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The Committee for Medicinal Products for Human Use ( CHMP ) of the European Medicines Agency ( EMA ) has adopted a positive opinion for 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 ( i.e. Gd-enhancing T1 lesions or active, new or enlarging, T2 lesions ).

While multiple sclerosis progression is different for each patient and influenced by multiple factors, including use of MS disease-modifying treatments, it is estimated that up to 80% of patients will eventually transition from relapsing remitting multiple sclerosis ( RRMS ) to SPMS.

Mayzent will be the first and only oral treatment specifically indicated for patients with active secondary progressive multiple sclerosis based on a randomized clinical trial of a broad SPMS patient population.

The positive CHMP opinion for Mayzent is based on groundbreaking data from the phase III EXPAND study, a randomized, double-blind, placebo-controlled trial, comparing the efficacy and safety of Mayzent versus placebo in people with SPMS.
EXPAND also investigated 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.
Results from EXPAND in the overall population showed that Mayzent significantly reduced the risk of three-month confirmed disability progression ( 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 ).

In the subgroup of Mayzent-treated patients with active disease, results showed:

a) time to onset of three‑month and six‑month CDP was significantly delayed by 31% compared to placebo and by 37% compared to placebo, respectively;

b) the annualized relapse rate ( ARR – confirmed relapses ) was reduced by 46% compared to placebo;

c) significant favorable outcomes in other relevant measures of MS disease activity, including MRI disease activity and brain volume loss.

In March 2019, Novartis received approval from the US Food and Drug Administration ( FDA ) for Mayzent for the treatment of relapsing forms of multiple sclerosis ( RMS ), to include clinically isolated syndrome ( CIS ), relapsing remitting disease, and active secondary progressive disease, in adults.

Siponimod is a next generation, selective sphingosine 1-phosphate receptor modulator. In relation to the S1P1 receptor, it prevents the lymphocytes from egressing the lymph nodes and as a consequence, from entering the 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.

EXPAND is a randomized, double-blind, placebo-controlled study, comparing the efficacy and safety of Mayzent 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.
Mayzent has demonstrated a safety profile that was overall consistent with the known effects of S1P receptor modulation.
It 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, however, 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 ). ( Xagena )

Source: Novartis, 2019

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