Regulatory Decision Summary for Mayzent

Multiple sclerosis (MS) is a serious, progressive and severely debilitating chronic autoimmune and neurodegenerative disease of the central nervous system (CNS) that has been estimated to affect approximately 2.3 million people worldwide.

Mayzent (siponimod) is a new, orally administered, chemical entity that acts as a sphingosine-1-phosphate (S1P) receptor modulator that includes 5 G-protein coupled receptors S1P1-S1P5. Preventing entry of T cells into the blood and their infiltration into the CNS is thought to be the mechanism by which siponimod may reduce inflammation in the CNS.

The efficacy of siponimod 2 mg/day was demonstrated in a single large, Phase 3, randomized, placebo controlled, time to event clinical trial. The study enrolled patients who, following an initial course of relapsing-remitting multiple sclerosis (RRMS), were to have documented evidence of a progressive increase in disability of at least 6 months duration in the absence or independent of relapses. Patients also had to have documented evidence of disability progression in the prior 2 years as measured by the Expanded Disability Status Scale (EDSS) (> 1 point increase for EDSS < 6.0 at screening; > 0.5 point increase for EDSS > 6.0 screening); no evidence of relapse in the 3 months prior to study enrollment; and, an EDSS score of 3.0 to 6.5 at study entry. A total of 1105 patients were randomized to siponimod and 546 to placebo. At baseline, the mean age of the study population was 48 years, the median disease duration was 16 years and median EDSS score was 6.0 (56% had baseline EDSS > 6.0). The majority of patients did not have pre-study evidence of recent or active inflammatory disease activity at baseline. The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), which was defined as an increase from baseline EDSS score of at least 1 point (or 0.5 point increase for patients with baseline EDSS > 5.5). In the overall study population, there was a statistically significant 21% reduction in the risk of 3-month CDP with siponimod compared to placebo. The risk of 6-month CDP was also reduced by 26% with siponimod compared to placebo. Relative to placebo, secondary endpoints were favourable to siponimod.

Subgroup analyses that were planned to evaluate the extent to which the effect of siponimod on disability progression may have been independent of inflammatory disease processes (relapses, new lesion activity) demonstrated that the effect of siponimod on 3-month and 6-month CDP was greater in patients with pre-study evidence of active inflammatory disease processes superimposed on progression. Results support an indication for treatment of patients with active secondary progressive multiple sclerosis (SPMS), characterized by the presence of relapses and/or imaging features that are consistent with MS inflammatory activity.

During the Phase 3 pivotal clinical trial in patients with SPMS, the median duration of exposure to siponimod was approximately 18 months (range 0-37 months); 884 patients had >12 months exposure; 322 patients had > 24 months exposure. All or most of the following safety concerns that were reported with siponimod have also been reported during clinical experience with fingolimod, another S1P modulator, and presented in the Mayzent Product Monograph (PM) as contraindications or in warnings. The PM has recommendations for monitoring for these adverse events to mitigate the risk of potentially serious outcomes.

Siponimod induces a reduction in lymphocytes in peripheral blood to approximately 20-30% of baseline counts, which persists throughout treatment and can increase the risk of infections, including serious and life-threatening infections. For example, Herpes zoster infections were more frequently reported in SPMS patients treated with siponimod (2.5%) compared to placebo (0.7%). Prior to initiating treatment, varicella zoster virus (VZV) antibody status should be determined and vaccination of VZV antibody-negative patients is recommended. Serious opportunistic infections reported with siponimod during clinical development included one patient with a disseminated herpes zoster infection (herpes zoster meningitis) and one patient with cryptococcal meningitis. Reduced immune surveillance may increase the risk of cancer but an increased risk cannot be well characterized due to the duration of clinical trials. During the Phase 3 study in SPMS patients, basal cell carcinoma was reported at a similar rate with siponimod and placebo but other types of skin cancers (e.g., malignant melanoma, squamous cell carcinoma) and non-cutaneous cancers (seminoma) were also reported, in one or two patients treated with siponimod but not with placebo.

Siponimod causes a marked transient reduction in heart rate and may cause conduction delays, which manifest as bradycardia and/or first or second degree atrioventricular block Mobitz I, upon treatment initiation. When treatment was initiated using the recommended 6-day titration procedure, the effect on heart rate and conduction was gradual and less pronounced, and serious or symptomatic events were largely mitigated. However, based on the thorough QTc study and results from the Phase 3 trial, it is recommended that all patients have pre-treatment assessments of cardiovascular status including an electrocardiogram (ECG) and review of medications and possibly a cardiologists evaluation if deemed necessary. For patients with sinus bradycardia (heart rate < 55 bpm), first or second degree atrioventricular block Mobitz I, or a history of myocardial infarction or heart failure, it is recommended to administer the first dose of siponimod in a clinical setting where the patient can be monitored for at least 6 hours (hourly vital signs, ECG pre-dose and 6 hours post-dose).

Other types of adverse events that occurred with siponimod included macular edema usually within the first 3 to 4 months of treatment, increases in blood pressure or new hypertension, and decreases in pulmonary function tests suggesting a small effect on airway resistance. Vascular events such as cerebrovascular accident, ischemic stroke, and peripheral occlusive arterial disease were also reported in patients treated with siponimod (<0.5%) but not with placebo. Siponimod has not been studied in pregnant women. In view of reproductive toxicology studies that clearly demonstrated teratogenic effects of siponimod in rats and rabbits, and the increased risk in congenital malformation seen with fingolimod in the post-market setting, a contraindication during pregnancy and in women of childbearing potential has also been applied to siponimod.

Other adverse events that occurred more frequently with siponimod compared to placebo in the Phase 3 pivotal trial included: seizures, elevations in liver transaminases [mainly asymptomatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations; no cases meeting Hys law criteria] and, an imbalance in suicidal ideation and suicidal behavior.

The metabolism of siponimod is attributed mainly to the cytochrome P450 2C9 (CYP2C9) (79%) and cytochrome P450 3A4 (CYP3A4) (18.5%) enzymes. Because CYP2C9 is polymorphic, prior to initiating treatment, patients must be genotyped to determine CYP2C9 metabolizer status as exposure to siponimod highly depends on this status. As stated in the Mayzent PM, the sponsor will offer CYP2C9 genotyping through its Patient Support Program.

In summary, the efficacy of siponimod for delaying progression of physical disability was demonstrated mainly in patients with SPMS who are progressing but who still have superimposed inflammatory disease activity. It remains uncertain whether there is an effect on disability progression that is independent of the effect on inflammatory disease activity. However, in the context of limited effective treatment options for patients with SPMS, the delay in progression of physical disability that was demonstrated with siponimod in patients with some superimposed inflammatory disease activity can be considered clinically meaningful. For these patients a delay in the progression of physical disability may make a difference in the time it takes to progress from not needing walking aids to needing them, needing two walking aids rather than one or, primarily needing a wheelchair. The extent to which siponimod may increase the risk of harms related to immunosuppression that have not been identified in the clinical development program, such as other opportunistic infections and cancers cannot be well characterized in the context of placebo controlled clinical trials with limited duration. Based on the available data, the overall benefit-harm-uncertainty for siponimod for the treatment of patients with active SPMS characterized by the presence of relapses or imaging features characteristic of MS inflammatory activity is considered acceptable when used under the conditions provided in the Mayzent PM.