If approved, Mayzent® (siponimod) will be the first and only oral treatment specifically indicated for patients with active secondary progressive multiple sclerosis (SPMS) in Europe[1])

CHMP opinion is based on the Phase III EXPAND trial, the largest randomized clinical study in a broad SPMS patient population (EDSS score 3.0 to 6.5 at baseline), showing Mayzent significantly reduced the risk of disease progression, including physical disability and cognitive decline[2]

Up to 80% of patients with relapsing remitting multiple sclerosis (RRMS) will develop SPMS[3]; if approved, Mayzent would be a viable treatment option for those patients with active SPMS
Basel, November 15, 2019 — Novartis today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for Mayzent® (siponimod) for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (i.e. Gd-enhancing T1 lesions or active, new or enlarging, T2 lesions). While MS progression is different for each patient and influenced by multiple factors, including use of MS disease-modifying treatments, it is estimated that up to 80% of patients will eventually transition from RRMS to SPMS [3]. If approved, Mayzent is expected to be the first and only oral treatment specifically indicated for patients with active SPMS based on a randomized clinical trial of a broad SPMS patient population.

“Today’s CHMP opinion marks a milestone in supporting people in Europe who are living with active SPMS,” said Christoph Thalheim, Director External Affairs, European Multiple Sclerosis Platform. “This decision brings hope of a possible new and beneficial therapy.”

The positive CHMP opinion for Mayzent is based on groundbreaking data from the Phase III EXPAND study, a randomized, double-blind, placebo-controlled trial, comparing the efficacy and safety of Mayzent versus placebo in people with SPMS. EXPAND also investigated a subgroup of patients with active disease (n=779), defined as patients with relapses in the two years prior to the study and/or presence of Gd-enhancing T1 lesions at baseline. The baseline characteristics were similar except for signs of activity compared to the overall population. Results from EXPAND in the overall population showed that Mayzent significantly reduced the risk of three-month confirmed disability progression (CDP) (primary endpoint; 21% reduction versus placebo, p=0.013) and meaningfully delayed the risk of six-month CDP (26% versus placebo, p=0.0058) [2].

In the subgroup of Mayzent-treated patients with active disease, results showed:

Time to onset of three?month and six?month CDP was significantly delayed by 31% compared to placebo and by 37% compared to placebo, respectively [4].
The annualized relapse rate (ARR – confirmed relapses) was reduced by 46% compared to placebo [4].
Significant favorable outcomes in other relevant measures of MS disease activity, including MRI disease activity and brain volume loss (brain shrinkage) [4].
Additional analyses of the EXPAND study were presented this year at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), demonstrating that Mayzent:

Can help patients keep their mobility for over four years longer on average*[5].
Reduced grey matter volume loss at one and two years, a key driver of disability progression and cognitive decline in patients with SPMS [6,7].
“For people living with MS, it is extremely important to delay disability progression and preserve cognition, so that they can live independent lives for longer,” said John Tsai, Head Global Drug Development and Chief Medical Officer, Novartis. “Mayzent is a testament to the Novartis mission to reimagine medicine for an underserved population such as people living with active SPMS.”

In March 2019, Novartis received approval from the US Food and Drug Administration (FDA) for Mayzent for the treatment of relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome (CIS†), relapsing remitting disease, and active secondary progressive disease, in adults. In November 2019, Novartis received approval from the Australian Therapeutic Goods Administration (TGA) for Mayzent for adult patients with SPMS. Novartis is committed to bringing Mayzent to patients worldwide, and additional regulatory filings are currently underway in Switzerland, Japan, Canada and China.

About Mayzent® (siponimod)
Mayzent is a next generation, selective sphingosine 1-phosphate receptor modulator approved by the FDA for the treatment of relapsing forms of multiple sclerosis (RMS), to include clinically isolated syndrome (CIS†), relapsing remitting disease, and active secondary progressive disease, in adults. Mayzent selectively binds to S1P1 and S1P5 receptors. In relation to the S1P1 receptor, it prevents the lymphocytes from egressing the lymph nodes and as a consequence, from entering the CNS of patients with MS [2]. This leads to the anti-inflammatory effects of Mayzent [8]. Mayzent also enters the CNS [9,10,11] and binds to the S1P5 sub-receptor on specific cells in the CNS, including astrocytes and oligodendrocytes and has shown pro-remyelinating and neuroprotective effects in preclinical models of MS [12,13,14].

About the EXPAND Study [2]
EXPAND is a randomized, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of Mayzent versus placebo in people with SPMS with varying levels of disability, EDSS scores of 3·0–6·5. It is the largest randomized, controlled study in SPMS to date, including 1,651 people with a diagnosis of SPMS from 31 countries. Mayzent demonstrated a safety profile that was overall consistent with the known effects of S1P receptor modulation. It reduced the risk of three-month CDP by a statistically significant 21% (p=0.013; primary endpoint). CDP was defined as a 1-point increase in EDSS, if the baseline score was 3·0 - 5·0, or a 0·5-point increase, if the baseline score was 5·5 - 6·5. No significant differences were found in the Timed 25-Foot Walk Test, however, T2 lesion volume was reduced by 79% as compared to placebo. Additional secondary endpoints included a relative reduction in the ARR by 55%, and compared to placebo, more patients were free from Gd-enhancing lesions (89% vs 67% for placebo) and from new or enlarging T2 lesions (57% vs 37% for placebo).

