SPMS disability progression delayed with Mayzent

MAYZENT® WAS PROVEN TO DELAY DISABILITY PROGRESSION IN EXPAND 1

MAYZENT® WAS PROVEN TO DELAY DISABILITY PROGRESSION IN EXPAND 1

SEE OPEN-LABEL EXTENSION STUDY (INTERIM ANALYSIS DATA UP TO 5 YEARS)2

CORE STUDY

DELAYED DISABILITY PROGRESSION: CORE STUDY1POST HOC ACTIVE SPMS SUBGROUP ANALYSIS4

Primary End Point Post Hoc Analysis
21% relative risk reduction after 3 months 21% relative risk reduction after 3 months

MAYZENT demonstrated a 21% relative risk reduction in time to 3-month CDP1,3


  • The proportion of patients with 3-month CDP for MAYZENT was 26% vs 32% for placebo1

  • 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 months3

  • Although MAYZENT had a significant effect on CDP in patients with active SPMS (relapse in the 2 years prior to study entry), its effect in patients with nonactive SPMS was not statistically significant3

HOW TO ASSESS EDSS SCORES HOW CDP IS ASSESSED
31% risk reduction after 3 months with MAYZENT 31% risk reduction after 3 months with MAYZENT

MAYZENT showed a 31% relative risk reduction in time to 3-month CDP vs placebo4

  • Active SPMS was defined as the presence of relapses in the 2 years prior to screening and/or ≥1 T1 GdE lesions at baseline

  • The separate analysis evaluated the efficacy of MAYZENT in delaying disability progression (time to 3-month CDP) in a subgroup of patients showing progression in RMS (active SPMS)

  • The proportion of patients with 3-month CDP for MAYZENT was 25% vs 35% for placebo

HOW TO ASSESS EDSS SCORES HOW CDP IS ASSESSED

PATIENTS WITH DISABILITY IN EXPAND

56% of patients required walking assistance at
baseline in EXPAND. Therefore, upon study entry,
more than half of the patients in this trial relied on
a walker or cane to get around1,5

PATIENT BASELINE
CHARACTERISTICS

PATIENTS WITH DISABILITY IN EXPAND

56% of patients required walking assistance at baseline in EXPAND. Therefore, upon study entry, more than half of the patients in this trial relied on a walker or cane to get around1,5

PATIENT BASELINE
CHARACTERISTICS

MAYZENT WAS STUDIED IN SPMS PATIENTS WITH MODERATE-TO-ADVANCED DISABILITY ACROSS A BROAD RANGE OF END POINTS1

Key secondary end point results3*

T25-FW Test Score

T25-FW TEST

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

T2-lesion-volume

CNS TISSUE MEASURE

T2 LESION VOLUME

Reduced the expansion of T2 lesion volume at 12 and 24 months vs placebo (adjusted mean; P<0.01†)

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

†Nominal P value, not corrected for multiple comparisons.

*

  • In EXPAND, a prespecified hierarchical analysis consisted of the primary end point and these 2 key secondary end points3

  • The T25-FW test key end point was not significant; therefore, the T2 lesion volume key secondary end point was considered nominal1,3

  • The remaining end points were not corrected for multiple comparisons; no conclusions of statistical or clinical significance can be drawn1

Additional secondary end point results1,3

ANNUALIZED RELAPSE RATE

Annualized Relapse Rate

55% relative reduction in ARR vs placebo

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

CNS TISSUE MEASURE:

NEW OR ENLARGING
T2 LESIONS

New or enlarging T2 lesions

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

6-MONTH CDP

6-month CDP

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

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

CNS TISSUE MEASURE:

T1 GdE LESIONS

T1 GdE lesions

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

CNS TISSUE MEASURE:

BRAIN VOLUME
LOSS

Brain volume loss

23% relative reduction in brain volume loss vs placebo

  • Change in brain volume from baseline was evaluated in 1342 patients (903 MAYZENT vs 439 placebo) at Month 12 and in 709 patients (470 MAYZENT vs 239 placebo) at Month 24 (adjusted mean percentage change from baseline was 0.50% for patients on MAYZENT vs 0.65% for placebo)

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

Additional secondary end point results1,3

ANNUALIZED RELAPSE RATE

Annualized Relapse Rate

55% relative reduction in ARR vs placebo

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

6-MONTH CDP

6-month CDP

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

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

CNS TISSUE MEASURE:

NEW OR ENLARGING
T2 LESIONS

New or enlarging T2 lesions

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

CNS TISSUE MEASURE:

T1 GdE LESIONS

T1 GdE lesions

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

CNS TISSUE MEASURE:

