Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA42

Mechanism of action

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively to two out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P1 and S1P5. By acting as a functional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymph nodes. This reduces the recirculation of T cells into the central nervous system (CNS) to limit central inflammation.

Pharmacodynamic effects

Reduction of the peripheral blood lymphocytes
Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, due to the reversible sequestration of lymphocytes in lymphoid tissues.

With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1*1 or *1*2 non-Japanese SPMS patient, corresponding to 20-30% of baseline. Low lymphocyte counts are maintained with daily dosing.

In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. After stopping siponimod treatment residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.

Heart rate and rhythm
Siponimod causes a transient reduction in heart rate and atrioventricular conduction on treatment initiation (see sections 4.4 and 4.8), which is mechanistically related to the activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation leading to cellular hyperpolarisation and reduced excitability. Due to its functional antagonism at S1P1 receptors, initial titration of siponimod successively desensitises GIRK channels until the maintenance dose is reached.

Potential to prolong the QT interval
The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarisation were investigated in a thorough QT study. The results did not suggest an arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the placebo-corrected baseline-adjusted mean QTcF (ΔΔQTcF) by more than 5 ms, with a maximum mean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound of the one-sided 95% CI for the ΔΔQTcF at all time points remained below 10 ms. Categorical analysis revealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of more than 60 ms and no corrected or uncorrected QT/QTc value exceeded 500 ms.

Pulmonary function
Siponimod treatment with single or multiple doses for 28 days is not associated with clinically relevant increases in airway resistance as measured by forced expiratory volume in 1 second (FEV1) and forced expiratory flow (FEF) during expiration of 25 to 75% of the forced vital capacity (FEF25-75%). A slight trend of reduced FEV1 was detected at non-therapeutic single doses (>10 mg).
Multiple doses of siponimod were associated with mild to moderate changes in FEV1 and FEF25-75% which were not dose- and daytime-dependent and were not associated with any clinical signs of increased airway resistance.


MAY API MAR24 V7                              Page 14 of 23                            EU SmPC Jan.2024 Clinical efficacy and safety

The efficacy of siponimod has been investigated in a phase III study evaluating once-daily doses of 2 mg in patients with SPMS.

Study A2304 (EXPAND) in SPMS
Study A2304 was a randomised, double-blind, placebo-controlled, event and follow-up duration driven, phase III study in patients with SPMS who had documented evidence of progression in the prior 2 years in the absence or independent of relapses, no evidence of relapse in the 3 months prior to study enrolment and with a median Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry. The median EDSS was 6.0 at baseline. Patients above 61 years of age were not included.
With regard to disease activity, features characteristic of inflammatory activity in SPMS can be relapse- or imaging-related (i.e. Gd-enhancing T1 lesions or active [new or enlarging] T2 lesions).

Patients were randomised 2:1 to receive either once-daily siponimod 2 mg or placebo. Clinical evaluations were performed at screening and every 3 months and at the time of relapse. MRI evaluations were performed at screening and every 12 months.

The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP) determined as at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5 or more) sustained for 3 months. Key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25W) and change from baseline in T2 lesion volume. Additional secondary endpoints included time to 6-month CDP, percent brain volume change and measures of inflammatory disease activity (annualised relapse rate, MRI lesions). Change in cognitive processing speed on Symbol Digit Modality Test score was an exploratory endpoint.

Study duration was variable for individual patients (median study duration was 21 months, range: 1 day to 37 months).

The study involved randomisation of 1,651 patients to either siponimod 2 mg (N=1,105) or placebo (N=546); 82% of patients treated with siponimod and 78% of placebo-treated patients completed the study. Median age was 49 years, median disease duration was 16 years and median EDSS score was 6.0 at baseline. 64% of patients had no relapses in the 2 years prior to study entry and 76% had no gadolinium (Gd)-enhancing lesions on their baseline MRI scan. 78% of patients had been previously treated with a therapy for their MS.

Time to onset of 3-month and 6-month CDP was significantly delayed for siponimod, with reduction in risk of 3-month CDP by 21% compared to placebo (hazard ratio [HR] 0.79, p=0.0134) and reduction in risk of 6-month CDP by 26% compared to placebo (HR 0.74, p=0.0058).


