities to existing drugs of abuse or subjective effects that may be related
to drug abuse, such as reinforcing, mood-elevating, sedative, stimulant or hallucinogenic effects
(Section 3.4.2.4.4). Therefore, it can be concluded that siponimod has no abuse or dependence
potential and it is not expected to be subject to abuse, misuse or diversion in the community, or
result in harm to the public health as a result of abuse, misuse or diversion.
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Cellular uptake
The results of [DMPK R0800531] and [DMPK R1300921], for which the mechanism of
intestinal uptake of siponimod was investigated in Caco-2 cell monolayers in the presence and
absence of inhibitors of efflux transporters, are discussed in Section 3.1.1 (absorption) and
Section 3.3.1.2.1 (details in Table 5-6) (assessment of DDI risk concerning transporters
involved in absorption).
Transporter inhibition
Efflux, uptake and SLC transporter inhibition by siponimod, M3 and M17 was assessed in
19 studies (detailed below). Potential clinical implications for DDIs from these in vitro results
for siponimod, M3 and M17 acting as a perpetrator drug are discussed in Section 3.3.1.1.1
(details in Table 5-5).
For efflux transporters, inhibition by siponimod is described in [DMPK R1200722] (P-gp,
BCRP), [DMPK R1300847] (BSEP) and [DMPK R1300849] (MRP2). Inhibition by M3 is
described in [DMPK R1300852] (BSEP) and [DMPK R1300853] (P-gp, BCRP). Inhibition by
M17 is described in [DMPK R1500825] (P-gp, BCRP) and [DMPK R1500826] (BSEP, MRP2).
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a flooring effect. Only small increments of further decreases in the mean ALC AUEC0-24 were
observed at doses above 5 mg (i.e., ≥10 mg). This flooring effect is consistent with observations
for the HR effects (discussed above). An ALC reduction of at least 80% was reached at the
10-mg dose or higher. Mean values for ALC changed by ≥ -1.0 × 109/L for all doses ≥ 5 mg.
Recovery was not observed until the End-of-Study (EOS) Visit for subjects receiving the
highest dose (75 mg). The nadirs of the decline in ALC (median TEmax0-24h values) ranged
from 3.00 to 7.00 hours with the exception of doses ≥ 10 mg.
After single doses above 1 mg the mean ALC did not show a clear trend for recovery at 24 hours
post dose. At 48 hours post dose mean ALC returned to normal values after single doses of 2.5
mg and showed a clear trend of recovery after single doses of 5 mg, 10 mg and 17.5 mg. Based
on the observed ALC recovery dynamics and supported by an apparent terminal T1/2 of 27 to
57 hours, a qd dosing regimen was considered appropriate to maintain reduced ALC levels in a
multiple dose setting.
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AE were in the siponimod 20-mg dose group (the other 2 subjects in the 0.3 mg siponimod and
placebo groups), suggesting a dose effect relationship.
Siponimod steady-state concentrations were achieved in all 5 cohorts following approximately
6 days of multiple dosing for most of the subjects, and comparable PK parameters were defined
on Days 7 and 28. The mean Racc ranged between 1.88 and 2.72 on Day 28, with similar values
determined on Day 7 (between 1.82 and 2.42). The effective T1/2, estimated after multiple
administrations based on drug accumulation at steady state (Boxenbaum and Battle 1995),
ranged between 22 and 36 hours and was comparable to the apparent terminal T1/2 determined
in the SAD study. Systemic exposure was not to exceed the cap values set by the FDA (Cmax
of 2700 ng/mL or an AUC0-24h of 35000 h*ng/mL). The maximum individual Cmax/Cmax,ss
and AUC0-24h/AUCtau values were well below this limit (498 ng/mL and 9235 h*ng/mL,
respectively).
A dose-dependent reduction of mean ALC, when compared to Day -1, was observed for all
doses of siponimod ≥ 1 mg ([Study A2105-Figure 11-7]). Dose-dependent effects were
observed for ALC %Emax0-12h, Emax0-12h and AUEC0-12h. The means of Emax0-12h on
Day 1 and Day 28, as adjusted to Day -1, ranged from 1.71 to 0.62 × 109/L and 1.09 to
0.37 × 109/L, respectively, across dose groups (compared to 1.70 and 1.71 × 109/L for placebo).
For all dosing groups, the maximal reduction in peripheral lymphocyte counts on Day 1 was
observed at approximately 4 to 6 hours post dose and was maintained throughout the 28-day
treatment. At the EOS Visit (14 to 21 days post treatment completion), recovery to Baseline of
ALC was observed for subjects receiving 0.3 to 10 mg siponimod and incompletely at the dose
of 20 mg.
The effect of siponimod on leukocyte/lymphocyte subsets (T cells, monocytes, natural killer
(NK) cells, dendritic cells (DCs) and B cells) was also assessed. Relative levels of both T and
B lymphocytes were reduced in a dose-dependent manner. The 2 major T cell subpopulations,
CD4+ and CD8+ cells, were affected to different degrees by siponimod
([Study A2105-Figure 11-8]). While the CD4+ cells showed a clear dose-dependent reduction
among all T lymphocytes, the relative proportion of CD8+ T cells was increasing. The most
pronounced increase was observed for siponimod 2.5 and 10 mg, on Days 14 and 28, when
compared to the placebo group. Central memory (CM), peripheral effector memory (PEM) and
naïve (N) subtypes of both CD4+ and CD8+ T cells responded differently to siponimod. CD4N
T cells were reduced for siponimod 10 and 20 mg. CD8N T cells showed a pronounced
reduction for siponimod 2.5 mg and an even stronger response at the highest doses. In contrast,
relative proportions of CD4PEM and CD8PEM T cells were increasing in the siponimod
10- and 20-mg dose groups and in the siponimod 2.5-mg dose group for CD8PEM T cells. PEM
T cells are present primarily in peripheral tissues and are endowed with immediate effector
functions (Sallusto and Lanzavecchia 2009). The observed preferential effect on naïve T cells and
the less pronounced effects on PEM T cells may indicate a preservation of the relative capacity of the
immune system to mediate recall responses to known antigens or to vaccinations. Further detail can
be found in [Study A2105-Section 11.4.5.2].
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the DT1 or DT2 groups (both 0.25 to 10 mg), a fixed-dose group (10 mg qd), or a placebo group
(Table 2-1). The starting doses of both tested DT schemes were selected based on the results of
[Study A2101] showing that a single dose of 0.3 mg was devoid of any relevant
bradyarrhythmic effect. DT1 applied an arithmetic algorithm starting with stable dosing over
the first 3 days and subsequent daily dose increases using a factor of 2 for dose increments,
while DT2 used incremental dose increases based on the Fibonacci algorithm. The arithmetic
DT regimen is based mainly on PK-based considerations, while the Fibonacci-based dose
titration was designed mainly based on empirical observations of adaptive processes in
biological systems (i.e., PD-based considerations).
The primary PD evaluations of this study were the daily chronotropic effects of the 2 DT
regimens compared to the chronotropic effect of the 10 mg qd regimen and of placebo over
12 days, and the frequency of AV blocks and sinus pauses (RR > 2 seconds) over the course of
each DT regimen using daily 24-hour, 12-lead digital Holter electrocardiogram (ECG)
recording over the entire dosing period. Overall, DT2 was identified as the most robust DT at
mitigating negative chronotropic effects and was used in subsequent multiple dose studies and
in Phase 2 and 3 studies.
Both DT regimens effectively attenuated the initial bradycardia observed on Day 1 of treatment
with siponimod 10 mg. HR in the non-titration regimen showed considerable separation from
placebo throughout the study (Figure 2-1). There was no statistically significant reduction in
HR versus placebo on Day 1 in either DT regimen. On Days 3 to 7, subjects in DT1 and DT2
experienced minor reductions in HR. There were no subjects in the DT groups that displayed
significant bradycardia during the trial, in contrast to the 3 subjects in the 10 mg group that had
bradycardia ranging from 34 to 54 bpm on Day 1. The 2 DT regimens only induced a decrease
of 4 bpm over 7 days; this effect on HR is not considered to be clinically relevant. By Day 9,
HR in both DT regimens was comparable to placebo. This effect was maintained until end of
treatment on Day 12.
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Figure 2-1 Mean daily minimum heart rate after once daily dosing administered
over 12 days as a fixed dose or uptitration to 10 mg
PBO = placebo.
Source: [Study A2107-Figure 11-3]
There was no difference between treatment groups in the number of subjects with
supraventricular ectopy (SVE) and ventricular ectopy (VE) ([Study A2107-Table 11-3]).
With regards to their ability to attenuate bradyarrhythmic effects of siponimod both DT
regimens were similar, with slightly more favorable data seen with the Fibonacci algorithm
(DT2). The results of the standard analysis of the Holter data did not show any significant
difference between the 2 DT schemes. In DT2 only 1 subject experienced at least 1 sinus pause
compared to DT1 and the 10 mg treatment groups, where 4 subjects experienced at least 1 sinus
pause ([Study A2107-Table 11-4]). No sinus pauses were observed in the placebo group.
Second degree AV blocks (Mobitz I) were reported in 4 subjects (2 subjects in DT1 and 1
subject each in the DT2 and placebo groups) and a 2:1 AV block was noted in 1 subject (10 mg
non-titrated group). Based on the placebo-like occurrence of AV blocks and sinus pauses in
DT2, this Fibonacci regimen was implemented in the Phase 2 and 3 studies in MS patients as
well as in the Phase 2 studies in PM/DM patients where it successfully attenuated the known
bradyarrhythmic effects of siponimod.
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and 16% lower and the geometric mean AUC0-inf of F10 and F16 were 16% and 51%.
The relative bioavailability of the 2 MR formulations is discussed in [SBP-Section 3.2.2].
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HR decrease of 6.21 bpm compared to propranolol alone, while the mean minimum hourly
average HR remained above 50 bpm.
The HR data for each treatment group over 24 hours is plotted in Figure 2-2. The combination
treatment at steady state (Groups A and B combined) showed an additional decrease of mean
Emax HR by 6.21 bpm (95% CI: 2.32, 10.11; p = 0.002) when compared to propranolol alone
(Group D). Propranolol treatment introduced on top of siponimod steady state (Group A) led to
a less than additive additional mean Emax HR decrease of 5.04 bpm (95% CI: 0.52, 9.56;
p = 0.0292) and siponimod treatment introduced on top of propranolol steady state (Group B)
led to additional mean Emax HR decrease of 7.39 bpm (95% CI: 2.87, 11.90; p = 0.0016),
in comparison to propranolol alone at steady state. The mean (range) Emax HR decreases from
Baseline were 15.44 (6.4, 23.6) and 7.77 (2.0, 29.9) bpm with propranolol (Group D, Day 20)
and placebo (Group C, Day 20), respectively. The maxima in mean (range) Emax HR decrease
in Groups A and B occurred on Day 16, and were 21.34 (10.5, 40.6) and 28.14 (15.9, 37.7) bpm,
respectively. The corresponding decreases in the propranolol (Group D) and placebo (Group C)
groups were 17.96 (2.1, 31.8) and 9.99 (-0.3, 46.0) bpm, respectively.
Figure 2-2 Emax heart rate (bpm) by time (0 to 24 hours) and treatment group for
co-administration of siponimod and beta blocker propranolol
Group A = propranolol added on top of siponimod, Group B = siponimod added on top of propranolol,
Group C = siponimod-placebo/propranolol-placebo, Group D = siponimod-placebo/propranolol
Source: [Study A2116-Figure 11-1]
All detected bradyarrhythmic events were asymptomatic and there was no second degree AV
block or sinus pause of > 3 sec duration noted in the study in subjects receiving siponimod
(during combination treatment or while receiving siponimod alone).
Changes in pulmonary function (FEV1) with the individual drugs or with the combination
treatment were not clinically significant in view of the magnitude of change, placebo effect and
the week-to-week variability (Pellegrino et al 2005).
A slight decrease in Emax MABP (2.93 mmHg, p = 0.0734) in the combination treatment
(Groups A and B combined, Day 20) in comparison to propranolol alone and a trend for slight
increase in PR interval (2.45 msec at 2.5 hours post dose, p = 0.5341; 7.06 msec at 6.5 hours
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post dose, p = 0.0485) with the combination treatment (Groups A and B combined) were noted,
which were overall not considered to be clinically relevant.
Based on the cardiac safety results (Emax HR, MABP, PR interval, AV block, sinus pause) of
this study the use of beta blockers (previously prohibited) was permitted in the Phase 3
[Study A2304] in SPMS patients, using a specific decision algorithm dependent on the Baseline
HR prior to initiation of concomitant therapy. The results of this study indicated that due to the
less than additive HR effects beta blocker treatment can be safely initiated in patients on stable
siponimod maintenance treatment. In patients receiving a stable dose of beta blocker, the resting
HR should be considered before introducing siponimod treatment. If the resting heart rate
is > 50 bpm under chronic beta blocker treatment, siponimod can be introduced. If resting heart
rate is ≤ 50 bpm, then beta blocker treatment should be interrupted until the Baseline HR
is > 50 bpm prior to initiating siponimod treatment. The beta blocker treatment can be re-
initiated after siponimod has been uptitrated to the target maintenance dose.
Combination treatment did not significantly alter the exposure of siponimod. Mean siponimod
AUCtau,ss and Cmax,ss were approximately 7% lowered when co-administered with
propranolol. However, the test/reference ratio 90% CI remained within bioequivalence limits
(0.80 to 1.25). No change in siponimod Tmax,ss was observed.
Decreases in propranolol exposure in the presence of siponimod were considered not to be
clinically relevant (Cmax,ss and AUCtau,ss decreased by 15% and 18%, respectively).
Propranolol Tmax,ss was similar in presence of siponimod.
