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Mayzent for adult patients with secondary progressive multiple sclerosis with active disease, approved in European Union

The European Commission ( EC ) has approved Mayzent ( Siponimod ) for the treatment of adult patients with secondary progressive multiple sclerosis ( SPMS ) with active disease evidenced by relapses or imaging features of inflammatory activity.
Up to 80% of relapsing remitting multiple sclerosis ( RRMS ) patients will transition to SPMS.
The European marketing authorization makes Mayzent the first and only indicated oral treatment proven in SPMS patients with active disease based on a randomized clinical trial of a broad range of SPMS patients.

The EC’s approval is based on data from the EXPAND study, a randomized, double-blind, placebo-controlled trial, comparing the efficacy and safety of Siponimod versus placebo in a broad range of SPMS patients ( EDSS score 3·0–6·5 at baseline ).

EXPAND included a subgroup of patients with active disease ( n=779 ), defined as patients with relapses in the two years prior to the study and/or presence of Gd-enhancing T1 lesions at baseline.
The baseline characteristics were similar except for signs of activity compared to the overall population.

In the subgroup of Siponimod-treated patients with active disease, results showed: a) the risk of three‑month and six‑month confirmed disability progression ( CDP ) was significantly reduced by 31% compared to placebo and by 37% compared to placebo, respectively;
b) significant favorable outcomes in other relevant measures of MS disease activity, including annualized relapse rate ( ARR – confirmed relapses ), MRI disease activity and brain volume loss ( brain shrinkage ).

Results in the overall population showed that Siponimod significantly reduced the risk of three-month CDP ( primary endpoint; 21% reduction versus placebo, p=0.013 ) and meaningfully delayed the risk of six-month CDP ( 26% versus placebo, p=0.0058 ).
Siponimod, also, has a meaningful benefit on cognition and demonstrated clinically relevant effects on cognitive processing speed.

Siponimod is a sphingosine 1-phosphate receptor modulator that selectively binds to S1P1 and S1P5 receptors.
In relation to the S1P1 receptor, it prevents the lymphocytes from egressing the lymph nodes and as a consequence, from entering the central nervous system ( CNS ) of patients with multiple sclerosis. This leads to the anti-inflammatory effects of Siponimod.
Siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS, including astrocytes and oligodendrocytes and has shown pro-remyelinating and neuroprotective effects in preclinical models of multiple sclerosis.

In the European Union, Mayzent is indicated for the treatment of adult patients with SPMS with active disease evidenced by relapsing or imaging features of inflammatory activity.

EXPAND is a randomized, double-blind, placebo-controlled phase III study, comparing the efficacy and safety of Siponimod versus placebo in people with SPMS with varying levels of disability, EDSS scores of 3·0–6·5.
It is the largest randomized, controlled study in SPMS to date, including 1,651 people with a diagnosis of SPMS from 31 countries.
Siponimod has demonstrated a safety profile that was overall consistent with the known effects of S1P receptor modulation.
Siponimod reduced the risk of three-month CDP by a statistically significant 21% ( p=0.013; primary endpoint ). CDP was defined as a 1-point increase in EDSS, if the baseline score was 3·0–5·0, or a 0·5-point increase, if the baseline score was 5·5–6·5.
No significant differences were found in the Timed 25-Foot Walk Test.
T2 lesion volume was reduced by 79% as compared to placebo.
Additional secondary endpoints included a relative reduction in the ARR by 55%, and compared to placebo, more patients were free from Gd-enhancing lesions ( 89% vs 67% for placebo ) and from new or enlarging T2 lesions ( 57% vs 37% for placebo ).
Additional exploratory analyses demonstrated Siponimod can help patients keep their mobility for over four years longer on average.

Multiple sclerosis disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss.
Multiple sclerosis, which affects approximately 2.3 million people worldwide, is often characterized into three forms: primary progressive multiple sclerosis ( PPMS ), relapsing-remitting multiple sclerosis ( RRMS ), and SPMS, which follows from an initial RRMS course and is characterized by physical and cognitive changes over time, in presence or absence of relapses, leading to a progressive accumulation of neurological disability.
Approximately 85% of patients initially present with relapsing forms of multiple sclerosis. ( Xagena )

Source: Novartis, 2020