MAY API MAR24 V7                              Page 15 of 23                            EU SmPC Jan.2024 Figure 1                                                 Patients with 3- and 6-month CDP based on EDSS-Kaplan-Meier curves (full analysis set, study A2304)

Ti e to 3- o th CDP versus pla e o                                                                              Ti e to 6- o th CDP versus pla e o (Primary endpoint)
50                                                                                                              50 Percentage of subjects with 3-month CDP



Percentage of subjects with 6-month CDP
40                                                                                                              40 

30                                                                                                              30 

20                                                                                                              20 

10                                                                                                              10 Hazard ratio: 0.79, p=0.0134; (95% Cl: 0.65,                                                                    Hazard ratio: 0.74, p=0.0058; (95% 0.95); risk reduction: 21%                                                                                      Cl: 0.60, 0.92); risk reduction: 26% 0                                                                                                                0 0   6        12      18     24     30       36      42                                                          0   6       12     18        24    30    36      42 Study month                                                                                                   Study month Number of patients at risk                                                                                       Number of patients at risk 
Siponimod                                           1099    947      781     499    289    101       4      0    Siponimod                                           1099   960     811    525       306   106    5      0 Placebo                                           546    463      352     223    124     35       0      0       Placebo                                           546   473     361    230       128    37    1      0 

Siponimod (N=1099)                                                                Placebo (N=546) 

MAY API MAR24 V7                                                                                      Page 16 of 23                                                                                   EU SmPC Jan.2024 Table 3      Clinical and MRI results of study A2304

Endpoints                                                          A2304 (EXPAND) Siponimod 2 mg         Placebo
(n=1,099)           (n=546)
Clinical endpoints
Primary efficacy endpoint:                                   26.3%                     31.7% Proportion of patients with 3-month confirmed disability progression (primary endpoint)
Risk reduction1                                                      21% (p=0.0134) Proportion of patients with 3-month confirmed                39.7%                     41.4% 20% increase in timed 25-foot walk test
Risk reduction1                                                       6% (p=0.4398) Proportion of patients with 6-month confirmed                19.9%                     25.5% disability progression
Risk reduction1                                                     26% [(p=0.0058)]6 Annualised relapse rate (ARR)                                 0.071                     0.152 Rate reduction2                                                     55% [(p<0.0001)]6 MRI endpoints
Change from baseline in T2 lesion volume                   +184 mm3                  +879 mm3 3 3
(mm )
Difference in T2 lesion volume change                             -695 mm3 (p<0.0001)7 Percentage brain volume change relative to                  -0.497%                   -0.649% baseline (95% CI)3
Difference in percentage brain volume change                      0.152% [(p=0.0002)]6 Average cumulative number of Gd-enhancing T1                  0.081                     0.596 4 weighted lesions (95% CI)
Rate reduction                                                      86% [(p<0.0001)]6 Proportion of patients with 4-point worsening in             16.0%                     20.9% Symbol Digit Modality Test5
Risk reduction1                                                     25% [(p=0.0163)]6 1
From Cox modelling for time to progression
2
From a model for recurrent events
3
Average over month 12 and month 24
4
Up to month 24
5
Confirmed at 6 months
6
[Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for multiplicity]
7
Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint 
Results from the study showed a variable but consistent risk reduction in the time to 3- and 6-month CDP with siponimod compared to placebo in subgroups defined based on gender, age, pre-study relapse activity, baseline MRI disease activity, disease duration and disability levels at baseline.

In the subgroup of patients (n=779) with active disease (defined as patients with relapse in the 2 years prior to the study and/or presence of Gd-enhancing T1 lesions at baseline) the baseline characteristics were similar to the overall population. Median age was 47 years, median disease duration was 15 years and median EDSS score at baseline was 6.0.