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Figure 2-3 Estimated mean difference and 2-sided 90 percent CI for change from
placebo-adjusted time-matched Baseline in QTcF (msec) by time point
and siponimod treatment (2 and 10 mg)
Siponimod therapeutic dose (2 mg) on Day 10 Siponimod supratherapeutic dose (10 mg) on Day 18
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The frequency of categorical QT/QTc outliers in the siponimod group was low and could not
be differentiated from placebo. Categorical analysis revealed no treatment-emergent QTcF
values above 480 msec and no QTcF increases from Baseline of more than 60 msec on any of
the on-treatment assessment days. No corrected or uncorrected QT/QTc value exceeded
500 msec ([Study A2118-Tables 11-4 and 11-9]). Correlations between ΔQTc and plasma
concentrations of siponimod, M3 and M5 were characterized by prediction lines of negative
slopes with the upper bound of the 2-sided 90% confidence band remaining below 10 msec
within the investigated exposure range ([Study A2118 Addendum-Figures 2-3, 2-4 and 2-5]).
Positive correlations were found between the siponimod, M3 and M5 plasma concentrations
and ΔHR, which translated into corresponding negative correlations between the respective
plasma concentrations and ΔQT due to the interdependence of HR and QT
([Study A2118 Addendum-Figures 2-12, 2-13 and 2-14]). There was no delayed PD response
on ΔΔQTcF, ΔΔQTcI and ΔΔHR for any of the investigated analytes (siponimod, M3 and M5).
No notable repolarization changes or arrhythmias occurred under siponimod treatment and the
incidence of T-wave abnormalities was low in all treatment groups with no trend between the
treatment groups and assessment days.
All observed episodes of second degree AV blocks and sinus pauses were asymptomatic and
considered not to be of clinical relevance.
Plasma exposure and steady-state PK were consistent with previous studies in healthy subjects:
geometric mean Cmax,ss of 30.4 ng/mL and AUCtau,ss of 558 h*ng/mL on Day 10, the fifth
day of 2 mg qd dosing. From Day 10 to Day 18, the fifth day of 10 mg dosing, dose-proportional
(5-fold) increases in siponimod Cmax,ss and AUCtau,ss (to 152 ng/mL and 2680 h*ng/mL,
respectively) were observed; thus the 10 mg supratherapeutic dose of siponimod was
considered appropriate to investigate the effects of siponimod on QT/QTc at substantial
multiples of the anticipated maximum therapeutic exposure. The PK results for M3 and M5 and
the additional PK/PD analyses are reported separately in an addendum to this study
(Section 3.1.7.3).
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Figure 3-1 Effect of intrinsic and extrinsic factors on siponimod PK (geometric mean ratios and 90 percent confidence
intervals)
Source: [Study A2128-Table 11-5], [Study A2129-Tables 11-5 and 11-8], [Study A2122-Tables 11-5 and 11-13], [Study A2101-Table 11-7],
[Study A2111-Tables 11-4 and 11-5], [Study A2119-Table 11-9].
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Absorption
In vitro, siponimod was classified as a highly permeable compound. Intestinal uptake data of
siponimod in [DMPK R0800531] and [DMPK R1300921] (Table 5-2; membrane permeability
characteristics presented in [DMPK R0800531-Table 2-1] and [DMPK R1300921-Table 1-1])
suggest that luminal membrane permeability occurs most likely by a passive permeation process
without an involvement of drug efflux transporters (Table 5-6). In vitro assessments of DDI
risk concerning transporters and enzymes involved in absorption is summarized in
Section 3.3.1.2.1.
A representative figure of siponimod absorption in clinical studies is presented in Figure 3-2.
The median Tmax ranged between 2 and 6 hours following single oral administrations of
various solid oral dosage forms including the clinical service formulation (CSF) capsule, market
formulation (MF) tablet and final market image (FMI) tablet ([Studies A2101 and A2111]).
Similarly, the median Tmax,ss after multiple doses ranged between 3 and 4 hours ([Studies
A2105 and A2125]). In individual subjects, the median Tmax ranged from 1.5 to 24 hours
(Study A2101). Further comparison of siponimod absorption between different oral
formulations is discussed below.
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Absolute bioavailability
The PK results of Part 1 of [Study A2126] are discussed in detail in [SBP-Section 3.2.1].
The absolute bioavailability of siponimod (FMI tablet) as a single 0.25-mg dose administered
orally was 84% compared with a single 0.25-mg siponimod iv dose: geometric mean AUClast
and AUCinf were 63.6 and 67.4 h*ng/mL, respectively after oral administration, compared to
76.0 and 80.1 h*ng/mL, respectively, following iv administration. The ratios of the geometric
means reveal the Cmax of oral siponimod was approximately 52% of iv siponimod: oral Cmax
of 1.71 ng/mL, compared to iv Cmax of 3.22 ng/mL. Median oral siponimod Tmax was
observed 8 hours after dosing, while median iv siponimod Tmax was observed at the end of the
3-hour infusion. Similar apparent terminal T1/2 results were observed for oral (26.7 hours) and
iv (27.4 hours) administration.
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AUC0-24h and AUCinf ([Studies A2101 and A1101]) rose in an apparent dose-proportional
manner over the investigated dose range.
Exploratory pooled statistical analyses using a power model for PK parameters Cmax and
AUC0-24h and linear regression for dose-normalized PK parameters were performed.
The statistical analysis indicates Cmax and AUC0-24h increased in a dose-proportional manner
considering the slope (≈ 1.00) and 90% CI (0.98 to 1.04). From the regression analysis of
dose-normalized PK parameters versus dose, the slope ≈ 0 indicates that dose-normalized PK
parameters are comparable at different dose levels.
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[Study A2101] data considered: 0.1-, 0.3-, 1-, 2.5-, 5-, 10-, 17.5-, 25- and 75-mg doses
[Study A2105] data considered (Day 1): 0.3-, 1-, 2.5-, 10- and 20-mg doses
Cmax intercept = 7.849; slope = -0.003.
Source: (SCP Appendix-Figure 11-1.1)
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[Study A2101] data considered: 0.1-, 0.3-, 1-, 2.5-, 5-, 10-, 17.5-, 25- and 75-mg doses
[Study A2105] data considered (Day 1): 0.3-, 1-, 2.5-, 10- and 20-mg doses
AUC0-24h intercept = 129.644; slope = -0.073.
Source: (SCP Appendix-Figure 11-1.1)
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Table 3-4 Main PK parameters after siponimod single dose administration (0.1 to 75 mg) to healthy subjects
Siponimod 0.1 mga 0.3 mga 1.0 mga 2.5 mga 2.5 mgb 5.0 mgb 10.0 mgb 17.5 mgb 25.0 mgb 75.0 mgb
Treatment (N = 11) (N = 8) (N = 8) (N = 6) (N = 7) (N = 8) (N = 8) (N = 8) (N = 8) (N = 8)
Tlag 0.25 0.00 0.00 0.13 0.75 (0.50- 0.25 (0.00- 0.25 0.25 0.25 0.25
(h)c (0.00-0.27) (0.00-0.25) (0.00-0.25) (0.00-0.25) 0.77) 0.50) (0.00-0.50) (0.00-0.52) (0.00-0.50) (0.25-0.50)
Tmax 4.00 5.00 5.00 4.00 6.00 3.00 5.00 4.00 3.50 6.00
(h)c (3.00-8.00) (4.00-8.00) (4.00-15.67) (3.00-8.00) (4.00-8.02) (2.00-8.02) (3.85-16.00) (2.00-8.00) (1.50-12.00) (2.00-24.00)
T1/2 33.06 [26] 33.21 [28] 45.68 [26] 27.02 [22] 29.31 [17] 31.27 [19] 32.03 [17] 42.32 [38] 47.68 [20] 56.69 [12]
(h)d
Cmax 0.618 [39] 2.26 [6] 7.43 [42] 21.9 [35] 19.3 [19] 38.5 [21] 77.3 [25] 111 [32] 217 [29] 491 [51]
(ng/mL)d
AUCinf 24.6 [39] 89.3 [20] 349 [28] 766 [36] 745 [25] 1260 [20] 2710 [14] 4230 [25] 8140 [24] 18600 [51]
(h*ng/mL)d
AUC0-t 22.9 [41] 87.2 [20] 345 [27] 743 [36] 721 [26] 1240 [21] 2680 [13] 4200 [25] 8110 [24] 18500 [51]
(h*ng/mL)d
CL/F 4.07 [39] 3.36 [20] 2.86 [28] 3.26 [36] 3.36 [25] 3.95 [20] 3.69 [14] 4.14 [25] 3.07 [24] 4.03 [51]
(L/h)d
Vz/F 194 [31] 161 [19] 189 [32] 127 [34] 142 [23] 178 [21] 170 [22] 253 [36] 211 [29] 330 [58]
(L)d
a CSF liquid formulation
b CSF capsule formulation
c Median (min-max)
d Geometric mean [% geometric mean coefficient of variation]
Source: [Study A2101-Table 11-3, Table 16.2.5-2.23, Table 16.2.5-2.24, Table 16.2.5-2.25, Table 16.2.5-2.26, Table 16.2.5-2.27, Table 16.2.5-2.28, Table 16.2.5-2.30,
Table 16.2.5-2.31, Table 16.2.5-2.32, Table 16.2.5-2.33]
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For the 2-mg therapeutic dose, in [Study A2118] the geometric mean Cmax,ss was 30.4 ng/mL,
Cmin,ss was 14.5 ng/mL and AUCtau,ss was 558 h*ng/mL on Day 10 following 5 days of 2
mg qd dosing preceded by a 5-day DT, consistent with steady-state PK in the MAD study and
other previous studies in healthy subjects.
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The inter-subject variability in Cmax and AUClast remained constant over the whole treatment
duration for the DT1 cohort, with a similar variability as previously observed in [Study A2105].
For the 10 mg qd and the DT2 cohorts, a slightly higher variability was noticed toward the end
of the treatment period compared to the variability observed on the first 6 days of treatment.
This was mainly due to 2 outliers. Consequently, the mean siponimod exposure observed on
Day 12 for the 10 mg qd and for the DT2 cohorts were slightly higher compared to the DT1
cohort.
Figure 3-6 Daily geometric mean plasma concentrations of siponimod after once
daily dosing administered over 12 days as a fixed dose or uptitration
to 10 mg
T02 = siponimod 10 mg
T03 = DT#1
T04 = DT#2
Source: [Study A2107-Figure 11-1]
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3.1.7 Metabolism
This section describes the biotransformation pathways identified in the metabolism of
siponimod, the resultant metabolites formed and their clinical relevance in the pharmacological
activity of siponimod. Overall, no active or toxic siponimod metabolites were identified in
humans (Section 3.1.7.2, Section 3.1.7.3, [Toxicology Written Summary]). Consistent with in
vitro findings (Section 3.1.7.1), the primary phase I metabolic pathway identified in the
dedicated human ADME [Study A2104] was hydroxylation of siponimod to form M5, M6 and
M7 (Section 3.1.7.2). Subsequent phase II glucuronidation of M5 yields M3. An additional
metabolite, M17, was first identified in a mouse ADME study ([Table 2.6.5.9A-DMPK
R1300411-02; PK Written Summary-Section 5.2.1]); its presence in human was later confirmed
in [Study A2126]. The above 2 clinical studies together with [Studies A2118 and A2304]
revealed M3 and M17 as the main metabolites of siponimod (Section 3.1.7.3). Unbound Cmax
and EC50 values suggest that M3 and M17 systemic exposure are unlikely to translate into a
significant increase in pharmacological activity on S1P1 or S1P5 receptors. Additional details
of all of the siponimod metabolites in human are provided in the [PK Written
Summary-Section 5.2.4] and [PK Tabulated Summary], and the contribution of siponimod
metabolites to pharmacological activity on S1P receptors is further discussed in the
[Pharmacology Written Summary].
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Metabolite M3
The PK of M3 following 2- and 10-mg doses of siponimod is summarized in the addendum to
(Study A2118). Following multiple oral administration of siponimod, M3 plasma
concentrations peaked at approximately 6 hours post dose (median). Based on molar ratios, M3
AUClast and Cmax,ss represented 35% to 39% and 33% to 35% of siponimod AUCtau,ss and
Cmax,ss, respectively. These results for M3, as well as those for M5 also summarized in the
addendum, are consistent with (Study A2104) observations. Dose proportional increases in M3
Cmax,ss and AUClast were observed from Day 10 (2 mg) to Day 18 (10 mg). Taking into
consideration the single dose data of (Study A2104), it can be concluded that, like siponimod,
M3 was at steady state levels on Days 10 and 18. This is consistent with a similar T1/2 of
approximately 30 hours for siponimod and M3 (Study A2104).
Unbound M3 AUCtau,ss values and EC50 are presented in Table 3-6. The EC50 value of M3
tested on human S1P1 receptors was > 10000 nmol/L, demonstrating very weak or no activity
compared to the parent drug (EC50 of 1.1 ± 0.41 nmol/L ([Pharmacology Tabulated Summary-
Table 2.6.3.2-RD-2012-00145]). Hence the observed M3 unbound systemic exposure is
unlikely to translate into any pharmacological activity on S1P1 receptors).
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Metabolite M17
In Part 1 of the absolute bioavailability study of siponimod (0.25 mg single dose;
[Study A2126]), discussed in detail in [SBP-Section 3.2.1], M17 represented about 81% to 97%
of the parent exposure (based on AUCinf) and was identified as the most prominent systemic
metabolite in human. A summary of M17 PK parameters is presented in Table 3-7, and the
concentration-time profile is depicted in [Study A2126-Figure 11-2a]. The PK of M17 was
comparable following 0.25 mg siponimod oral and iv administrations; however, an earlier peak
in the plasma concentration-time profiles of M17 was observed 6 hours after oral administration
only. For the 0.25 mg oral dose, M17 plasma levels peaked at 96 hours. The geometric means
of the T1/2, Cmax and AUCinf were 155 hours, 0.356 ng/mL and 112 h*ng/mL, respectively.
