KIENDRA Film-coated tablet Ref.[115230] Active ingredients: Siponimod

Pharmacotherapeutic group: Selective immunosuppressants
ATC code: L04AA42

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively on 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. Siponimod spares effector memory T-cells in peripheral tissues and blood and does not impair lymphocyte activation.

Siponimod readily crosses the blood brain barrier.

In animal studies direct effects have been demonstrated for siponimod on neural cells, via S1P₁ on astrocytes and S1P5 on oligodendrocytes. In a mouse model of experimental autoimmune encephalomyelitis a direct neuroprotective effect, independent from effects on lymphocytes, was also demonstrated for siponimod applied centrally (via intracerebroventricular infusions).

Immune system

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 to 1.08) cells/nL in a typical CYP2C9*1*1 or *1*2, non-Japanese SPMS patient, corresponding to 20 to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing.

Before initiating treatment, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Absolute lymphocyte counts <0.2 × 10⁹/l, if confirmed, should lead to dose reduction to 1 mg, because in clinical studies siponimod dose was reduced in patients with absolute lymphocyte counts <0.2 × 10⁹/l. Confirmed absolute lymphocyte counts <0.2 × 10⁹/l in a patient already receiving siponimod 1 mg should lead to interruption of siponimod therapy until the level reaches 0.6 × 10⁹/l when re-initiation of siponimod can be considered.

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

Cardiac electrophysiology

Heart rate and rhythm

Siponimod causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation (see section 4.8). The maximum decline in heart rate is seen in the first 6 hours post-dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to physical exercise, are not affected by siponimod treatment.

A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of siponimod, that plateaued at doses ≥5 mg and bradyarrhythmic events (AV Blocks and sinus pauses) were detected at a higher incidence under siponimod treatment compared to placebo.

No second degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg with notably higher incidence under non titrated conditions compared to dose titration conditions.

The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.

Potential to prolong the QT interval

The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarization were investigated in a thorough QT study. The results did not suggest an arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the mean 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 doses 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.

Concomitant treatment of siponimod with propranolol resulted in minimal decrease of FEV1 in comparison to propranolol alone. The changes with the individual medicines or with the combination were within the physiological variability of FEV1 and not clinically significant.

Clinical studies

Study A2304 (EXPAND) in SPMS

Study A2304 was a randomised, double-blind, placebo-controlled, event and follow-up duration driven, phase 3 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 3 months prior to study enrollment and with Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry.

Patients were randomised 2:1 to receive either once daily siponimod 2 mg or placebo. 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 (T25FW) and change from baseline in T2 lesion volume. Additional secondary endpoints included time to 6-month CDP, percent brain volume change, measures of inflammatory disease activity.

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

Median age was 49.0 years, median disease duration was 16.0 years and median EDSS score was 6.0 at baseline; 63.9% of patients had no relapses in the 2 years prior to study entry and 78% had no gadolinium (Gd)-enhancing lesions on their baseline MRI scan; 78.3% of patients had been previously treated with a therapy for their MS.

Time to onset of 3-month confirmed disability progression (primary endpoint) was significantly delayed for siponimod with a 21.2% risk reduction compared to placebo (hazard ratio (HR) 0.79, p<0.0134).

The results for this study are summarized in Table 3 and Figure-1.

Table 3. Overview of results from efficacy endpoints:

All analyses are based on the full analysis set (FAS), which includes all randomized subjects who took at least one dose of study medication. p values are two-sided.
¹ Hazard ratio (siponimod/placebo), Cox proportional hazard model.
² Treatment difference in the average over mean changes at Months 12 and 24, repeated measures model.
³ ARR ratio (siponimod/placebo), negative binomial model.
⁴ Treatment difference in the average over all visits, repeated measures model.
⁵ Rate ratio (siponimod/placebo) up to and including Month 24, negative binomial model.
⁶ Rate ratio (siponimod/placebo) per scan, average over Months 12 and 24, negative binomial model.

Figure 1. Patients with 3-month and 6-month CDP based on EDSS-Kaplan-Meier curves (FAS):

Siponimod did not significantly delay time to 3-month confirmed ≥20% deterioration in the T25FW (a numerical 6.2% risk reduction was observed).

Results from the study showed a consistent risk reduction in the time to 3-month CDP with siponimod in subgroups defined based on gender, age, prior multiple sclerosis therapy, pre-study relapse activity, baseline MRI disease activity and disability levels at baseline.