Time to onset of 3-month and 6-month CDP was significantly delayed in siponimod-treated patients with active disease, by 31% compared to placebo (hazard ratio [HR] 0.69; 95% CI: 0.53, 0.91) and by 37% compared to placebo (HR 0.63; 95% CI: 0.47, 0.86), respectively. The ARR (confirmed relapses) was reduced by 46% (ARR ratio 0.54; 95% CI: 0.39, 0.77) compared to placebo. The relative rate reduction of cumulative number of Gd-enhancing T1 weighted lesions over 24 months was 85% (rate ratio 0.155; 95% CI: 0.104, 0.231) compared to placebo. The differences in T2 lesion volume change and in percentage of brain volume change (average over months 12 and 24) compared to placebo were -1163 mm3 (95% CI: -1484, -843 mm3) and 0.141% (95% CI: 0.020, 0.261%), respectively.
MAY API MAR24 V7                              Page 17 of 23                           EU SmPC Jan.2024 Figure 2                                                  Patients with 3- and 6-month CDP based on EDSS-Kaplan-Meier curves – Subgroup with active SPMS (full analysis set, study A2304)


Ti e to 3- o th CDP versus pla e o                                                            Ti e to 6- o th CDP versus pla e o (Primary endpoint)
50                                                                                                             40 Percentage of patients with 3-month CDP



Percentage of patients with 6-month CDP
40
30

30
20
20

10
10
Hazard ratio: 0.69 (95% Cl: 0.53,                                                                              Hazard ratio: 0.63 (95% Cl: 0.47, 0.91); risk reduction: 31%                                                                                     0.86); risk reduction: 37% 0                                                                                                              0 0     6     12     18      24     30       36      42                                                          0     6       12     18        24    30    36     42 Study month                                                                                                       Study month Number of patients at risk                                                                                      Number of patients at risk Siponimod                                               516   439   376    245     149     48       1      0    Siponimod                                              516   447     391    258       156    51    1      0 Placebo                                              263   221   164    112      68     19       0      0       Placebo                                             263   225     171    115        68    20    0      0 

Siponimod (N=516)                                                                   Placebo (N=263) 

In the subgroup of patients (n=827) without signs and symptoms of disease activity (defined as patients without relapse in the 2 years prior to the study and without presence of Gd-enhancing T1 lesions at baseline), effects on 3-month and 6-month CDP were small (risk reductions were 7% and 13%, respectively).

A post-hoc analysis of study A2304 (EXPAND) showed that siponimod delayed progression to EDSS ≥7.0 (sustained until end of study, i.e. time to wheelchair), resulting in a risk reduction of 38% (HR from Cox model 0.62; 95% CI: 0.41, 0.92). The Kaplan-Meier estimate of percentage of patients progressed to EDSS ≥7.0 at month 24 was 6.97% in the siponimod group and 8.72% in the placebo group. In the subgroup of patients with active SPMS, the risk reduction was 51% (HR 0.49; 95% CI: 0.27, 0.90) and the Kaplan-Meier estimates at month 24 were 6.51% in the siponimod group and 8.69% in the placebo group. As these results were exploratory in nature, they should be interpreted with caution.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
The time (Tmax) to reach maximum plasma concentrations (Cmax) after multiple oral administration of siponimod is about 4 hours (range: 2 to 12 hours). Siponimod absorption is extensive (≥70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimod given once daily over 10 days, a mean Cmax of 30.4 ng/ml and mean AUCtau of 558 h*ng/ml were observed on day 10. Steady state was reached after approximately 6 days of multiple once-daily administration of siponimod.

Despite a delay in Tmax to 8 hours after a single dose, food intake had no effect on the systemic exposure of siponimod (Cmax and AUC), therefore siponimod may be taken without regard to meals (see section 4.2).


MAY API MAR24 V7                                                                                     Page 18 of 23                                                                                     EU SmPC Jan.2024 Distribution

Siponimod is distributed to body tissues with a moderate mean volume of distribution of 124 litres.
The siponimod fraction found in plasma is 68% in humans. Siponimod readily crosses the blood-brain barrier. Protein binding of siponimod is >99.9% in healthy subjects and in patients with hepatic or renal impairment.

Biotransformation

Siponimod is extensively metabolised, mainly by cytochrome P450 2C9 (CYP2C9) (79.3%), and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%).

The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.