The geometric means of the individual metabolite-to-parent molecular ratios for AUCinf and
Cmax were 0.974 and 0.122, respectively.
Based on (Study A2126) data and assuming dose linearity and time independent PK for M17,
it is estimated that, following multiple administration of siponimod 2 mg qd, M17 AUCtau at
steady state should be about 896 h*ng/mL and Cav,ss about 37 ng/mL. M17 was measured at
the EOS Visit in [Study A2304], 24 hours after the last siponimod dose. The geometric mean
concentration of M17 after a 2 mg qd dosing was 30.6 ng/mL. The M17 to parent molar
concentration ratio (based on geometric means) was 0.889. The M17 concentration of
30.6 ng/mL reported in the current study, 24 hours after the last dose, is close to this estimated
Cav,ss. Considering the long M17 T1/2 observed in healthy subjects (~155 hours), a flat
exposure profile is expected for M17 at steady state following daily siponimod administration,
(i.e., limited difference between Cmin,ss and Cav,ss should be observed).
Unbound M17 AUCtau values and EC50 are presented in Table 3-8. While the EC50 values of
M17 tested on human S1P1 and S1P5 receptors were in the nanomolar range (341 ± 86 nmol/L
and 159 ± 9 nmol/L), M17 is ~70- to 80-fold less potent on S1P receptors than the parent drug
(EC50 of 4.3 ± 0.5 nmol/L ([Table 2.6.3.2-RD-2015-00301]). Hence the observed unbound
M17 systemic exposure is unlikely to translate into a significant increase in pharmacological
activity on S1P1 and S1P5 receptors (contribution of about 3% to total pharmacological activity
on S1P1 and S1P5).
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Table 3-8 Unbound M17 AUCtau and EC50 on human S1P1 and S1P5 receptors
Dose Geo-Mean AUCtau,ss,u S1P1 EC50 ± SD S1P5 EC50 ± SD
(mg) (ng/mL*h)a (nmol/L*h)b (nmol/L) (nmol/L)
2 (multiple dose) 0.408c 0.460c 341 ± 86 159 ± 9
a Calculated using fu of 0.0455 for M17
b Calculated using MW of M17 of 885.25 g/mol
c Calculated from values extrapolated from [Study A2126] data assuming dose and time linearity PK
for M17
Source: [Study A2126-Table 14.2-5.4a], [Table 2.6.3.2-RD-2015-00301]
3.1.8 Elimination/Excretion
Overall, siponimod is primarily metabolized through hydroxylation forming M5, M6 and M7
and subsequent glucuronidation or sulfation, with fecal/biliary excretion as the major route of
elimination. The apparent clearance of siponimod was low. The effective T1/2 ranged from
22 to 36 hours.
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Elimination
In [Study A2104] (10-mg dose), the apparent clearance of siponimod was 3.97 L/h.
The apparent terminal T1/2 of total radiolabeled components (radioactivity) and siponimod in
plasma were 171 and 56.6 hours, respectively (noncompartmental PK analysis). For M3, M5,
M6 and M7, the apparent elimination T1/2 ranged between 29.3 and 35.2 hours. For M17, the
geometric mean T/12 was 155 hours in [Study A2126] (0.25-mg dose; Table 3-7). Hence, M17
likely contributed to the longer T1/2 of total radioactivity.
Similarly, in other single and multiple dose studies in healthy subjects ([Studiy A2101 and
Study A2105]) an apparent CL/F of about 3.5 L/h was estimated, and in the 2 PopPK analyses
the typical CL/F value was 3.11 to 3.15 L/h. In the single dose study siponimod disappeared
from the systemic circulation in an apparent monophasic manner, with a geometric mean
apparent terminal T1/2 of 27.02 to 56.69 hours. In the multiple dose study, the decay in
siponimod plasma concentration over time after 28 days of dosing appeared to be biexponential
(Section 3.1.5.1). The effective T1/2 based on drug accumulation at steady state was 22 to
36 hours, comparable to the apparent terminal T1/2 in the single dose study.
Metabolites in excreta
In (Study A2104), siponimod was eliminated mainly by metabolism with fecal/biliary excretion
as the major route of elimination. The main metabolic pathways identified were hydroxylation
forming M5, M6 and M7 and subsequent glucuronidation or sulfation of hydroxylated
metabolites (Figure 3-7). Other metabolites formed by cleavage/hydrolysis of the oxime ether
(sum of M1, M2 and M8 in excreta) were minor in human (≤ 2.1% of the dose;
[DMPK RCBAF312A2104c-Table 10]).
In the feces, unchanged siponimod accounted for 9.2% of the radioactive dose in the feces
during 0 to 192 hours. The major hydroxylated metabolite M5 amounted to 45.1% ± 9.0% of
the radioactive dose. M4a, M4b, M4c, M6 and M7 represented between 1.6% and 6.4% of the
excretion in feces (Study A2104); [DMPK RCBAF312A2104d]). Overall, M4, M5, M6 and
M7 covered 67.3% of the dose ([DMPK RCBAF312A2104c-Table 10]).
In urine, only a minor amount of radioactivity was excreted. Unchanged siponimod was not
detected in urine. M3, the major metabolite in urine, amounted to 2.1% of the dose
([DMPK RCBAF312A2104c-Table 10]). M1, M2 and M8 accounted for 0.2% to 0.5% of the
radioactive dose; the hydroxylated metabolites were detected in traces (< 0.1% each).
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Based on the results of a study with bile-duct cannulated rats dosed intravenously with
[14C]siponimod, indicating that M3 was one of the major metabolites detected in bile while low
amounts only were observed in feces, M3 (glucuronide of M5) was likely de-conjugated to M5
in the feces [PK Written Summary-Section 5.2.4].
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As in the Phase 1/Phase 2 PopPK analysis, siponimod PK in the Phase 3 study was well
described by a 2-compartment disposition model with first order elimination and combined
zero- and first-order absorption. The typical values of CL/F (3.11 L/h), Vc/F (126 L) and Vp/F
(28 L), the body weight effect on CL/F and Vc/F and the CYP2C9 genotype effect on CL/F
were also consistent with the first PopPK analysis. All the parameters were estimated with good
precision (relative SE: 1% to 7%). The IIV for CL/F (CV = 24.2%) and Vc/F (CV = 33.0%)
were moderate. The shrinkages of individual random effects were estimated as 34% for CL/F
and 83% for Vc/F.
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compared to healthy subjects (92 samples). In addition, the PK samples were collected within
a larger elapsed time range in the MS trials compared to the healthy subject study.
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Figure 3-8 Box plot by dose for comparison of steady state pharmacokinetic
trough concentrations between healthy subjects and patients with
multiple sclerosis
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exposure was higher than observed in previous healthy subject studies ([Study A2105]). In
[Study X2206], arithmetic mean siponimod trough plasma levels were comparable to the mean
Cmin,ss values observed in [Studies A2118 and A2105] at the same dose levels, confirming
adequate exposure. In Period 1, values were more comparable to previous observations
(approximately 3.2 to 6 ng/mL in the 0.5 mg/2 mg dose group, 26.8 to 31.9 ng/mL in the
2 mg/2-mg dose group, and 53.6 to 100 ng/mL in the 10 mg/2-mg dose group), whereas
Period 2 values were more variable.
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The increased systemic exposure of M3 and M5 associated with no significant changes in the
parent drug exposure suggests that the elimination pathway of the metabolites may be impacted
in subjects with hepatic impairment. M3, a glucuronidated metabolite, is likely a substrate of
the hepatic multidrug resistance-associated protein 2 (MRP2) transporters mediating its biliary
excretion. MRP2 is known to be down-regulated in cholestasis (Denson et al 2002). The
reduced excretion of M3 into the bile may lead to increased systemic concentrations as well as
an increase of hepatocytes M3 concentrations. In hepatocytes, M3 can possibly be
de-glucuronidated back to M5, consequently leading to an elevated systemic exposure of this
metabolite. However, as discussed in Section 3.1.7.3 and [Pharmacology Tabulated Summary-
Table 2.6.3.2-RD-2012-00145], considering the EC50 values of M3, M5 and siponimod
(> 10000, 470 and 1.1 nmol/L, respectively), the observed systemic exposure increase for both
M3 and M5 in hepatic impairment is unlikely to translate into any increase in pharmacological
activity on S1P1 receptors.
There was no rationale in the current study or in [Study A2129] (in renally impaired subjects)
to investigate M3/M5 protein binding, since these 2 metabolites are neither pharmacologically
active nor toxic.
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The data indicate that in subjects with severe renal impairment the relevant non-renal clearance
pathways of siponimod are not affected and metabolism remains unchanged, as also confirmed
by M3 and M5 data. The same results are expected for the mild and moderate renal impairment
stages.
3.2.5 Genotype
The polymorphic enzyme CYP2C9 is the major metabolizing enzyme for siponimod. Exposure
to siponimod is dependent on the CYP2C9 genotype. More than 50 single nucleotide
polymorphisms (SNPs) have been described in the regulatory and coding regions of the
CYP2C9 gene, but only 2 coding SNPs, namely CYP2C9*2 and CYP2C9*3, are considered to
lead to a clinically relevant reduction in enzyme activity. These 2 SNPs lead to 6 different
CYP2C9 genotype groups conferring to 3 functionally different phenotypes, namely extensive
(*1*1), intermediate (*1*2, *1*3 and *2*2) and poor metabolizers (*2*3 and *3*3). Table 3-
11 presents the prevalence of the 6 genotypes in Caucasian, Asian and African subjects.
Section 3.2.5.1 discusses differences in siponimod exposure between extensive and poor
metabolizers (CYP2C9*1*1 genotype versus *2*3 or *3*3 genotypes, respectively) in
[Study A2128]. Section 3.2.5.2 describes differences in siponimod PK across additional
CYP2C9 genotypes in the 2 PopPK analyses and [Study A2124]. Section 3.2.5.3 recommends
maintenance dose adjustments from 2 mg to 1 mg in CYP2C9*1*3 and *2*3 subjects with
reduced apparent metabolic clearance and exclusion of *3*3 subjects (not evaluated in Phase 3
[Study A2304], due to expected significantly higher chronic exposure with potential safety
implications) from a marketing authorization.
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For M3, the median Tmax was 12 and 24 hours in subjects with CYP2C9*2*3 and *3*3
genotypes compared to 6 hours in *1*1 carriers. A similar delay in median Tmax was observed
in M5 poor metabolizers: 7 and 48 hours in CYP2C9*2*3 and *3*3 genotypes, respectively,
compared to 4 hours in *1*1 carriers. Overall, metabolite mean apparent terminal T1/2 was
prolonged in poor metabolizers. For M3, T1/2 was 54.8 and 96 hours in CYP2C9*2*3 and *3*3
subjects compared to 32.9 hours in *1*1 subjects. For M5, T1/2 was 105 hours in CYP2C9*2*3
subjects compared to 37.9 hours in *1*1 subjects. The M5 T1/2 could not be determined in
CYP2C9*3*3 subjects due to the very low plasma level allowing for only very few observations
48 hours post dose.
In Part 2, while subjects with CYP2C9*2*3 and *3*3 genotypes were comparably exposed to
siponimod, the Cmax and AUC0-24h for M3 and M5 were lower (range: 4- to 5-fold) in
CYP2C9*3*3 subjects compared to CYP2C9*2*3 carriers. For M3, median Tmax was 8 hours
for both groups. For M5, median Tmax was 10 hours in CYP2C9*2*3 subjects and 7 hours in
the *3*3 carriers.
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Table 3-14 Estimated siponimod CL/F per CYP2C9 genotype in the two
population pharmacokinetic analyses for a typical 69 to 70 kg subject
Differences in the PK of CYP2C9*1*2 and *1*3 subjects following a single 0.25-mg dose of
siponimod in [Study A2124] are consistent with the PopPK results. On Day 1, siponimod PK
in CYP2C9*1*2 subjects (Table 3-18) was consistent with historical data ([Study A2111]).
Siponimod was rapidly absorbed in CYP2C9*1*2 subjects, with a median Tmax of 4 hours. In
CYP2C9*1*3 subjects, median Tmax was slightly delayed (6 hours). While geometric mean
Cmax was comparable between CPY2C9*1*2 and *1*3 subjects, geometric mean AUCinf and
AUClast were approximately 29% higher in *1*3 compared to *1*2 subjects. Accordingly,
siponimod geometric mean T1/2 was longer and CL/F smaller in CYP2C9*1*3 versus *1*2
subjects (39.9 versus 27.2 hours and 2.58 L/h versus 3.33 L/h, respectively).
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3.2.6 Gender
The CL/F and Vc/F data in 224 males and 182 females in the Phase 1/Phase 2 PopPK analysis
(Section 3.1.9.1) and the CL/F data in 413 males and 632 females in the Phase 3 PopPK analysis
of SPMS patients (Section 3.1.9.2) suggest that gender had no significant impact on these
siponimod PK parameters.
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The weight effects on CL/F and Vc/F were 0.0085 and 0.0069 kg-1, respectively. For the range
of weights in the analysis (42 to 126 kg), CL/F ranged from 18% lower to 28% higher and Vc/F
from 24% lower to 47% higher compared to a 70.5-kg individual.
In the Phase 3 PopPK analysis of SPMS patients (Section 3.1.9.2), both Vc/F and CL/F
increased with weight with the power coefficient of 1 and 0.75, respectively (i.e., as (BW/70)1
and (BW/70)0.75). For the range of weights in the population (40 to 142 kg), Vc/F ranged from
43% lower to 101% higher and CL/F ranged from 35% lower to 69% higher compared to a
70.5-kg individual. Subjects with a body weight of 40 and 142 kg have a 53% higher and 40%
lower exposure, respectively, compared to subjects with a body weight of 70.5 kg. Considering
the limited effect on siponimod exposure, no dose adjustment is warranted to compensate for
the body weight effect.
