EXPAND trial largest secondary progressive multiple sclerosis study

MAYZENT® WAS EVALUATED IN EXPAND—THE LARGEST PHASE III STUDY OF SPMS TO DATE1-3

TRIAL DESIGN

Expand Design Chart for SPMS Expand Design Chart for SPMS

A broad range of patients with moderate-to-advanced disability was represented in EXPAND (N=1651)1,2

BASELINE PATIENT CHARACTERISTICS FOR PATIENTS RECEIVING SIPONIMOD

Age (mean)

48 YEARS
(Range: 21-61 years)


Previous treatment

78 % (n=860)
had received a DMT


Time since onset
of MS (mean)

17 YEARS


Time since initial MS diagnosis (mean)

13 YEARS
(Range: 0-44 years)


Patients with GdE
lesions

22 %
of patients


Patients with at least 1 relapse within the 2 years prior to study entry

36 %
of patients


EDSS progression documented in the 2 years prior to study

100 %
of patients


EDSS Score (mean)

5.4
(Range: 3.0-6.5)

HOW TO ASSESS EDSS SCORES Download Button

A range of end points was examined in the EXPAND trial1,2,4

Primary end point

  • Time to 3-month CDP


Key secondary end points

  • Time to 3-month confirmed deterioration by ≥20% from baseline on the T25-FW test

  • Change from baseline in T2 lesion volume


Select additional secondary end points

  • ARR

  • Time to 6-month CDP

  • Number of new or enlarging T2 lesions

  • Number of T1 GdE lesions


Select exploratory end points

  • Symbol Digit Modalities Test score

  • Brief Visuospatial Memory Test Revised score

  • Paced Auditory Serial Addition Test score

HOW CDP WAS ASSESSED Download Button

ARR=annualized relapse rate; CDP=confirmed disability progression; DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; GdE=gadolinium-enhancing; MRI=magnetic resonance imaging; MS=multiple sclerosis; SPMS=secondary progressive MS; T25-FW=timed 25-foot walk.

*Median drug exposure of 18 months.2

In EXPAND, a prespecified hierarchical analysis consisted of the primary end point and the 2 key secondary end points. The T25-FW test key end point was not significant; therefore, the T2 lesion volume key secondary end point was considered nominal. The remaining end points were not corrected for multiple comparisons.1

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. New Novartis analyses at AAN show siponimod's efficacy on disability and cognition in secondary progressive MS patients. Novartis website. https://www.novartis.com/news/media-releases/new-novartis-analyses-aan-show-siponimods-efficacy-disability-and-cognition-secondary-progressive-ms-patients. Published April 20, 2018. Accessed April 4, 2019. 4. 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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