SPMS disability progression delayed with Mayzent

MAYZENT® WAS PROVEN TO DELAY DISABILITY PROGRESSION IN PATIENTS WITH SPMS1,2

Risk Reduction chart Risk Reduction chart

MAYZENT demonstrated a 21% relative risk reduction in disability progression,

as measured by time to 3-month CDP, compared to placebo (P=0.013)


HOW TO ASSESS EDSS SCORES HOW CDP IS ASSESSED

  • The proportion of patients on MAYZENT with 3-month CDP was 26% vs 32% for those on placebo

  • CDP was defined as a ≥1-point increase from baseline in EDSS score (0.5-point increase for patients with a baseline EDSS score of ≥5.5) sustained for 3 months

  • Although MAYZENT had a significant effect on CDP in patients with active SPMS (relapse in 2 years prior to study entry), its effect in patients with non-active SPMS was not statistically significant

HOW TO ASSESS EDSS SCORES HOW CDP IS ASSESSED

MAYZENT SHOWED A FAVORABLE RISK REDUCTION IN THE TIME TO 3-MONTH CDP ACROSS VARIOUS PATIENT SUBGROUPS1

PATIENT BASELINE
CHARACTERISTICS

MAYZENT SHOWED A FAVORABLE RISK REDUCTION IN THE TIME TO 3-MONTH CDP ACROSS VARIOUS PATIENT SUBGROUPS1

PATIENT BASELINE
CHARACTERISTICS

EFFICACY RESULTS FOR MAYZENT

Key secondary end points1

T25-FW Test Score

T25-FW TEST SCORES

Time to 3-month confirmed deterioration by ≥20% on the T25-FW test was not statistically significant compared to placebo (P=NS)

T2-lesion-volume

T2 LESION VOLUME

MAYZENT reduced the expansion of T2 lesion volume at 12 and 24 months compared to placebo (adjusted mean; P<0.01*)

  • Change from baseline T2 lesion volume: 184 mm3 for patients on MAYZENT vs 879 mm3 for patients on placebo

*Nominal P value, not corrected for multiple comparisons.

Additional secondary end points1,2

ANNUALIZED RELAPSE RATE

Annualized Relapse Rate Annualized Relapse Rate

55% relative reduction in ARR compared with placebo

  • ARR is the average number of confirmed relapses per year (0.071 for MAYZENT vs 0.160 for placebo)

6-MONTH CDP

6-month CDP 6-month CDP

26% relative risk reduction in disability progression as measured by time to 6-month CDP, compared to placebo

  • The proportion of patients with 6-month CDP for MAYZENT was 20% vs 26% for patients on placebo

NEW OR ENLARGING T2 LESIONS

New or enlarging T2 lesions New or enlarging T2 lesions

81% reduction in the mean number of new or enlarging T2 lesions (0.70 for patients on MAYZENT vs 3.60 for patients on placebo) over all visits

T1 GdE LESIONS

T1 GdE lesions T1 GdE lesions

86% risk reduction in the number of T1 GdE Lesions on an MRI at 2 years for patients taking MAYZENT vs those on placebo (0.08 for patients on MAYZENT vs 0.60 for patients on placebo)

These analyses have not been adjusted for multiple comparisons. No conclusions of statistical or clinical significance can be drawn.

Exploratory cognitive end points3

3 COGNITIVE TEST RESULTS†

  • SDMT: MAYZENT demonstrated a positive effect on cognitive processing speed‡

    • MAYZENT showed a 2.48-point difference vs placebo at 24 months (adjusted mean)

    • The overall risk reduction for a decrease in SDMT scores by ≥4 points was 21.3% for patients taking MAYZENT

  • PASAT: MAYZENT demonstrated a favorable effect for patients with active SPMS; there was no clinically meaningful difference between MAYZENT and placebo for patients with non-active SPMS

  • BVMT-R: there was no clinically meaningful difference between MAYZENT and placebo

SAFETY

ARR=annualized relapse rate; BVMT-R=Brief Visuospatial Memory Test Revised; CDP=confirmed disability progression; CI=confidence interval; EDSS=Expanded Disability Status Scale; GdE=gadolinium-enhancing; MRI=magnetic resonance imaging; MS=multiple sclerosis; NS=not significant; PASAT=Paced Auditory Serial Addition Test; SDMT=Symbol Digit Modalities Test; SPMS=secondary progressive MS; T25-FW=timed 25-foot walk.