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Figure 3-9 Effect of concomitant medications on siponimod PK and effect of siponimod on comedication PK (geometric
mean ratios and 90 percent confidence intervals)
Source: [Study A2108-Table 11-4], [Study A2125-Table 11-9], [Study A2124-Table 11-13], [Study A2121-Table 11-3], [Study A2116-Table 11-5].
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a Oral absorption of siponimod was estimated based on metabolite patterns in excreta and
extrapolation to total administered dose, assuming that the drug and metabolites are stable against
intestinal bacterial enzymes.
b Based on SimCYP simulations ([DMPK R1600759-01])
c Fractional contribution of CYP enzymes based on phenotyping data ([DMPK R0500432])
Source: DMPK R1600759-01
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Graphical displays did not reveal differences in siponimod concentrations if measured while on
CYP3A4 inducer(s) or not or on CYP3A4 inhibitor(s) or not. CYP2C9 inducers or inhibitors,
always administered along with comedications affecting CYP3A4, did not seem to influence
siponimod concentrations either.
Also siponimod plasma concentrations associated with CYP3A4 inducers or CYP3A4 weak,
moderate or strong inhibitors were predicted using the PopPK model (that did not include
concomitant medication as a covariate) and compared with the observed values. There appeared
to be no bias between the predicted and the observed values. This analysis could not be repeated
on CYP2C9 inducers or CYP2C9 inhibitors as there was not enough data.
Finally, the inclusion of weak CYP3A4 inhibitors as a covariate in the PopPK model was found
not to be significant.
Overall, these investigations do not confirm the clinical DDI results and suggest that CYP3A4
inducers or inhibitors do not impact siponimod PK. These results should however be interpreted
with caution as the pooled analysis of comedications was irrespective of their daily dose and
treatment duration, which may have led to heterogeneous induction or inhibition conditions. In
addition, the effect of comedications affecting CYP3A4 activity are most evident, especially
for inhibitors, in the CYP2C9 intermediate and poor metabolizer genotypes (Section 3.3.1.2.3),
which were either excluded (CYP2C9*3*3) or represented a small percentage of the PopPK
population (Table 3-13). No conclusion can be drawn from these analyses for drugs affecting
CYP2C9 due to the limited data available.
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([DMPK R1600759-01]): *1*1 and *1*2 extensive metabolizers, *1*3 and *2*2 intermediate
metabolizers and *2*3 and *3*3 poor metabolizers. The PBPK model was established using a
mixed approach combining in vitro data and PK parameters derived from clinical studies as
detailed in [DMPK R1600759-01-Section 3.2].
The model was used to evaluate the effects of itraconazole (strong CYP3A inhibitor),
fluconazole (moderate CYP3A/CYP2C9 inhibitor), fluvoxamine (weak CYP3A/CYP2C9
inhibitor) (Table 3-19), rifampin (strong CYP3A inducer with moderate induction potential for
CYP2C9) and efavirenz (moderate CYP3A inducer) (Table 3-20) on siponimod systemic
exposure. As there are no marketed drugs showing strong CYP2C9 inhibition or induction
potential so far, only moderate and weak CYP2C9 perpetrator drugs were used clinically and/or
for the modeling. Although a PBPK model of a strong CYP2C9 inhibitor sulfaphenazole is
available in SimCYP, the performance to predict the DDI effects might not be fully evaluated.
In addition, as no selective CYP2C9 inhibitors or inducers are available on the market, dual
perpetrator drugs impacting also the CYP3A4 pathways were selected. However, the fractional
contribution of the CYP2C9 pathway was confirmed using poor metabolizer PK data
(CYP2C9*2*3 and *3*3). The DDI simulation design parameters used are summarized in
[DMPK 1600759-01-Table 3-3 and DMPK 1600759-01-Table 3-4] for siponimod as a victim
with CYP enzyme inhibitors and inducers, respectively.
Effect of inhibitors
Strong CYP3A4 inhibitors
In the presence of the strong CYP3A4 inhibitors itraconazole and ketoconazole, there was a
tendency of an increase in predicted siponimod AUCinf inhibition ratios with the decrease in
CYP2C9 metabolic activity. The ratios increased from 1.17 in CYP2C9*1*1 up to 1.37 in
CYP*2*3 in presence of itraconazole, and from 1.24 in CYP2C9*1*1 up to 1.51 in
CYP2C9*2*3 in presence of ketoconazole. The CYP2C9*3*3 genotype population shows a
significantly higher DDI risk, with predicted AUC ratios of 3.25 and 4.42 for itraconazole and
ketoconazole, respectively (Table 3-19). Ratios for Cmax (predicted and observed) were not
affected in the presence of any of the inhibitors and did not differ among the CYP2C9 genotypes;
the geometric means for the predicted Cmax ratios ranged from 1.00 to 1.07.
In the itraconazole DDI [Study A2124] siponimod AUCinf decreased by 10% and 24% in
subjects with the CYP2C9*1*2 and *1*3 genotypes, respectively, in the presence of
itraconazole, while SimCYP predictions indicated 18% and 30% increases, respectively, in
these 2 genotypes. A potential explanation for this discrepancy could be the induction of another
metabolizing pathway, such as CYP1A1, which was identified in vitro as a minor siponimod
metabolic pathway ([DMPK R0500432]). It was not implemented in the SimCYP model, as in
a non-induced state the abundance of this enzyme is very low (Kim et al 2004). Hepatocyte
investigations performed to better characterize the itraconazole inhibition/induction properties
in vitro indicated that while itraconazole weakly induces CYP1A1 (about 1% relative to the
induction by the positive control), the itraconazole net effect on CYP1A1 is an inhibition effect
([DMPK R1701078]). Itraconazole did not lead to a significant induction of CYP2B6, 2C9 or
3A4. The influence of smoking, a known potent CYP1A inducer, on siponimod PK was
investigated graphically with data from [Study A2304]. Siponimod concentrations were
stratified by CYP2C9 genotype and compared between smokers and non-smokers. The graphs
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did not reveal any apparent difference in steady-state siponimod concentrations as a function of
the smoking status ([BAF312_exposure_and_smoking_status]). Based on these results likely
indicating no clinically relevance of CYP1A pathway in siponimod metabolism, and
considering that the fraction metabolized via CYP3A4 was verified by the fluconazole and
rifampicin DDI study data, the SimCYP model was still considered as valid. While the
underlying mechanism leading to a reduced exposure of siponimod in presence of itraconazole
is not understood, these results should therefore not be extrapolated to other strong and specific
CYP3A4 inhibitors (such as clarithromycin).
Moderate CYP3A4 inhibitors
For erythromycin (moderate CYP3A4 inhibitor), the predicted AUC inhibition ratios were also
larger for the CYP2C9*3*3 genotype (2.46) compared to the other genotypes (1.14 to 1.32;
Table 3-19).
Moderate CYP3A4/2C9 inhibitors
In the presence of fluconazole (moderate CYP3A4/2C9 inhibitor) and fluvoxamine
(weak CYP3A4/2C9 inhibitor), little difference between the 6 different CYP2C9 genotypes
was predicted, with an AUC ratios ranging from 2.15 to 2.52 for fluconazole and 1.12 to 1.41
for fluvoxamine as both metabolic pathways are inhibited by this dual inhibitor (Table 3-19).
The predicted AUC ratio for CYP2C9*1*1 subjects (2.15) in the presence of fluconazole was
in line with the corresponding clinical observation (1.98) in [Study A2128].
Effect of inducers
Strong CYP3A4/moderate CYP2C9 inducers
In presence of rifampin (strong CYP3A4 and moderate 2C9 inducer), both siponimod metabolic
pathways are impacted and only a small difference in the induction effect was predicted between
CYP2C9 genotypes (AUC ratios ranging from 0.32 to 0.21, Cmax ratios ranging from 0.5 to
0.27; Table 3-20). Predicted siponimod ratios for CYP2C9*1*1 subjects (AUC ratio of 0.32,
Cmax ratio of 0.5) when co-administered with rifampin were comparable to the corresponding
clinical observations (AUC ratio of 0.43, Cmax ratio of 0.55) in [Study A2125].
Moderate CYP3A4 inducers
When co-administered with efavirenz (moderate CYP3A4 inducer), slightly higher siponimod
AUC and Cmax ratios were predicted for CYP2C9*3*3 (AUC ratio of 0.35, Cmax ratio of 0.41);
similar AUC and Cmax ratios were estimated for the other CYP2C9 genotypes (AUC ratios
between 0.58 and 0.71 and Cmax ratios between 0.65 and 0.79; Table3-20).
Table 3-19 Predicted siponimod single dose inhibition area under the curve
ratios in the presence of CYP3A4 and CYP3A4/CYP2C9 inhibitors in
various CYP2C9 genotypes
Moderate
Strong 3A4 Strong 3A4 Moderate 3A4 2C9/3A4 Weak 3A4/2C9
inhibitor: inhibitor: inhibitor: inhibitor: inhibitor:
CYP2C9 Itraconazole Ketoconazole Erythromycin Fluconazole Fluvoxamine
genotype AUCi/AUCa AUCi/AUCa AUCi/AUCa AUCi/AUCa AUCi/AUCa
*1*1 1.17 1.24 1.14 2.15 1.41
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Moderate
Strong 3A4 Strong 3A4 Moderate 3A4 2C9/3A4 Weak 3A4/2C9
inhibitor: inhibitor: inhibitor: inhibitor: inhibitor:
CYP2C9 Itraconazole Ketoconazole Erythromycin Fluconazole Fluvoxamine
genotype AUCi/AUCa AUCi/AUCa AUCi/AUCa AUCi/AUCa AUCi/AUCa
(1.16 – 1.18) (1.23 – 1.26) (1.13 – 1.16) (2.11 – 2.18) (1.38 – 1.45)
1.18 1.26 1.16 2.15 1.41
*1*2
(1.17 – 1.19) (1.25 – 1.28) (1.15 – 1.17) (2.11 – 2.19) (1.37 – 1.44)
1.24 1.34 1.21 2.18 1.37
*2*2
(1.23 – 1.26) (1.32 – 1.37) (1.19 – 1.22) (2.14 – 2.22) (1.34 – 1.41)
1.30 1.42 1.26 2.20 1.35
*1*3
(1.28 – 1.32) (1.39 – 1.45) (1.24 – 1.28) (2.16 – 2.24) (1.32 – 1.38)
1.37 1.51 1.32 2.22 1.32
*2*3
(1.35 – 1.40) (1.48 – 1.55) (1.29 – 1.35) (2.18 – 2.26) (1.29 – 1.34)
3.25 4.42 2.46 2.52 1.12
*3*3
(2.99 - 3.51) (4.14 – 4.70) (2.29 – 2.63) (2.45 – 2.58) (1.11 – 1.13)
a Geometric mean (90% CI)
Source: [DMPK 1600759-01-Tables 6-11, 6-12, 16-13, 6-14 and 6-15]
Table 3-20 Predicted siponimod steady state induction area under the curve and
maximum concentration ratios in the presence of CYP3A4 and
CYP3A4/CYP2C9 inducers in various CYP2C9 genotypes
Strong 3A4/moderate 2C9 inducer:
CYP2C9 Rifampin Moderate 3A4 inducer: Efavirenz
genotype AUCi/AUCa Cmaxi/Cmaxa AUCi/AUCa Cmaxi/Cmaxa
*1*1 0.32 (0.31 – 0.33) 0.50 (0.49 – 0.51) 0.71 (0.69 – 0.73) 0.79 (0.77 – 0.80)
*1*2 0.32 (0.31 – 0.33) 0.49 (0.48 – 0.50) 0.70 (0.68 – 0.71) 0.77 (0.76 – 0.79)
*2*2 0.31 (0.30 – 0.32) 0.46 (0.45 – 0.47) 0.65 (0.63 – 0.67) 0.73 (0.71 – 0.74)
*1*3 0.30 (0.29 – 0.31) 0.43 (0.42 – 0.44) 0.61 (0.59 – 0.63) 0.69 (0.67 – 0.71)
*2*3 0.29 (0.28 – 0.30) 0.41 (0.40 – 0.42) 0.58 (0.56 – 0.60) 0.65 (0.63 – 0.67)
*3*3 0.21 (0.20 – 0.22) 0.27 (0.27 – 0.29) 0.35 (0.33 – 0.38) 0.41 (0.39 – 0.43)
a Geometric mean (90% CI)
Source: [DMPK 1600759-01-Tables 6-16 and 6-17]
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Inhibitors
Under the proposed genotype-based dosing recommendations and considering an acceptance of
a maximum 2-fold exposure increase (conservative approach), siponimod may be combined
with all types of CYP3A4/CYP2C9 inhibitors without relevant implications on safety or
efficacy for concomitant treatment in most patients. Particular caution should be applied in
patients with a CYP2C9*2*2 genotype for combination treatment with moderate
CYP2C9/CYP3A4 inhibitors (e.g. fluconazole) due to a higher exposure (AUC ratio 2.7; Table
3-21). Dosage adjustment to 1 mg daily may be considered in these patients.