About Multiple Sclerosis
MS disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss [15]. MS, which affects approximately 2.3 million people worldwide [3], is often characterized into three forms: primary progressive MS (PPMS) [16], relapsing-remitting MS (RRMS), and SPMS, which follows from an initial RRMS course and is characterized by physical and cognitive changes over time, in presence or absence of relapses, leading to a progressive accumulation of neurological disability [17]. Approximately 85% of patients initially present with relapsing forms of MS [3]. There remains a high unmet need for safe and effective treatments to help delay disability progression in SPMS with active disease (with relapses and/or evidence of new MRI activity) [17].

About Novartis in MS
The Novartis multiple sclerosis portfolio includes Gilenya® (fingolimod, an S1P modulator), which is indicated in the European Union for the treatment of adult patients and children and adolescents 10 years of age and older with RMS. In the United States, Gilenya is approved for the treatment of adults and pediatric patients aged 10 years and older with RMS, to include CIS†, relapsing remitting disease and active secondary progressive disease.

In March 2019, the FDA approved Mayzent for the treatment of relapsing forms of MS, to include CIS†, relapsing remitting disease and active secondary progressive disease. The approval is based on the Phase III EXPAND trial, the largest controlled clinical study of a broad SPMS patient population, showing Mayzent significantly reduced the risk of disease progression, including impact on physical disability and cognitive decline [2]. In November 2019, Novartis received approval from the Australian TGA for Mayzent for adult patients with SPMS. Novartis is committed to bringing Mayzent to patients worldwide, and additional regulatory filings are currently underway with other health authorities outside the US.

Ofatumumab (OMB157), a fully human anti-CD20 monoclonal antibody (mAb) that targets B-cells, is in development for treating RMS. Positive Phase III data presented in September 2019 show ofatumumab met primary endpoints to reduce the ARR in patients with RMS [18]. Novartis plans to initiate submissions to health authorities by the end of 2019. If approved, ofatumumab will potentially become a treatment for a broad RMS population and the first subcutaneous B-cell therapy that can be self-administered at home.

Extavia® (interferon beta-1b for subcutaneous injection) is approved in the US for RMS, to include CIS†, relapsing remitting disease and active secondary progressive disease. In Europe, Extavia is approved to treat people with RRMS, SPMS with active disease and people who have had a single clinical event suggestive of MS.

In the US, the Sandoz Division of Novartis markets Glatopa® (glatiramer acetate injection) 20mg/mL and 40mg/mL, generic versions of Teva's glatiramer acetate.

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” etc. etc..
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*As measured by prolonged time to wheelchair dependence for patients with SPMS by an average of 4.3 years versus placebo.
†Clinically isolated syndrome (CIS) is defined as a first episode of neurologic symptoms that lasts at least 24 hours and is caused by inflammation or demyelination in the central nervous system [19].

References
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[3.] Multiple Sclerosis International Federation. Atlas of MS 2013. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Accessed March 2019.
[4.] Gold R, Kappos L, Bar-Or A, et al. Efficacy of Siponimod in Secondary Progressive Multiple Sclerosis Patients With Active Disease: The EXPAND Study Subgroup Analysis. P750. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.
[5.] Vermersch P, Gold R, Kappos L, et al. Siponimod Delays the Time to Wheelchair in Patients with SPMS: Results from the EXPAND study. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 2019.
[6.] Arnold D, Giovannoni G, Cree B, et al. Relationship Between Grey Matter Atrophy, Disability and Cognition in Patients with Secondary Progressive Multiple Sclerosis: Analysis from the EXPAND Study. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 2019.
[7.] Arnold D, Fox R, Bar-Or A, et al. Effect of Siponimod on Cortical Grey Matter and Thalamic Volume in Patients with Secondary Progressive Multiple Sclerosis - Results of the EXPAND Study. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 2019.
[8.] Gergely P, Nuesslein-Hildesheim B, Guerini D, et al (2012) The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Brit J Pharm; 167:1035-47.
[9.] Tavares A, Barret O, Alagille D, et al. Brain distribution of MS565, an imaging analogue of siponimod (BAF312), in non-human primates. Eur J Neurol. 2014;21(Suppl 1):504-PP2067.
[10.] Briard E, Rudolph B, Desrayuad S, et al. MS565: A SPECT tracer of evaluating the brain penetration of BAF312 (sipinomod). Chem Med Chem. 2015; 10(6):1008-18.
[11.] Bigaud M, Perdoux J, Ramseier P et al. Pharmacokinetic/Pharmacodynamic Characterization of Siponimod (BAF312) in Blood versus Brain in Experimental Autoimmune Encephalomyelitis Mice. Neurology. 2019;P2.2-066.
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[13.] Martin E, Urban B, Beerli C, et al. Siponimod (BAF312) is a potent promyelinating agent: preclinical mechanistic observation. P1376. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.
[14.] Dietrich M, Hecker C, Ramseier P, et al. Neuroprotective potential for siponimod (BAF312) revealed by visual system readouts in a model of experimental autoimmune encephalomyelitis-optic neuritis (EAEON). P844. 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.
[15.] PubMed Health. Multiple Sclerosis (MS). http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001747/. Accessed March 2019.
[16.] MS Society. Types of MS. https://www.mssociety.org.uk/what-is-ms/types-of-ms. Accessed March 2019.
[17.] National Multiple Sclerosis Society. Secondary Progressive MS (SPMS). https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progr.... Accessed March, 2019.
[18.] Hauser S. Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. Oral presentation. ECTRIMS 2019.
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