BRAIN VOLUME LOSS

Brain volume loss

23% relative reduction in brain volume loss vs placebo

  • Change in brain volume from baseline was evaluated in 1342 patients (903 MAYZENT vs 439 placebo) at Month 12 and in 709 patients (470 MAYZENT vs 239 placebo) at Month 24 (adjusted mean percentage change from baseline was 0.50% for patients on MAYZENT vs 0.65% for placebo)

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

Exploratory cognitive end point results6-9

3 Cognitive Tests

3 COGNITIVE TESTS

SDMT is a written and oral test for assessing cognitive processing speed—the most frequently affected cognitive domain in progressing patients. The test involves both rapid information processing and attention skills.‡


  • 21.3% overall reduction in the risk of sustained decrease in SDMT score of ≥4 points for patients on MAYZENT (a 4-point SDMT change is regarded as a clinically meaningful change)


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


The results from PASAT and BVMT-R showed no clinically meaningful difference between MAYZENT and placebo.§

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

Post hoc analysis results from an EXPAND substudy on cortical and thalamic grey matter volume10

Cortical grey matter and thalamic grey matter volume were assessed in a post-hoc analysis of pooled data from EXPAND. The dataset included patients who participated in a prospective high-resolution T1 MRI substudy and a post-hoc analysis of patients who underwent conventional MRI. The full analysis set (no exclusions applied) and the per-protocol set (excluding patients with major protocol deviations and efficacy data after discontinuation) were assessed.10

PER-PROTOCOL SET ANALYSIS10,11:

CNS TISSUE MEASURE:

GREY MATTER VOLUME LOSS

Grey Matter Volume Loss

CNS TISSUE MEASURE:

GREY MATTER VOLUME LOSS

Grey Matter Volume Loss

63% RELATIVE REDUCTION
in cortical grey matter volume loss

vs placebo in 1029 patients (692 MAYZENT vs 337 placebo) at Month 24 (adjusted mean percentage change from baseline was -0.39 for patients on MAYZENT vs -1.04 for placebo)

42% RELATIVE REDUCTION
in thalamic grey matter volume loss

vs placebo in 1038 patients (696 MAYZENT vs 342 placebo) at Month 24 (adjusted mean percentage change from baseline was -1.02 for patients on MAYZENT vs -1.77 for placebo)

The full analysis set of MAYZENT vs placebo showed a relative reduction of 43% for cortical grey matter volume loss in 1315 patients (886 vs 429) and 31% for thalamic grey matter volume loss in 1329 patients (892 vs 437) at Month 24, respectively.10

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

POST HOC SUBGROUP ANALYSIS

Progression to wheelchair use was assessed in the most progressed patients in EXPAND1,12

POST HOC SUBGROUP ANALYSIS

Progression to wheelchair use was assessed in the most progressed patients in EXPAND1,12

  • The analysis evaluated the efficacy of MAYZENT in delaying disability progression in patients with an EDSS score of 6.5 (at baseline) to an EDSS score of ≥7, throughout the trial period12||

  • The EDSS equates a score of 6.5 with the requirement of assistance to walk (eg, walker), and a score of 7.0 with the use of a wheelchair5

Patient wheelchair dependence progression reduction chart with MAYZENT Patient wheelchair dependence progression reduction chart with MAYZENT
Wheel Chair Progression icons

MAYZENT reduced the risk of progressing from an EDSS score of 6.5 to ≥7 by 37% vs placebo

Wheel Chair Progression icons

MAYZENT reduced the risk of progressing from an EDSS score of 6.5 to ≥7 by 37% vs placebo

The proportion of patients with an EDSS score of 6.5 (at baseline) to ≥7 (at trial’s end) was 19.2% for MAYZENT vs 26.1% for placebo.

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

EXPAND OPEN-LABEL
EXTENSION STUDY INTERIM ANALYSIS OF SAFETY AND EXPLORATORY DATA1,2

SELECT EFFICACY ASSESSMENTS UP TO 5 YEARS WERE CONSISTENT WITH THE CORE STUDY1,2¶

OPEN-LABEL EXTENSION INTERIM ANALYSIS

In the open-label extension study, the efficacy of MAYZENT demonstrated a 22% relative risk reduction in time to 6-month CDP In the open-label extension study, the efficacy of MAYZENT demonstrated a 22% relative risk reduction in time to 6-month CDP

In this analysis, patients who started in the MAYZENT treatment arm experienced a greater reduction in the risk of disability progression vs patients who switched to MAYZENT later

STUDY DESIGN

ANNUALIZED RELAPSE RATE

Annualized Relapse Rate Annualized Relapse Rate

52% RELATIVE REDUCTION in ARR vs placebo-switch group

  • Defined as the average number of confirmed relapses per year (0.051 for MAYZENT vs 0.106 for placebo-switch group)