Inducers
Strong CYP3A4/moderate CYP2C9 inducers are predicted to reduce siponimod exposure by
approximately 61% to 76% (Table 3-22). Moderate CYP3A4 inducers are predicted to reduce
siponimod exposure by approximately 19% to 51% (Table 3-22). Caution should therefore be
applied when siponimod is used in combination with:
Strong CYP3A4/moderate CYP2C9 inducers for all genotypes (e.g., rifampin,
carbamazepine)
Moderate inducers of CYP3A4 in patients with a CYP2C9*1*3 or *2*3 genotype
(e.g., efavirenz, modafinil)
Table 3-21 Net inhibition effect ratios (inhibition x CYP2C9 genotype exposure
ratios)
CYP2C9- Moderate
genotype Strong 3A4 Strong 3A4 Moderate 3A4 2C9/3A4 Weak 3A4/2C9
based inhibitor: inhibitor: inhibitor: inhibitor: inhibitor:
CYP2C9 dosing Itraconazole Ketoconazole Erythromycin Fluconazole Fluvoxamine
genotype (mg) AUC ratioa,b AUC ratioa,b AUCi/AUCa,b AUC ratioa,b AUC ratioa,b
*1*1 2 1.17 1.24 1.14 2.15 1.41
*1*2 2 1.18 1.26 1.16 2.15 1.41
*2*2 2 1.55 1.68 1.51 2.73 1.71
*1*3 1 1.05 1.15 1.02 1.78 1.09
*2*3 1 1.32 1.46 1.27 2.13 1.27
a Calculated using DDI ratios from Table 3-19 multiplied by the genotype effect on exposure
(CYP2C9-genotype based dosing adjustment factor)
b Geometric mean (90% CI)
Source: [DMPK 1600759-01-Tables 6-11, 6-12, 16-13, 6-14 and 6-15]
Table 3-22 Net induction effect ratios (induction x CYP2C9 genotype exposure
ratios)
Therapeutic Strong 3A4/moderate 2C9 Moderate 3A4 inducer:
CYP2C9 maintenance inducer: Rifampin Efavirenz
genotype dose (mg) AUC ratioa,b Cmax ratioa,b AUC ratioa,b Cmax ratioa,b
*1*1 2 0.32 0.50 0.71 0.79
*1*2 2 0.32 0.49 0.70 0.77
*2*2 2 0.39 0.58 0.81 0.91
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3.4 Pharmacodynamics
The primary focus of this section is the across-study pooled analyses of primary and secondary
PD effects of siponimod in healthy subjects (single and multiple dose studies) and PM/DM
patients (multiple dose studies); a summary of the assessment methodology, including types of
assessments for each analysis and categories of interest, is presented in Table 5-3. A by-study
summary of clinical PD evaluations of siponimod is presented for healthy subjects in
Section 2.2, including hepatic and renal impairment subjects (not included in the pooled
analyses) in Section 2.2.10.1, and in MS and PM/DM patients in Section 2.3.1 and Section 2.3.2,
respectively.
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Table 3-24 Incidence of AEs (at least 2 percent) by SOC and PT in single dose
studies in healthy subjects
Subjects with at least 1 AE Siponimod Placebo
N = 348 N = 41
n (%) n (%)
Cardiac disorders 37 (10.6) 0
AV block second degree 12 (3.4) 0
Bradycardia 15 (4.3) 0
Gastrointestinal disorders 30 (8.6) 1 (2.4)
Nausea 19 (5.5) 1 (2.4)
General disorders and administration site conditions 28 (8.0) 0
Fatigue 12 (3.4) 0
Infections and infestations 19 (5.5) 0
Upper respiratory tract infection 7 (2.0) 0
Nervous system disorders 125 (35.9) 4 (9.8)
Dizziness 42 (12.1) 1 (2.4)
Headache 113 (32.5) 2 (4.9)
Somnolence 8 (2.3) 1 (2.4)
n = number of subjects with at least 1 AE in the category.
Source: [SCS Appendix 1-Tables 12-1.1.1 and 12-1.2.1 and Listing 16.2.7-1.1p]
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Table 3-25 Incidence of AEs (at least 2 percent) by SOC and PT in multiple dose
studies in healthy subjects
Subjects with at least 1 AE Siponimod Placebo
N = 544 N = 393
n (%) n (%)
Gastrointestinal disorders 72 (13.2) 30 (7.6)
Constipation 11 (2.0) 6 (1.5)
Diarrhoea 12 (2.2) 3 (0.8)
Nausea 23 (4.2) 6 (1.5)
General disorders and administration site conditions 41 (7.5) 11 (2.8)
Fatigue 15 (2.8) 2 (0.5)
Investigations 52 (9.6) 3 (0.8)
Alanine aminotransferase increased 19 (3.5) 1 (0.3)
Musculoskeletal and connective tissue disorders 45 (8.3) 14 (3.6)
Back pain 15 (2.8) 2 (0.5)
Nervous system disorders 137 (25.2) 31 (7.9)
Dizziness 31 (5.7) 3 (0.8)
Headache 113 (20.8) 25 (6.4)
Respiratory, thoracic and mediastinal disorders 25 (4.6) 13 (3.3)
Oropharyngeal pain 13 (2.4) 5 (1.3)
n = number of subjects with at least 1 AE in the category.
Source: [SCS Appendix 1-Tables 12-1.1.2 and 12-1.2.2 and Listing 16.2.7-1.2p]
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Overall, under single dose conditions in healthy subjects, across all investigated dose levels HR
changes from Baseline in siponimod-treated subjects were predominantly Category 1 events
(HR change from Baseline > 25% and ≤ 35%) which occurred at a lower frequency than in
placebo-treated subjects. New HR values in Category 4 (HR value below 30 bpm) only occurred
at doses ≥ 10 mg. Under multiple dose conditions in healthy subjects across all investigated
doses and regimens, cases of HR change from Baseline in siponimod-treated subjects were
mainly events of Category 1 and Category 2 (HR change from Baseline > 35% and ≤ 50%). No
new HR values of Category 4 were observed. Importantly, in subjects under the 2-mg siponimod
DT regimen, the incidence of Category 1 and 2 events and cases in the combined Category 8
(HR decrease > 25% from Baseline to a HR < 50 bpm) were similar to placebo, underlining the
effectiveness of the DT regimen in attenuating the bradyarrhythmic effects of siponimod.
Under multiple dose conditions (non-titrated and titrated) in healthy subjects, the percentages
of siponimod-treated subjects with Category 1 and 2 events were 54.2% and 31.1%, respectively,
based on Holter ECG analyses (Table 3-26) and 11.2% and 5.5%, respectively, based on 12-lead
ECG analyses. The corresponding percentages of placebo-treated subjects were 38.7% and
21.8%, respectively, based on Holter ECG analyses and 8.7% and 4.3%, respectively, based on
12-lead ECG analyses. At doses ≤ 2 mg, this difference was mainly driven by the siponimod
treatment groups without a preceding DT and the majority of Category 1 and 2 events occurred
at doses > 2 mg. The Category 1 and 2 percentages for the 2 mg DT dose group were 18.6%
and 6.8%, respectively, based on Holter ECG analyses and 0.4% and 0%, respectively, based
on 12-lead ECG analyses, indicating a placebo-like occurrence of these events. None of the
subjects showed a HR value below 30 bpm in any group (Category 4) based on 12-lead ECG
or Holter analyses. Cases in the combined Category 8 were seen in 19.8% of siponimod-treated
subjects (mainly at doses > 2 mg) compared to 0.4% of placebo-treated subjects based on Holter
ECG analyses, while no cases were seen in 12-lead ECG analyses. In the 2 mg DT group only
1.7% of subjects showed Category 8 events based on Holter ECG analyses, indicating a
placebo-like occurrence of these events.
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Table 3-26 Heart rate categorical outlier analysis (Holter data) – multiple dose studies
HR change from Baseline New HR values compared to Combined category
Baseline
Category 1 2 3 4 5 6 7 8 9
HR decrease HR increase
≥ 30 bpm ≥ 40 bpm ≥ 45 bpm > 25% from > 25% from
> 25% and > 35% and and and and Baseline to a Baseline to a
≤ 35% ≤ 50% > 50% < 30 bpm < 40 bpm < 45 bpm < 50 bpm HR < 50 bpm HR > 100 bpm
Treatment n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
BAF312 0.3 mg (N=15) 11 (73.3) 8 (53.3) 4 (26.7) 0 0 0 1 ( 6.7) 0 6 (40.0)
BAF312 1 mg (N=15) 9 (60.0) 4 (26.7) 2 (13.3) 0 0 2 (13.3) 2 (13.3) 3 (20.0) 2 (13.3)
BAF312 2.5 mg (N=16) 13 (81.3) 8 (50.0) 3 (18.8) 0 0 3 (18.8) 8 (50.0) 8 (50.0) 4 (25.0)
BAF312 10 mg (N=32) 18 (56.3) 7 (21.9) 3 ( 9.4) 0 3 ( 9.4) 6 (18.8) 16 (50.0) 14 (43.8) 5 (15.6)
BAF312 20 mg (N=18) 11 (61.1) 6 (33.3) 3 (16.7) 0 4 (22.2) 7 (38.9) 10 (55.6) 12 (66.7) 5 (27.8)
BAF312 0.5 mg 4 (33.3) 2 (16.7) 0 0 0 3 (25.0) 4 (33.3) 2 (16.7) 0
preceded by up-titration
(N=12)
BAF312 2 mg 22 (18.6) 8 ( 6.8) 0 0 1 ( 0.8) 1 ( 0.8) 16 (13.6) 2 ( 1.7) 0
preceded by up-titration
(N=118)
BAF312 10 mg 75 (62.5) 47 (39.2) 6 ( 5.0) 0 1 ( 0.8) 3 ( 2.5) 8 ( 6.7) 2 ( 1.7) 3 ( 2.5)
preceded by up-titration
(N=120)
BAF312 in 4 (10.5) 1 ( 2.6) 1 ( 2.6) 0 1 ( 2.6) 4 (10.5) 16 (42.1) 11 (28.9) 0
combinationa (N=38)
Comparator alone 80 (61.1) 54 (41.2) 13 ( 9.9) 0 0 3 ( 2.3) 14 (10.7) 2 ( 1.5) 6 ( 4.6)
(N=131)
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AV blocks
Under single dose conditions in healthy subjects, asymptomatic first degree AV blocks were
observed in Holter ECGs in 2.8% of the siponimod-treated subjects and had a comparable
incidence of 0% in placebo-treated subjects. As some of the pooled single-dose studies were
open-label studies and did not include a placebo group, this slight imbalance in the incidence
of first degree AV blocks should be interpreted with caution. All detected second degree AV
blocks were Mobitz I type, which resolved spontaneously without requiring medical
intervention and were mostly asymptomatic; no second degree AV blocks with 2:1 or 3:2
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conduction or higher degree AV blocks were observed. The incidence of AV blocks Mobitz I
in Holter ECGs was 6.5% after a single dose of siponimod compared to 0% in placebo subjects
and none of the observed second degree AV blocks occurred at doses below 2.5 mg. The
corresponding figures for second degree AV blocks based on online cardiac monitoring
(telemetry) data were 2.7% in siponimod-treated subjects compared to 0% in placebo subjects,
with 80% of these observations occurring at doses of 4 mg.
In multiple dose studies, asymptomatic first degree AV blocks were observed in Holter ECGs
in 5.0% of the siponimod-treated subjects and in 1.2% of placebo-treated subjects, with the
incidences ranging between 0% and 6.3% in non-titrated groups compared to only 0% to 1.7%
in DT conditions for siponimod-only treatment (Table 3-27). As some of the pooled multiple-
dose studies were open-label studies and did not include a placebo group, this imbalance in the
incidence of first degree AV blocks should be interpreted with caution. In Holter ECG-based
analyses, the majority of detected second degree AV blocks was Mobitz I type and observed at
an incidence of 3.5% in siponimod-treated subjects compared to 1.8% in placebo-treated
subjects, while second degree AV blocks with 2:1 or 3:2 conduction did occur in 1% and 0.2%
of the siponimod subjects, respectively (0% in placebo subjects). The Holter-based incidence
of second degree AV blocks of Mobitz I type showed a clear imbalance between non-titrated
groups (0% to 18.8% (0% to 13.3% at doses ≤ 2 mg)) compared to 0% to 1.7% in DT groups,
indicating the efficient mitigation of bradyarrhythmic events under the DT regimen.
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Sinus pauses
Under single dose conditions in healthy subjects, asymptomatic sinus pauses (defined as
RR > 2 sec) were observed in Holter ECGs in 19.6% of the siponimod-treated subjects
compared to 2.4% in placebo-treated subjects. The majority of detected sinus pauses had a RR
interval of < 3 sec and was observed mainly at oral doses above or equal to 2.5 mg. As some of
the pooled single dose studies were open-label studies and did not include a placebo group, this
imbalance in the incidence of sinus pauses should be interpreted with caution. All detected sinus
pauses resolved spontaneously without requiring medical intervention.
Under multiple dose conditions in healthy subjects, the overall incidence of sinus pauses (RR >
2 sec) based on Holter ECG data was 9.9% in siponimod-treated subjects compared to 1.8% in
placebo-treated subjects (Table 3-27). All identified sinus pauses were asymptomatic, and
resolved spontaneously without medical intervention. The detected sinus pauses occurred
mainly at oral doses > 2 mg; within individual dose groups, incidences ranged between 0 and
6.7% at oral non-titrated doses ≤ 2 mg, while incidences ranged between 1.6% and 55.6% at
non-titrated oral doses between 2.5 and 20 mg. As with second degree AV blocks, the incidence
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of sinus pauses was notably lower in DT groups, with 1.7% for DT to 2 mg and 4.2% for DT to
10 mg, demonstrating the efficient mitigation of bradyarrhythmic events by the DT regimen.
QT interval/cardiac repolarization
Treatment with siponimod did not reveal an arrhythmogenic potential related to QT
prolongation ([Study A2118]).
The pooled categorical analyses of predefined QTcF events by 12-lead ECG and Holter ECG
asssessments, described in Table 5-3, are available in [SCS Appendix 1-Table 12-3.1.1 to SCS
Appendix 1-Table 12-3.1.3 and SCS Appendix 1-Table 12-3.2.2], respectively for studies in
healthy subjects (single and multiple dose) and PM/DM patients. Fridericia-corrected QT
values were used as an appropriate HR correction method for a drug with known effects on HR
and to enhance the QTcF-based categorical analysis in the thorough QT study.
The QTcF profile in the pooled analyses across single and multiple dose studies was overall
consistent with the categorical QTcF analyses in the dedicated thorough QT (Study A2118).
