MAYZENT Mechanism of Action

MECHANISM OF DISEASE

MECHANISM OF DISEASE


IN RELAPSING MS PROGRESSION, THERE’S AN INVERSE RELATIONSHIP BETWEEN INFLAMMATION AND NEURODEGENERATION1,2

Relapsing MS is progressive and changes over time, with central inflammation contributing to cumulative, irreversible disability2-4

Relapsing MS is progressive and changes over time, with central inflammation contributing to cumulative, irreversible disability2-4

From inflammation to neurodegeneration, progressing patients will have different needs5,6

In RMS progression there is an inverse relationship between inflammation and neurodegeneration
In RMS progression there is an inverse relationship between inflammation and neurodegeneration

LOOK BEYOND RELAPSES

Patients with more progressed RMS, including active SPMS, typically have fewer relapses and/or diminishing MRI activity but are showing signs of progression. So when it comes to early identification of progression in your patients—look further. Monitor for physical and cognitive changes7-9

LOOK BEYOND RELAPSES

Patients with more progressed RMS, including active SPMS, typically have fewer relapses and/or diminishing MRI activity but are showing signs of progression. So when it comes to early identification of progression in your patients—look further. Monitor for physical and cognitive changes7-9

MECHANISM OF ACTION

MECHANISM OF ACTION


THE DUAL MOA OF MAYZENT® TARGETS S1P1,5—2 KEY
RECEPTORS THOUGHT TO PLAY A ROLE IN RMS
INFLAMMATION AND NEURODEGENERATION10-14


THE DUAL MOA OF MAYZENT® TARGETS S1P1,5—2 KEY RECEPTORS THOUGHT TO PLAY A ROLE IN RMS INFLAMMATION AND NEURODEGENERATION10-14

MAYZENT is an oral, selective S1P receptor modulator for progressing patients along the RMS continuum10

  • Works in the periphery to limit active lymphocytes from leaving the lymph nodes, which may reduce lymphocyte migration into the CNS10

  • Lymphocytes are stored, not destroyed, in the lymph nodes; upon discontinuation, blood lymphocyte counts rapidly recover within 10 days10*†

  • Works in the periphery to limit active lymphocytes from leaving the lymph nodes, which may reduce lymphocyte migration into the CNS10

  • Lymphocytes are stored, not destroyed, in the lymph nodes; upon discontinuation, blood lymphocyte counts rapidly recover within 10 days10*†

The Dual MOA of MAYZENT targets S1P1,5—2 key receptors thought to play a role in RMS inflammation and neurodegeneration The Dual MOA of MAYZENT targets S1P1,5—2 key receptors thought to play a role in RMS inflammation and neurodegeneration

The mechanism by which siponimod exerts therapeutic effects on MS is unknown but may involve reduction of lymphocytes in the CNS.10

IDENTIFYING RMS PROGRESSION

CNS=central nervous system; EDSS=Expanded Disability Status Scale; MOA=mechanism of action; MOD=mechanism of disease; MRI=magnetic resonance imaging; MS=multiple sclerosis; RMS=relapsing MS; RRMS=relapsing-remitting MS; S1P=sphingosine 1-phosphate; SPMS=secondary progressive MS.

*In 90% of patients.10

†After stopping MAYZENT treatment, residual lowering of peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose.10

‡Based on animal studies.10

References: 1. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76. 2. Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053-1065. 3. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(Pt 11):2705-2712. 4. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9)545-558. doi:10.1038/nri3871. 5. Bradl M, Lassmann H. Progressive multiple sclerosis. Semin Immunopathol. 2009;31(4):455-465. 6. Types of MS. National Multiple Sclerosis Society website. https://www.nationalmssociety.org/What-is-MS/Types-of-MS. Accessed November 29, 2020. 7. Fox RJ, Cohen JA. Multiple sclerosis: The importance of early recognition and treatment. Cleve Clin J Med. 2001;68(2):157-171. 8. Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function. Lancet. 2017;389(10076):1357-1366. 9. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-1452. 10. Mayzent [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; January 2021. 11. O’Sullivan C, Schubart A, Mir AK, Dev KK. The dual S1PR1/S1PR5 drug BAF312 (siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016;13:31. 12. Gergely P, Nuesslein-Hildesheim B, Guerini D, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012;167(5):1035-1037. 13. Mannioui A, Vauzanges Q, Fini JB, et al. The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination. Mult Scler. 2018;24(11):1421-1432. 14. Choi JW, Chun J. Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta. 2013;1831(1):20-32. 15. Briard E, Rudolph B, Desravaud S, Krauser JA, Auberson YP. MS565: A SPECT Tracer for Evaluating the Brain Penetration of BAF312 (Siponimod). ChemMedChem. 2015;10(6):1008-1018. 16. Behrangi N, Fischbach F, Kipp M. Mechanism of siponimod: anti-inflammatory and neuroprotective mode of action. Cells. 2019;8(24):1-11.

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Indication and Important Safety Information

COLLAPSE

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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.

Please click here for full Prescribing Information, including Medication Guide.