The new MS drug Siponimod, the further development of Fingolimod (Gilenya®), was recently approved by the Food and Drug Administration (FDA) in the USA and has been available there for some time for MS patients under the trade name Mayzent™ . Also in Europe, the Committee for Medicinal Products for Human Use (CHMP) recommended approval on 14.11.2019, i.e. Siponimod will soon be available in Europe – and Siponimod is also eagerly awaited by doctors and patients in Europe, as the substance was the first to show a albeit weak effect on disability progression in secondary progressive MS (SPMS).
During the recruitment of the study, importance was placed on examining a characteristic SPMS population, i.e. SPMS patients with a long duration of illness, a progression of disability independent of disease relapses and little/no inflammatory activity in magnetic resonance imaging. Given this study population, one could have expected that the approval would be exactly for this patient group – especially since there are few drug options for late SPMS and the benefit of anti-inflammatory therapy in this late phase of the disease has often been questioned in the past.
Surprisingly, however, the FDA defined the “label” of the substance completely differently than commonly expected. Literally it says “MAYZENT is (…) indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.” (Translation: MAYZENT is (…) indicated for the treatment of relapsing forms of Multiple Sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive disease in adult patients).
The drug has therefore been approved for the entire spectrum of relapsing MS, and not for the patients for whom the study was actually aimed. If SPMS patients are to be treated with Siponimod, according to US approval an active disease is a prerequisite. In this case, activity is defined by imposed disease relapses or new MRI lesions.
I find this decision by the FDA remarkable. Ultimately, the FDA’s Siponimod “label” proves that the authorities in the USA based their decision on the scientifically accepted concept of multiple sclerosis as a biphasic disease (early phases defined by inflammation, late phases by neurodegeneration). In Europe, the situation was not quite so progressive, but here too the CHMP’s recommendation for approval follows similar considerations. The indication for MAYZENT is “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity” (Translation: “Treatment of adult patients with secondary progressive Multiple Sclerosis (SPMS) with active disease, as evidenced by relapses or inflammatory activity in imaging”).
S1P antagonists such as Fingolimod or Siponimod are primarily anti-inflammatory drugs, even if experiments in cell culture and in animal models suggest that a neuroprotective effect could be mediated via S1P receptors on neurons, oligodendrocytes or astrocytes. Therefore, S1P antagonists should primarily be used when inflammatory activity can be demonstrated.
Even though only 20% of the patients included in the Siponimod approval study showed gadolinium-absorbing foci (= contrast-enhancing foci as signs of fresh inflammatory activity), it is a fact that the positive result of the study is driven by this (active) subgroup.
Accordingly, the study and the assessment of the study by the approval authorities prove that anti-inflammatory therapy is also useful in the late stages of the disease, when there is inflammatory activity, i.e. an active disease. Patients with SPMS who have not shown relapses or MRI activity for years, on the other hand, cannot be prescribed MAYZENT. This shows that the search for strategies that directly influence the neurodegenerative component of advanced MS is far from over.