Holter ECG analyses (data only available for multiple dose study healthy subjects) and 12-lead
ECG analyses revealed that the majority of events were QTcF changes from Baseline > 30 msec
and ≤ 60 msec (Category 1) or new QTcF values > 450 msec and ≤ 480 msec (Category 3)
which were observed in siponimod-treated subjects/patients with an incidence comparable to
placebo. QTcF changes from Baseline > 60 msec (Category 2) or new on-treatment QTcF
values > 480 msec (Categories 4 and 5) or the combination of both (Category 6) were seen in a
limited number of subjects (0% for most subjects, for both siponimod and placebo treatments).
As some of the pooled studies were open-label studies and did not include a placebo group, this
imbalance in the incidence of QTcF categories of interest should be interpreted with caution.
In single dose studies, 12-lead ECG data did not reveal any QTcF changes in Categories 2, 4, 5
or 6 in siponimod-treated subjects. QTcF changes in Category 1 were detected in 8.3% of
siponimod treated subjects compared to 9.8% in placebo subjects and did not show any clear
relation to the dose level. New QTcF values in Category 3 were seen in 2.8% of
siponimod-treated subjects compared to 0% in placebo subjects and occurred at single doses of
≥ 4 mg or at 1 mg iv over 24 hours.
Under multiple dose conditions in healthy subjects, 12-lead ECG data revealed occurrences of
predefined events only in siponimod-treated subjects for Categories 2 (3 subjects (0.6%)),
4 (1 subject) and 6 (1 subject). QTcF changes from Baseline in Category 1 were detected in 5.7%
of siponimod-treated subjects compared to 2.3% in placebo subjects and did not show any clear
relation to the dose level or difference between non-titrated and titrated dosing regimens. Holter
ECG analyses from 3 multiple dose studies did not reveal any events in Categories 2, 4, 5 or 6
in siponimod-treated subjects (Table 3-28). QTcF changes from Baseline in Category 1 were
detected in 18.4% of siponimod-treated subjects compared to 4.2% of placebo-subjects and did
not show any clear relation to the dose level. Category 3 events were seen in 3.4% of siponimod-
treated subjects compared to 0.4% in placebo-treated subjects and occurred at single doses of
10 mg.
Table 3-28 QTcF events categorical analysis (Holter data) - multiple dose studies
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In PM/DM patients, 12-lead ECG analyses showed a placebo-like incidence of Category 1 and
3 QTcF events, while the incidence of events in Categories 2, 4, 5 and 6 was higher in
siponimod-treated patients compared to patients under placebo. Due to the overall small sample
sizes in the pooled PM/DM studies and potential confounding effects of the underlying disease
condition and concomitant use of standard of care drugs for treatment of PM/DM, the described
imbalance in the incidence of certain QTcF categories of interest should be interpreted with
caution.
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Appendix 1-Table 12-6.2.1 to SCS Appendix 1-Table 12-6.2.3] (combined categories) for
studies in healthy subjects (single and multiple dose) and PM/DM patients.
In both healthy subjects and PM/DM patients there were no events in the combined Categories
5 and 6 (ALT or AST > 3-fold and bilirubin > 2-fold above ULN), confirming that no Hy’s law
cases were identified. Under single and multiple dose conditions in healthy subjects, ALT, AST
and GGT increases ≥ 3-fold ULN (Categories 2 to 4) generally occurred at placebo-like
frequencies of approximately 1% or less; these instances occurred primarily above the 2 mg
therapeutic dose in siponimod-treated subjects.
Under multiple dose conditions in healthy subjects, no events of AP elevations falling within
the predefined categories were identified. For bilirubin only Category 1 events were identified
and the overall incidence was very low (1.3% in siponimod-treated and 0.3% in placebo
subjects). For ALT, AST and GGT, the majority of events were in Category 1 (12.4%, 4.4%
and 6.5%, respectively) and were higher in siponimod-treated subjects (17.5%, 6.3% and 8.1%,
respectively) than placebo-treated subjects, generally occurring more often at doses > 2 mg
(siponimod-only titrated and non-titrated treatment; average: 30.0% (15.8% to 46.9%), 12.7%
(3.1% to 38.9%) and 13.2% (3.1% to 33.3%), respectively). For bilirubin only Category 1
events were identified and the overall incidence was very low (1.3% of siponimod-treated
subjects and 0.3% of placebo subjects). For ALT, AST and GGT, the majority of events were
in Category 1. For AST, 6.3% of siponimod-treated subjects (mainly at doses ≤ 2 mg) and 0.5%
of placebo-treated subjects had values in Category 1, compared to < 1% each for Categories 2,
3 or 4 for either treatment. For ALT, the incidence of Category 1 events was 17.5% of
siponimod-treated subjects compared to 3.3% of placebo-treated subjects, with an increase in
incidence at doses > 2 mg. Category 2 events were identified in 4.2% of siponimod-treated
subjects compared to 0.5% of placebo-treated subjects, with a clear increase in incidence at
doses > 2 mg. In Categories 3 and 4, the overall incidences were very low (1.0% and 0.1% of
subjects, respectively). For GGT, the incidence of Category 1 events was 17.5% of siponimod-
treated subjects (with similar proportions of subjects at doses ≤ 2 mg or > 2 mg), compared to
3.3% of placebo-treated subjects. Category 2 events were identified in 2.2% of siponimod-
treated subjects compared to 0% of placebo-treated subjects, with an increase in incidence at
doses > 2 mg. In Categories 3 and 4, the overall incidences were very low (0.7% and 0.1% of
subjects, respectively).
Due to the underlying disease effects on liver enzymes (Nathwani et al 2005, Wada et al 2016)
and multiple concomitant and standard of care medications in the PM/DM studies, an influence
of the disease activity and of co-administered drugs on the analyzed laboratory variables cannot
be ruled out; thus, the pooled LFT analyses in PM/DM patients should be interpreted in this
context. There were no patients in the PM/DM multiple dose studies with values in Categories 3
or 4 for any of the LFT parameters. For AP and bilirubin, there were also no patients with values
in Categories 1 or 2. The incidence of values in Categories 1 and 2 for ALT, AST and GGT
were higher in siponimod-treated patients compared to siponimod-treated healthy subjects:
ALT 20.9% and 11.6%, respectively; AST 16.3% and 7.0%, respectively; and GGT 12.2% and
8.2%, respectively. Comparing to placebo-treated PM/DM patients, similar percentages were
observed for ALT; however, Category 1 and 2 percentages were 10.0% and 15.0%, respectively,
for AST and 5.0% and 0%, respectively, for GGT in placebo-treated patients.
3.4.2.4.3 Infections
Considering the primary PD effect of siponimod on lymphocytes, potential translation to an
increased rate of infections was explored and is discussed in detail in [SCS-Section 2.1.5.1 and
SCS-Sections 2.1.5.2]. A pooled analysis of AEs by PT (detailed in Table 5-3) assessed the
incidence of infection-related AEs as reported in the Clinical Pharmacology and PM/DM
studies.
The most commonly reported infection-related AE was upper respiratory tract infection, with
overall slightly higher incidence rates for siponimod treatment (2.0%, 1.8% and 7.0% in single
dose, multiple dose and PM/DM studies, respectively) compared to placebo treatment (0%, 1.0%
and 0% in single dose, multiple dose and PM/DM studies, respectively). However, the
incidence of such infections was similar to placebo at the therapeutic dose of 2 mg (1.7%
incidence for siponimod uptitration to 2 mg, compared to 1.0%). Urinary tract infections were
reported at low incidence rates across all types of studies, at incidence rates of 0.3%, 0.2% and
4.7% for siponimod treatment in single dose, multiple dose, and PM/DM studies, respectively,
compared to no events for placebo treatment in the single dose, multiple dose or PM/DM studies.
Other types of infection-related AEs were reported in single subjects or at incidence rates ≤ 0.3%
without a distinguishable difference between siponimod- and placebo-treated subjects/patients;
these included herpes zoster infection (mild, skin involvement only), viral upper respiratory
tract infections, respiratory tract infection, tooth infection, viral infection and vulvovaginal
mycotic infection.
3.4.2.4.4 Abuse and dependence potential (8-factor drug abuse liability assessment)
A comprehensive 8-factor abuse potential assessment was carried on the basis of relevant
chemistry, nonclinical and clinical data of siponimod and including post-marketing data on
fingolimod ([Abuse Potential Assessment]).
Overall, chemistry, nonclinical and clinical data with siponimod do not indicate any signals of
abuse, misuse or dependence potential in animals or humans, nor do the data demonstrate any
potential pharmacological similarities to existing drugs of abuse or psychoactive effects that
may be of interest for drug abuse, such as reinforcing, mood-elevating, sedative, stimulant,
hallucinogenic or acute cognitive effects. These data are consistent with post-market data for
the pharmacologically similar drug fingolimod, which has not shown any signs of abuse, misuse,
diversion or dependence in the community. Therefore, it can be concluded that siponimod has
no abuse or dependence potential and is not expected to be subject to abuse, misuse or diversion
in the community, or result in harm to public health as a result of abuse, misuse or dependence.
Thus, siponimod does not meet the criteria for any of the schedules defined under the Controlled
Substances Act and therefore should not be scheduled.
The impact of population type, gender and Japanese ethnicity and also body weight and
CYP2C9 genotypes (significant predictors of siponimod plasma concentrations, as described in
Section 3.1.9.2) on lymphocyte response was evaluated using trough simulations
(500 lymphocyte count profiles were simulated for each subject). All were conducted over
130 days with 2 mg siponimod administered qd for 40 days (steady-state conditions) for a
typical subject (SPMS patient, male, 70.5 kg, non-Japanese with CYP2C9*1*1 or *1*2
genotype), or different subjects changing 1 covariate at a time and keeping the others at typical
values.
Figure 3-11 represents the obtained simulated median ALC for the typical subject and by gender,
population type (RRMS and healthy subjects) and Japanese ethnicity. This shows, for all
simulated populations, a sharp decrease in the lymphocyte count upon treatment initiation
(Day 0), then values remaining at a plateau during the chronic treatment followed by a return
to Baseline starting promptly after treatment discontinuation (Day 39). Similar graphs for
lymphocyte count profiles were produced for different body weights and different CYP2C9
genotypes, showing the same type of trajectories of lymphocyte count
([CBAF312A-Phase 3-PopPKPD]).
HV = healthy volunteer.
500 patients per profile, residual variability taken into account
Source: [CBAF312A-Phase 3-PopPKPD-Figure 5-20]
For each covariate, the lymphocyte count at steady state and the lymphocyte recovery time to a
level of 1.0 × 109/L after treatment discontinuation are displayed in Table 3-30 and Table 3-31,
respectively. The lymphocyte recovery time to a level of 90% of the Baseline value after
treatment interruption was also computed ([CBAF312A-Phase 3-PopPKPD-Table 5-15]).
These values are approximately 2 to 2.5 times greater than the values reported for the recovery
time to a level of 1.0 × 109/L (see below).
Compared to the typical SPMS patients (70.5 kg), for a 2-mg dose, lighter patients (49 kg, 5th
percentile of weight in the Phase 3 study) had a 9% lower nadir median steady-state lymphocyte
count and identical lymphocyte recovery time and heavier patients (100 kg, 95th percentile of
weight) had a 4% higher nadir median steady-state lymphocyte count and slightly faster
lymphocyte recovery ([CBAF312A-Phase 3-PopPKPD-Figure 5-16]). Patients with
CYP2C9*2*3 and *1*3 genotypes had comparable nadir lymphocyte count. The CYP2C9*2*2,
*1*3, *2*3 and *3*3 genotypes had lower nadir (9%, 12%, 16% and 26%, respectively)
lymphocyte count than the reference CYP2C9*1*1 (wild type) and *1*2 genotypes.
Lymphocyte counts recovered in the following order, by CYP2C9 genotype: *1*1 and *1*2
first, then *2*2, next *1*3 then *2*3 and lastly *3*3. In both cases, the lower lymphocyte
counts in lighter patients and poor metabolizers (CYP2C9*2*2, *1*3, *2*3 and *3*3) were due
to higher plasma siponimod exposures in lighter patients compared to heavier patients and
higher plasma siponimod exposure in intermediate and poor metabolizers compared to patients
with CYP2C9*1*1 or *1*2 genotypes. (PD assessments in CYP2C9 extensive and poor
metabolizers are described in Section 2.2.10.3.)
Females had an 8% lower nadir median steady-state lymphocyte count than males, and
lymphocyte counts in females recovered to 1.0 × 109/L at the same speed as in males. The lower
nadir lymphocyte count in females was due to the 37% (95% CI: 31% to 43%) smaller IC50 in
females compared to males.
Japanese patients had a 23% lower nadir median steady-state lymphocyte count than
non-Japanese, and lymphocyte recovery time to 1.0 × 109/L in Japanese patients was slightly
slower than in non-Japanese patients (1 day slower). The lower nadir lymphocyte count in
Japanese was due to the 10% (95% CI: 7% to 13%) higher Imax in Japanese compared to non-
Japanese. (PD assessments in Japanese subjects are described in Section 2.2.10.2.)
RRMS patients had a 16% higher nadir median steady-state lymphocyte count than SPMS
patients, and RRMS and SPMS patients had a 17% and 29%, respectively, lower nadir median
lymphocyte count than healthy subjects. In addition, lymphocyte counts in healthy subjects
recovered slightly more quickly to 1.0 × 109/L than in RRMS patients, both of whom had
quicker lymphocyte recovery time than SPMS patients. This was a result of RRMS and SPMS
patients having lower (17% (95% CI: 15% to 19%)) Baseline lymphocyte count than healthy
subjects, and SPMS patients having lower IC50 (39% (95% CI: 34% to 45%)) compared to
healthy subjects and RRMS patients. The median simulated lymphocyte counts at Baseline were
1.72 and 1.73 × 109/L for RRMS and SPMS patients, respectively, which was 17% and 16%
lower, respectively, than the median simulated lymphocyte count at Baseline for healthy
subjects.