†SDMT is a written and oral test for assessing cognitive processing speed, which is the most frequently affected cognitive domain in patients with SPMS; the test involves both rapid information processing and attention skills. PASAT is a test that assesses auditory information processing speed and flexibility. BVMT-R is an assessment of visuospatial memory.4-6

‡Results for SDMT oral scores reported at months 12 and 24.3

References: 1. Mayzent [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 2019. 2. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. 3. Data on file. Benedict AAN 2018. 4. Data on file. Benedict RHB et al. 2017. 5. Benedict RHB, DeLuca J, Phillips G, et al. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23(5):721-733. 6. Data on file. Mayzent® Core Study Report, Section 11.4.1.4.5. 2019.

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Indication and Important Safety Information

INDICATION

MAYZENT® (siponimod) 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.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Patients with a CYP2C9*3/*3 genotype

  • In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure

  • Presence of Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker

INDICATION

MAYZENT® (siponimod) 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.

Infections: MAYZENT may increase risk of infections with some that are serious in nature. Life-threatening and rare fatal infections have occurred.

Before starting MAYZENT, review a recent complete blood count (CBC) (ie, within 6 months or after discontinuation of prior therapy). Delay initiation of treatment in patients with severe active infections until resolved. Employ effective treatments and monitor patients with symptoms of infection while on therapy. Consider discontinuing treatment if patient develops a serious infection.

Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have occurred with MAYZENT. If CM is suspected, MAYZENT should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

No cases of progressive multifocal leukoencephalopathy (PML) were reported in MAYZENT clinical trials; however, they have been observed in patients treated with another sphingosine 1-phosphate (S1P) receptor modulator and other multiple sclerosis (MS) therapies. If PML is suspected, MAYZENT should be discontinued.

Cases of herpes viral infection, including one case of reactivation of varicella zoster virus leading to varicella zoster meningitis, have been reported. Patients without a confirmed history of varicella zoster virus (VZV) or without vaccination should be tested for antibodies before starting MAYZENT. If VZV antibodies are not present or detected, then VZV immunization is recommended and MAYZENT should be initiated 4 weeks after vaccination.

Use of live vaccines should be avoided while taking MAYZENT and for 4 weeks after stopping treatment.

Caution should be used when combining treatment (ie, anti-neoplastic, immune-modulating, or immunosuppressive therapies) due to additive immune system effects.

Macular Edema: In most cases, macular edema occurred within 4 months of therapy. Patients with history of uveitis or diabetes are at an increased risk. Before starting treatment, an ophthalmic evaluation of the fundus, including the macula, is recommended and at any time if there is a change in vision. The use of MAYZENT in patients with macular edema has not been evaluated; the potential risks and benefits to the individual patient should be considered.

Bradyarrhythmia and Atrioventricular Conduction Delays: Prior to initiation of MAYZENT, an ECG should be obtained to determine if preexisting cardiac conduction abnormalities are present. In all patients, a dose titration is recommended for initiation of MAYZENT treatment to help reduce cardiac effects.

MAYZENT was not studied in patients who had:

Reinitiation of treatment (initial dose titration, monitoring effects on heart rate and AV conduction [ie, ECG]) should apply if ≥4 consecutive daily doses are missed.

Respiratory Effects: MAYZENT may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy if clinically warranted.

Liver Injury: Elevation of transaminases may occur in patients taking MAYZENT. Before starting treatment, obtain liver transaminase and bilirubin levels. Closely monitor patients with severe hepatic impairment. Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked, and MAYZENT should be discontinued if significant liver injury is confirmed.

Increased Blood Pressure: Increase in systolic and diastolic pressure was observed about 1 month after initiation of treatment and persisted with continued treatment. During therapy, blood pressure should be monitored and managed appropriately.

Fetal Risk: Based on animal studies, MAYZENT may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping MAYZENT therapy.

Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for patients treated with MAYZENT in clinical trials. If patients develop any unexpected neurological or psychiatric symptoms, a prompt evaluation should be considered. If PRES is suspected, MAYZENT should be discontinued.

Unintended Additive Immunosuppressive Effects From Prior Treatment or After Stopping MAYZENT: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects.

Initiating treatment with MAYZENT after treatment with alemtuzumab is not recommended.

After stopping MAYZENT therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore, caution should be applied 3-4 weeks after the last dose of MAYZENT.

Severe Increase in Disability After Stopping MAYZENT: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of an S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping MAYZENT treatment, thus patients should be monitored upon discontinuation.

Most Common Adverse Reactions: Most common adverse reactions (>10%) are headache, hypertension, and transaminase increases.

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