In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once daily for all investigated CYP enzymes and transporters, and do not necessitate clinical investigation.

CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. PBPK modelling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated (see section 4.5).

Elimination

An apparent systemic clearance (CL/F) of 3.11 l/h was estimated in MS patients. The apparent elimination half-life of siponimod is approximately 30 hours.

Siponimod is eliminated from the systemic circulation mainly due to metabolism and subsequent biliary/faecal excretion. Unchanged siponimod was not detected in urine.

Linearity

Siponimod concentration increases in an apparent dose proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg.

Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing and steady-state levels are approximately 2- to 3-fold greater than after the initial dose. An up-titration regimen is used to reach the clinically therapeutic dose of 2 mg siponimod after 6 days and 4 additional days of dosing are required to reach the steady-state plasma concentrations.

Characteristics in specific groups or special populations

CYP2C9 genotype
The CYP2C9 genotype influences siponimod CL/F. Two population pharmacokinetic analyses indicated that CYP2C9*1*1 and *1*2 subjects behave as extensive metabolisers, *2*2 and *1*3 subjects as intermediate metabolisers and *2*3 and *3*3 subjects as poor metabolisers. Compared to CYP2C9*1*1 subjects, individuals with the CYP2C9*2*2, *1*3, *2*3 and *3*3 genotypes have 20%, 35-38%, 45-48% and 74% smaller CL/F values, respectively. Siponimod exposure is therefore approximately 25%, 61%, 91% and 284% higher in CYP2C9*2*2, *1*3, *2*3 and *3*3 subjects, respectively, as compared to *1*1 subjects (see Table 4) (see sections 4.2 and 4.4).

There are other less frequent occurring polymorphisms for CYP2C9. The pharmacokinetics of siponimod have not been evaluated in such subjects. Some polymorphisms such as *5, *6, *8 and *11 are associated with decreased or loss of enzyme function. It is estimated that CYP2C9 *5, *6, *8 and *11 alleles have a combined frequency of approximately 10% in populations with African ancestry, MAY API MAR24 V7                               Page 19 of 23                            EU SmPC Jan.2024 2% in Latinos/Hispanics and <0.4% in Caucasians and Asians.

Table 4      CYP2C9 genotype effect on siponimod CL/F and systemic exposure 
% of                % exposure
CYP2C9            Frequency in       Estimated CL/F
CYP2C9*1*1           increase versus genotype           Caucasians             (L/h)
CL/F                CYP2C9*1*1
Extensive metabolisers
CYP2C9*1*1               62-65               3.1-3.3               100                    - CYP2C9*1*2               20-24               3.1-3.3              99-100                  - Intermediate metabolisers
CYP2C9*2*2                1-2                2.5-2.6                80                    25 CYP2C9*1*3               9-12                1.9-2.1               62-65                  61 Poor metabolisers
CYP2C9*2*3              1.4-1.7              1.6-1.8               52-55                  91 CYP2C9*3*3              0.3-0.4                0.9                  26                   284 
Elderly
Results from population pharmacokinetics suggest that dose adjustment is not necessary in elderly patients (age 65 years and above). No patients over 61 years of age were enrolled in clinical studies.
Siponimod should be used with caution in the elderly (see section 4.2).

Gender
Results from population pharmacokinetics suggest that gender-based dose adjustment is not necessary.

Race/Ethnicity
The single-dose pharmacokinetic parameters were not different between Japanese and Caucasian healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of siponimod.

Renal impairment
No siponimod dose adjustments are needed in patients with mild, moderate or severe renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects. Total and unbound AUCs were only slightly increased (by 23 to 33%) compared to healthy subjects. The effects of end-stage renal disease or haemodialysis on the pharmacokinetics of siponimod have not been studied. Due to the high plasma protein binding (>99.9%) of siponimod, haemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations.

Hepatic impairment
Siponimod must not be used in patients with severe hepatic impairment (see section 4.3). No dose adjustments for siponimod are needed in patients with mild or moderate hepatic impairment. The unbound siponimod pharmacokinetics AUC is 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied. The mean half-life of siponimod was unchanged in hepatic impairment.