Table 3-30 Median lymphocyte count at the end of the last day of dosing in
patients with secondary progressive multiple sclerosis following
administration of 2 mg siponimod once daily for 40 days (steady-state
conditions)
Median (90% PI) lymphocyte count at
Category of patients end of last day of dosing (× 109/L)
Typical (70.5 kg male, *1*1 or *1*2, non-Japanese SPMS
0.560 (0.271-1.08)
patient)
Typical, but 49 kg only 0.510 (0.224-1.03)
Typical, but 100 kg only 0.583 (0.285-1.09)
Typical, but *2*2 CYP2C9 genotype only 0.509 (0.276-1.02)
Typical, but *1*3 CYP2C9 genotype only 0.491 (0.239-0.970)
Typical, but *2*3 CYP2C9 genotype only 0.473 (0.247-0.927)
Typical, but *3*3 CYP2C9 genotype only 0.416 (0.186-0.851)
Typical, but female only 0.515 (0.245-0.922)
Typical, but healthy subject only 0.784 (0.402-1.40)
Typical, but RRMS patient only 0.652 (0.309-1.22)
Typical, but Japanese only 0.434 (0.217-0.811)
Source: [CBAF312A-Phase 3-PopPKPD-Table 5-14]
Table 3-31 Time in days needed for absolute lymphocyte count recovery to
1.0 x 109/L for 2 mg siponimod once daily for 40 days (steady-state
conditions)
Median time for ALC recovery to 1.0 × 109/L
Categories of patients and doses
(90% PI) (days)
Typical (70.5 kg male, *1*1 or *1*2, non-
5 (1-11)
Japanese SPMS patient)
Typical, but 49 kg only 5 (1-13)
Typical, but 100 kg only 4 (1-10)
Typical, but *2*2 CYP2C9 genotype only 6 (1-15)
Typical, but *1*3 CYP2C9 genotype only 8 (2-18)
Typical, but *2*3 CYP2C9 genotype only 10 (2-23)
Typical, but *3*3 CYP2C9 genotype only 24 (4-48)
Typical, but female only 5 (2-12)
Typical, but healthy subject only 2 (1-6)
Typical, but RRMS patient only 3 (1-9)
Typical, but Japanese only 6 (2-12)
Source: [CBAF312A-Phase 3-PopPKPD-Table 5-16]
The PopPKPD model was also used to simulate the trough siponimod plasma concentration and
the absolute lymphocyte count at steady state as a function of siponimod dose in 70.5 kg healthy,
non-Japanese male subjects with CYP2C9*1*1 or *1*2 genotypes. The results, displayed in
Table 3-32 and Figure 3-12, show that while the trough siponimod concentrations increase in a
dose-proportional manner, the nadir lymphocyte count approaches a minimum value
asymptotically.
Table 3-32 Median (90 percent prediction interval) simulated trough siponimod
plasma concentration and trough lymphocyte count at steady state in
healthy subjects by dose
Median (90% PI)
Trough siponimod concentration (ng/mL) Trough lymphocyte count
Dose (mg) (× 109/L)
0.1 1.05 (0.54, 1.75) 1.73 (1.07, 2.60)
0.25 2.66 (1.35, 4.51) 1.43 (0.837, 2.22)
0.5 5.18 (2.62, 8.80) 1.21 (0.660, 1.90)
1 10.5 (5.57, 16.5) 0.978 (0.461, 1.59)
2 21.1 (11.2, 35.7) 0.782 (0.364, 1.28)
4 41.5 (20.9, 70.4) 0.636 (0.284, 1.10)
10 102 (53.3, 182) 0.547 (0.216, 0.935)
20 210 (108, 351) 0.517 (0.187, 0.914)
Source: [CBAF312A-Phase 3-PopPKPD-Table 5-17]
The width and height of the boxes represent the 90% PI.
Source: [CBAF312A-Phase 3-PopPKPD-Figure 5-23]
4 Special studies
Not applicable.
5 Appendix
Table 5-1 Clinical Pharmacology studies in healthy subjects and special populations and studies in patients with MS, PM
and DM
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
Healthy subjects and special population studies (N = 20)
[Study A2101] SAD study to explore safety, N = 98 healthy subjectsa: Two-part, single center, 0.1, 0.3, 1 and 2.5 mg
(completed) tolerability, PK and PD N = 80 to siponimod randomized, double-blind, (liquid); 2.5, 5, 10, 17.5, 25
placebo-controlled, SAD and 75 mg (CSF capsules)
N = 18 to placebo Phase 1 study
[Study A2102] MAD study to evaluate N = 60 healthy subjectsa: Randomized, parallel, double- 0.3 and 1.0 mg (liquid); 2.5,
(completed) safety, tolerability, PK and N = 45 to siponimod blind, placebo-controlled, 10 and 20 mg (CSF
PD time-lagged, MAD Phase 1 capsules)
N = 15 to placebo study
[Study A2105] MAD study to evaluate N = 50 healthy subjectsa: Randomized, parallel, 0.3 and 1.0 mg (liquid); 2.5,
(completed) safety, tolerability, PK and N = 37 to siponimod double-blind, 10 and 20 mg (CSF
PD (repeat of Study A2102) placebo-controlled, capsules)
N = 13 to placebo time-lagged, MAD Phase 1
study
[Study A2107] DT and fixed multiple dose N = 56 healthy subjectsa in 4 parallel treatment Double-blind, Uptitration (8 or 9 days) to
(completed) study to investigate the groups: placebo-controlled, 10 mg (0.25, 1, 4 and 5 mg
negative chronotropic effect N = 42 to siponimod 10 mg, including parallel-group Phase 1 study MF tablets)
of siponimod 2 DT regimens and 1 non-titrated regimen
(N = 14 each)
N = 14 to placebo
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study A2110] Multiple dose study to N = 138 healthy subjectsa to: Randomized, partially 0.5, 1, 2 and 4 mg (MF
(completed) investigate the effect of 7 treatment/discontinuation sequences (N = 19 double-blind, tablets)
siponimod treatment to 20 each), each consisting of 3 periods to placebo-controlled Phase 1
re-initiation on the initial evaluate a total of 4 dose levels of siponimod or study with 3 periods (10 days
negative chronotropic effect placebo and 5 discontinuation periods of single dose drug treatment,
(21 conditions total) drug discontinuation, 1 day of
single dose drug re-initiation)
[Study A2104] Single dose ADME study in N = 4 healthy male CYP2C9*1*1 subjects to Open-label, single oral dose 10 mg/2 mL [14C]siponimod
(completed) healthy subjects with the [14C]-siponimod Phase 1 study concentrate, diluted and
CYP2C9*1*1 genotype administered as 4 mL oral
solution
[Study A2111] Single dose study in healthy N = 62 healthy CYP2C9*1*1 subjects to 1 of 12 Randomized, open-label, 3- 0.25 mg MF tablet fasted
(completed) subjects with the sequences: period, 3-treatment, 0.25 mg FMI tablet fasted
CYP2C9*1*1 genotype to 6 sequences with 0.25 mg siponimod 6-sequence, single dose,
assess both the crossover Phase 1 study 0.25 mg FMI tablet fed
bioequivalence of the 6 sequences with 4 mg siponimod 4 mg MF tablet fasted
siponimod FMI tablet 4 mg FMI tablet fasted
formulation as compared to
4 mg FMI tablet fed
the siponimod MF and the
effect of food on the PK of
the FMI
[Study A2119] Single dose study to assess N = 60 healthy subjectsa: Randomized, double-blind, 4 mg for F16 and F10 (MR
(completed) the tolerability, PD and PK of N = 45 to siponimod F16, F10 and IR placebo-controlled, parallel formulations tablets) and IR
2 MR siponimod tablets tablet formulations (N = 15 each) group, single dose Phase 1 formulation (MF tablets)
(F16, F10) compared to the study
IR tablet (MF) and placebo N = 15 to placebo
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study A2125] Multiple dose, 2-period, N = 16 healthy CYP2C9*1*1 subjects: Open-label, 2-period, drug Uptitration (5 days) to 2 mg
(completed) single-sequence study in Period 1 (Days 1 to 12): siponimod interaction Phase 1 study (0.25, 0.5 and 2 mg FMI
healthy subjects with the uptitration to 2 mg tablets)
CYP2C9*1*1 genotype to
evaluate the effect of the Period 2 (Days 13 to 24): siponimod 2 mg
CYP2C9/3A4 inducer and rifampin 600 mg
rifampin on siponimod PK
[Study A2108] Single dose study in healthy N = 14 healthy CYP2C9*1*1 subjects: Open-label, single dose, 4 mg (MF tablets)
(completed) subjects with the Period 1 (14 days): siponimod single dose 2- period, drug interaction
CYP2C9*1*1 genotype to (Day 1) Phase 2 study
evaluate the safety,
tolerability and PK of Period 2 (20 days): siponimod single dose
siponimod when given alone (Day 3) and 200 mg qd fluconazole (Days
and in combination with the 1 to 19)
CYP2C9/3A4 inhibitor
fluconazole
[Study A2124] Single dose study in healthy N = 30 healthy CYP2C9*1*2 (17) and *1*3 (13) Open-label, 3-period, single- 0.25 mg (FMI tablets)
(completed) subjects with CYP2C9*1*2 subjects: sequence, crossover, drug
and *1*3 genotypes to Period 1 (Days 1 to 14): 0.25 mg interaction Phase 1 study
evaluate the effect of the siponimod single dose (Day 1)
CYP3A4 inhibitor
itraconazole on siponimod Period 2 (Days 15 to 18): 100 mg
PK, safety, and tolerability itraconazole bid
Period 3 (Days 19 to 32/36): 0.25 mg
siponimod single dose (Day 19), and
100 mg itraconazole bid (Days 19 to 31
(*1*2) or Days 19 to 35 (*1*3))
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study A2130] Multiple dose study to N = 136 healthy subjects (CYP2C9*3*3 Randomized, double-blind, Uptitration (5 days) to 2 mg
(completed) evaluate the modulation of genotype subjects excluded) to 4 treatment placebo-controlled, (0.25, 0.5, 1 and 2 mg FMI
immune response to T-cell groups: parallel-group, multiple dose tablets)
dependent and T-cell N = 34 to vaccination (Day 21) with Phase 1 study
independent antigen stimuli interrupted siponimod treatment (Days 1
by preceding, concomitant to 10 and 35 to 48)
and interrupted
administration of multiple N = 34 to vaccination (Day 21) with
therapeutic doses of preceding siponimod treatment (Days 1 to
siponimod 13)
N = 34 to vaccination (Day 21) under
concomitant siponimod treatment (Days
11 to 48)
N = 34 to vaccination (Day 21) with placebo
treatment
[Study A2121] Multiple dose study in N = 24 healthy female CYP2C9*1*1 subjects: Open-label, multiple dose, Uptitration (6 days) to 4 mg
(completed) female healthy subjects with Period 1 (Days 1 to 21): OC (30 µg EE 2-period Phase 1 study (0.25, 1 and 4 mg MF
the CYP2C9*1*1 genotype and 150 µg LVG) tablets)
to evaluate the effect of oral
siponimod on the PK and Period 2 (Days 29 to 49): 4 mg siponimod
PD of monophasic oral (uptitration beginning on Day 23, during a
contraceptive 7-day OC pill-free period) and OC (30 µg
EE and 150 µg LVG)
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study A2116] Multiple dose study to N = 76 healthy subjects (CYP2C9*3*3 genotype Randomized, double-blind, Uptitration (5 days) to 2 mg
(completed) evaluate PD and/or PK subjects excluded) to 1 of 4 parallel treatment placebo-controlled, multiple (0.25 and 1 mg MF tablets)
interaction of siponimod and arms (N = 19 each): dose Phase 1 study
propranolol Group A: propranolol 80 mg (Days 11 to
co-administration 20) added on top of siponimod 2 mg
(Days 1 to 20)
Group B: siponimod 2 mg (Days 11 to 20)
added on top of propranolol 80 mg (Days
1 to 20)
Group C: placebo (Days 1 to 20)
Group D: propranolol 80 mg (Days 1 to
20)
[Study A2126] Single dose, 2-part study in N = 33 healthy CYP2C9*1*1 subjects: Open-label, single dose, Part 1: 0.25 mg 3-hour iv
(completed) healthy subjects with the Part 1: N = 16 to 1 of 2 sequences of 2-part Phase 1 study infusion, and 0.25 mg FMI
CYP2C9*1*1 genotype to 2 periods each (2 sequences with 0.25 mg tablet
measure the absolute siponimod (oral and iv)) Part 2: 1.0 mg 24-hour iv
bioavailability, safety, infusion (4 consecutive
tolerability, and PD of oral Part 2: N = 17 (1 mg siponimod (iv))
6-hour iv infusions)
and iv siponimod
[Study A2118] Multiple dose thorough QT N = 304 healthy subjects (CYP2C9*3*3 Randomized, double-blind, Uptitration (5 days) to 2 mg
(completed) study to assess the effects genotype subjects excluded): parallel-group, placebo- and and (3 days) to 10 mg (0.25,
on QT interval (cardiac N = 99 to siponimod uptitration to 2 mg moxifloxacin-controlled Phase 1, 4 and 5 mg MF tablets)
repolarization) at oral (Days 1 to 10) and siponimod uptitration 1 study
therapeutic and to10 mg (Days 11 to 18)
supratherapeutic doses of
siponimod N = 103 to 400 mg moxifloxacin (Days 10
and 18)
N = 102 to placebo
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study A2122] Single dose study in N = 40 CYP2C9*1*1 subjects to siponimod: Single dose, open-label, 0.25 mg (MF tablets)
(completed) subjects with the N = 24 hepatic impairment (mild, parallel-group Phase 1 study
CYP2C9*1*1 to compare the moderate and severe; N = 8 each)
PK, safety and tolerability of
siponimod in subjects with N = 16 healthy control subjects
mild, moderate and severe
hepatic impairment and
healthy control subjects
[Study A2129] Single dose study in N = 16 CYP2C9*1*1 subjects to siponimod: Single dose, open-label, 0.25 mg (FMI tablets)