  • In this analysis, patients who started treatment on MAYZENT earlier saw a reduction in ARR vs patients who switched to MAYZENT later from placebo

COGNITIVE PROCESSING SPEED

Cognitive Processing Speed Cognitive processing speed

23% OVERALL REDUCTION in the risk of decrease in SDMT score vs placebo-switch group

  • SDMT was the only cognitive assessment conducted in the extension study

The extension study end points differ from the core study and were predefined as exploratory in the extension protocol.13

These exploratory analyses represent chance findings. No conclusions of statistical or clinical significance can be drawn. Consider interim analysis open-label extension study limitations when interpreting data. The open-label extension study is not blinded, not controlled, and includes inherent self-selection bias for remaining in the trial.

SDMT was assessed but was not an exploratory end point in the extension study. Additional long-term data that was collected but not listed: 6-month confirmed worsening of at least 20% from baseline in the T25-FW test, MRI parameters, Multiple Sclerosis Walking Scale-12 and EuroQoL.

6-month CDP, ARR, and SDMT were exploratory end points and assessments of efficacy measurements, respectively, in the EXPAND extension study.13

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; HR=hazard ratio; MOA=mechanism of action; MOD=mechanism of disease; MRI=magnetic resonance imaging; MS=multiple sclerosis; NS=not significant; PASAT=Paced Auditory Serial Addition Test; RMS=relapsing MS; SDMT=Symbol Digit Modalities Test; SPMS=secondary progressive MS; T25-FW=timed 25-foot walk.

‡Results for SDMT oral scores reported at Months 12 and 24.8

§PASAT is a test that assesses auditory information processing speed and flexibility; BVMT-R is an assessment of visuospatial memory.9

||Measured the length of time until a person reached an EDSS score of ≥7 based on sustained progression until the end of the EXPAND core phase. The survival analysis included a subset of patients with a baseline EDSS score of 6.5. Time to sustained progression to an EDSS score of ≥7 was assessed by a Cox proportional hazards model, with treatment as the covariate. The proportion of patients with sustained progression to an EDSS score of ≥7 was analyzed by Kaplan-Meier curves. Analyses excluded all EDSS assessments that were conducted during relapse. The adjusted/weighted survival analysis was performed in the overall patient population.12

References: 1. 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. 2. Data on file. Long-term Efficacy and Safety of Siponimod in Patients with SPMS: EXPAND Extension Analysis up to 5 Years. Novartis Pharmaceuticals Corp; May 2020. 3. Mayzent [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; January 2021. 4. Data on file. Efficacy of Siponimod in Secondary Progressive Multiple Sclerosis Patients With Active Disease: The EXPAND Study Subgroup Analysis. Novartis Pharmaceuticals Corp; August 2019. 5. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-1452. 6. Data on file. Impact of Siponimod on Cognition in Patients With Secondary Progressive Multiple Sclerosis: Results From Phase 3 EXPAND Study. Novartis Pharmaceuticals Corp; 2017. 7. Benedict RH, 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. 8. Data on file. Benedict AAN. Novartis Pharmaceuticals Corp; April 2018. 9. Data on file. Benedict Cognition Data. Novartis Pharmaceuticals Corp; 2017. 10. Data on file. Effect of Siponimod on Cortical Grey Matter and Thalamic Volume in Patients With Secondary Progressive Multiple Sclerosis–Results of the EXPAND Study. Novartis Pharmaceuticals Corp; May 2020. 11. Data on file. Siponimod Reduces Grey Matter Atrophy in Patients With Secondary Progressive Multiple Sclerosis: Subgroup Analyses From the EXPAND Study. Novartis Pharmaceuticals Corp; May 2020. 12. Data on file. Data Analysis Report Time to Wheelchair. Novartis Pharmaceuticals Corp; September 2019. 13. Data on file. A multicenter, randomized, double-blind, parallel-group, placebo-controlled variable treatment duration study evaluating the efficacy and safety of Siponimod (BAF312) in patients with secondary progressive multiple sclerosis followed by extended treatment with open-label BAF312. Novartis Pharmaceuticals Corp; July 2020.

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Indication and Important Safety Information

COLLAPSE

EXPAND

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.

Cutaneous Malignancies: Long-term use of S1P modulators, including MAYZENT, have been associated with an increased risk of basal cell carcinoma (BCC). Cases of other cutaneous malignancies, including melanoma and squamous cell carcinoma, have also been reported in patients treated with MAYZENT and in patients treated with another S1P modulator.

Periodic skin examination is recommended. Monitor for suspicious skin lesions and promptly evaluate any that are observed. Exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended.

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.

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.

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