(completed) CYP2C9*1*1 subjects (wild N = 8 severe renal impairment parallel-group Phase 1 study
type genotype) to compare
the PK, safety and N = 8 healthy control subjects
tolerability of siponimod in
subjects with renal
impairment and normal renal
function
[Study A1101] SAD study to evaluate N = 40 healthy male Japanese subjectsa: Randomized, double-blind, 0.5, 2.5, 5 and 10 mg (MF
(completed) safety, tolerability, PK and N = 8 each to 0.5 to 10 mg siponimod placebo-controlled, ascending tablets)
PD in Japanese subjects single dose Phase 1 study
N = 8 to placebo
[Study A2128] Study to assess the safety, N = 24 CYP2C9 poor and extensive Open-label, 2-part, single and 0.25 and 0.5 mg (MF tablets)
(completed) tolerability, and PK of metabolizer subjects: multiple dose Phase 1 study
siponimod in subjects with N = 12 CYP2C9*1*1 extensive
CYP2C9 extensive metabolizers
metabolizers (CYP2C9*1*1
genotype) and poor N = 12 CYP2C9*2*3/*3*3 poor
metabolizers (CYP2C9*2*3 metabolizers
or *3*3 genotype) Part 1: single dose of 0.25 mg siponimod
Part 2 (poor metabolizers only): 0.25 mg
siponimod (Days 1 and 2) and 0.5 mg
siponimod (Day 3)
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
Studies in patients with MS (N = 2)
[Studies A2201 and Study, with long-term Core: N = 297 RRMS patients (CYP2C9*3*3 Double-blind, randomized, Core: 0.5, 2 and 10 mg in
A2201E] extension, to evaluate genotype patients excluded): multi-center, adaptive, Period 1; 0.25 mg or
(completed) safety, tolerability, efficacy, N = 235 to siponimod dose-ranging, uptitration (4 days) to
and dose response curve of placebo-controlled, 1.25 mg in Period 2 (MF
siponimod in patients with N = 62 to placebo parallel-group, 2-period tablets)
RRMS Extension: N = 184 (from core study) to Phase 2 study Extension: 0.25 mg or
siponimod uptitration (2 days) to
0.5 mg, (4 days) to 1.25 mg,
(5 days) to 2 mg or (9 days)
to 10 mg in dose-blinded
phase; 2 mg (5-day
uptitration if had received
0.25- or 0.5-mg dose prior)
in open-label phase (MF and
FMI tablets)
[Study A2304] Study to evaluate efficacy, Core: N = 1651 SPMS patients: Multi-center, randomized, Core: Uptitration (5 days) to
(ongoing extension safety, and tolerability data N = 1105 siponimod double-blind, parallel-group, 2 mg (dose reduction to
part) in patients with SPMS, and placebo-controlled variable 1 mg was permitted) (FMI
to provide long-term data in N = 546 to placebo treatment duration Phase 3 tablets)
patients who complete the study
core part
Studies in patients with PM and DM (N = 3)
[Study A2202] Study to evaluate the N = 18 patients with PM (N = 11) and DM (N = Multi-center, parallel, double- Uptitration (9 days) to 10 mg
(completed) efficacy and tolerability of 7) (CYP2C9*3*3 genotype patients excluded): blind, placebo controlled, (0.25, 1, 4 and 5 mg tablets)
siponimod in patients with N = 8 to siponimod/siponimod proof-of-concept Phase 2 (MF tablets)
PM and DM (Period 1/Period 2 extension) study with an open-label
extension phase (Period 2)
N = 10 to placebo/siponimod
(Period 1/Period 2 extension)
Study (status) Study objective Number of subjects per dose/route Study design Siponimod dose/regimen
(formulations)
[Study X2205] Proof-of-concept study to N = 14 patients with PM (excluding Double-blind, randomized, Uptitration (5 days) to 2 mg
(completed) evaluate the efficacy and CYP2C9*3*3 genotype patients and potentially placebo-controlled, or (9 days) to 10 mg (0.25,
tolerability of siponimod in *1*3, 2*2*, and *2*3 genotype patients, parallel-group Phase 2 study 0.5, 1 and 2 mg tablets) (MF
patients with PM depending on concomitant medication use): with an extension phase and FMI tablets)
N = 7 to siponimod 2 mg/2 mg (Period 2)
(Period 1/Period 2 extension)
N = 2 to siponimod 10 mg/10 mg
(Period 1/Period 2 extension)
N = 4 to placebo/siponimod 2 mg
(Period 1/Period 2 extension)
N = 1 to placebo/siponimod 10 mg
(Period 1/Period 2 extension)
[Study X2206] Study to evaluate safety, N = 17 patients with DM (excluding Double-blind, randomized, Uptitration (2 days) to
(completed) tolerability, efficacy and CYP2C9*3*3 genotype patients and potentially placebo-controlled Phase 2 0.5 mg, (5 days) to 2 mg
preliminary dose-response *1*3, 2*2*, and *2*3 genotype patients, study with an extension and/or (9 days) to 10 mg
of siponimod in patients with depending on concomitant medication use) to: phase (Period 2) (0.25, 0.5, 1 and 2 mg
DM N = 5 to placebo/siponimod 2 mg tablets) (FMI tablets)
(Period 1/Period 2 extension)
N = 4 to siponimod 0.5 mg/2 mg
(Period 1/Period 2 extension)
N = 4 to siponimod 2 mg/2 mg
(Period 1/Period 2 extension)
N = 4 to siponimod 10 mg/2 mg
(Period 1/Period 2 extension)
a There were no specific inclusion/exclusion criteria related to subject CYP2C9 genotype.
Table 5-2 In vitro, ex vivo, and in silico studies using human biomaterials
Study Study objective Matrix Siponimod
concentration
In vitro and ex vivo plasma protein binding and stability
[DMPK R1300334] To determine the ex vivo binding of [14C]siponimod to Plasma samples from 24 subjects with single 0.25 mg oral
plasma proteins in selected human plasma samples impaired hepatic function (mild, moderate, dose of siponimod
from the clinical [Study A2122] severe) and from 16 healthy subjects
[DMPK To determine the free plasma circulating fraction of Human plasma samples from healthy and single 0.25 mg oral
RCBAF312A2129-01] siponimod (and M3 and M5) to assess whether protein renal impaired subjects dose of siponimod
binding was affected by renal insufficiency in selected
human plasma samples from the clinical [Study
A2129]
[DMPK R1400021] To assess the in vitro plasma protein binding and Human plasma 100 ng/mL
stability at 37°C of M3 and M5
Metabolism by CYP450 enzymes
[DMPK R0500432] To investigate the human CYP enzymes involved in Human liver microsomes, panel of 21 up to 300 μM
the oxidative metabolism of siponimod and assess the recombinant human CYPs [14C]siponimod
risk of potential drug-drug interactions by co
medications including in vitro metabolism of
[14C]siponimod and enzyme kinetics parameters (Km
and Vmax)
CYP450 induction and inhibition
[DMPK R0500496] To assess the potency of siponimod to induce Reporter gene cells (DPX2) up to 100 μM
CYP3A4 via the human pregnane X receptor (PXR)
[DMPK R0500497] To assess the potential of siponimod to inhibit CYP Human liver microsomes, 9 CYP-isoenzyme up to 200 μM
enzyme activity selective substrate probes
[DMPK R1200710] To examine siponimod for its potential to induce CYP Primary human hepatocytes up to 50 μM
enzyme 1A2, 2B6, 2C9, and 3A4 messenger
ribonucleic acid (mRNA) and activities
Table 5-3 Summary of pooled analyses included in the Summary of Clinical Pharmacology
Analysis/Studies Pooled Sample Size Description
Dose proportionality after single dose
[Studies A2101 and A2105] N = 117 healthy subjects Power model
Phase 1/2 Population PK
[Studies A2101, A2105, A2107, A1101 and A2201] N = 190 healthy subjects Nonlinear mixed effects modeling
N = 216 RRMS patients Subjects on active treatment only
Phase 3 Population PK
[Study A2304] N = 1045 SPMS patients Nonlinear mixed effects modeling
Subjects on active treatment only
Steady-state PK in healthy subjects and MS patients
[Studies A2105, A2118, A2201 and A2304] N = 126 healthy subjects Subjects on active treatment and with steady state PK
N = 217 RRMS patients concentration data. considered.
N = 1043 SPMS patients A2105 (Day 28, 0 hour)
A2118 (Day10 and Day 18, 0 hour)
A2201 (Month 1, Month 3)
A2304 (Day 28, Month 12)
Exposure-lymphocyte relationship
[Studies A2101, A2105, A2107, A1101, A2110, A2118, N = 688 healthy subjects Nonlinear mixed effects modeling
A2201 and A2304] N = 287 RRMS patients Subjects on active treatment and on placebo
N = 1616 SPMS patients
Categorical analysis of lymphocyte count
Healthy subjects, SD: [Studies A1101, A2101, A2104, Healthy subjects, SD: N = 365 Categories of interest for ALC level:
A2108, A2111, A2119, A2124, A2126 and A2128] Healthy subjects, MD: N = 872 1) Within Normal Range (1.2 × 109/L to 3.5 × 109/L)
Healthy subjects, MD: [Studies A2102, A2105, A2107, PM/DM patients, MD: N = 49 2) ≥ 0.6 × 109/L and < 1.2 × 109/L
A2110, A2116, A2118, A2121, A2125, A2128 and A2130]
3) ≥ 0.2 × 109/L and < 0.6 × 109/L
PM/DM patients, MD: [Studies A2202, X2205 and X2206]
4) < 0.2 × 109/L
Categorical analysis of heart rate
Table 5-4 Summary of in vitro and ex vivo plasma protein binding of siponimod
and metabolites
Compound Group fu ± SD (%)
(DMPK R1300334)
(Study A2122) Siponimod Healthy subjects 0.0134 ± 0.00264 (N = 14)a
Siponimod Mild impairment 0.0150 ± 0.00258 (N = 8)
Siponimod Moderate impairment 0.0155 ± 0.00183 (N = 8)
Siponimod Severe impairment 0.0186 ± 0.00606 (N = 8)
In vitro Siponimod In vitro human plasma pool 1 0.0136 ± 0.00135 (N = 1)b
Siponimod In vitro human plasma pool 2 0.0124 ± 0.000339 (N = 1)b
(DMPK RCBAF312A2129-01)
(Study A2129) (N = Siponimod Healthy subjects 0.0263 ± 0.00820
8)
Siponimod Severe impairment 0.0292 ± 0.0160
In vitrod Siponimod Blank human plasma pool 1 0.0206c
Siponimod Blank human plasma pool 2 0.0269c
d
[DMPK R1400021]
In vitro M3 In vitro human plasma 0.572 ± 0.00292
M5 In vitro human plasma 0.401 ± 0.0689
a 16 samples were received, but 2 samples were not analyzed (tube broke during centrifugation)
b One plasma pool from 2 different individuals, SD represents 3 runs
c One plasma pool from 2 different individuals
d fu results might be slightly underestimated as equilibrium was not completely reached after
6 hours incubation
n = number of subjects/samples
Source: [DMPK R1300334-Table 1-1], [DMPK RCBAF312A2129-01-Table 2-1] and
[DMPK R1400021-Table 1-1]
Cmax [ng/mL/mg]
15
10
0.1 5 10 17.5 25 75
Dose (mg)
Regression
200
150
100
50
0.1 5 10 17.5 25 75
Dose (mg)
Regression
Table 11-1.1
Dose proportionality of BAF312 PK parameters of primary interest for
siponimod single oral doses(0.1, 0.3, 1, 2.5, 5, 10, 17.5, 20, 25, 75 mg)
PK analysis set
90% CI for
slope
Slope
PK parameter (unit) estimate Lower Upper
AUC0-24h [hr*ng/mL] 1.01 0.98 1.03
Cmax [ng/mL] 1.02 0.99 1.04
Power model: The slope parameter estimate and the confidence interval are obtained from the
linear model of the
log transformed PK parameter value adjusted for an intercept and the log-transformed dose
(covariate), as fixed effects.
Data considered - CBAF312A2101 (Doses: 0.1 mg, 0.3 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 17.5 mg,
25 mg, 75 mg)
Data considered - CBAF312A2105 (Day 1) (Doses: 0.1 mg, 0.3 mg, 2.5 mg, 10 mg, 20 mg)
/tf_pk_doseprop_sd.sas@@/main/5 04MAR18:10:11
BAF312
Table 12_5.1
Lymphocytes categorical outlier analysis - Single dose studies
Safety analysis set
Studies included: A1101, A2101, A2104, A2108, A2111, A2119, A2124,A2126,A2128 (Part1 only).
Only events occurring at or after first drug intake were considered.
A subject minimum result was considered and was counted only once in the worst category.
N- Total number of subjects who got administered with at least one dose of respective treatment.
n- number of unique subjects meeting respective category criteria.
Lab parameter ranges (lower limit-upper limit): Lymphocytes ranges (10E9/L)(1.2 - 3.5)
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BAF312
Table 12_5.2
Lymphocytes categorical outlier analysis - Multiple dose studies
Safety analysis set
Studies included: A2102, A2105, A2107,A2110, A2116, A2118, A2121, A2125, A2128 (Part2), A2130.
Only events occurring at or after first drug intake were considered.
A subject minimum result was considered and was counted only once in the worst category.
N- Total number of subjects who got administered with at least one dose of respective treatment.
n- number of unique subjects meeting respective category criteria.
Lab parameter ranges (lower limit-upper limit): Lymphocytes ranges (10E9/L)(1.2 - 3.5)
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BAF312
Table 12_5.3
Lymphocytes categorical outlier analysis – PM/DM studies
Safety analysis set
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