Novartis receives positive CHMP opinion for Mayzent® (siponimod), the first and only oral treatment for secondary progressive multiple sclerosis with active disease

• Positive opinion based on pivotal Phase III EXPAND trial in a representative secondary progressive multiple sclerosis (SPMS) population, which showed Mayzent significantly reduced the risk of disease progression^[i]

• SPMS is characterised by a progressive accumulation of disability over time, affecting approximately a third of people living with MS^{[ii],[iii],[iv]}

• If approved, Mayzent will be the first and only oral disease-modifying therapy for active SPMS proven to delay disease progression, slow the advance of physical symptoms and positively impact cognition^i,[v],[vi]

Frimley, UK, November 15, 2019 – Novartis today announced that 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. If approved, Mayzent will be the first and only oral disease-modifying therapy for this patient population.

There are an estimated 110,000 people living with MS in the UK, of which approximately 85% are considered to have relapsing remitting MS (RRMS) at their point of diagnosis^iii,[vii]. While MS progression is different for each person and influenced by multiple factors, including the use of MS disease-modifying treatments, studies have shown that between 24% and 40% of people with RRMS progress to SPMS within 10 years from diagnosis^{[viii],[ix],[x]}. SPMS leads to progressive, irreversible disability, and once diagnosed, management options available to patients are currently limited^[xi]. In SPMS, relapses may occasionally occur, as well as periods of stabilityⁱⁱ. Active SPMS can be characterised by the presence of relapses or new inflammatory activity, as evidenced by changes on MRIⁱⁱ.

“Until recently, although we have made considerable strides in reducing relapses and long term disability in patients with relapsing remitting disease, there was little to offer patients who had reached the secondary progressive stage of the disease. Results from the EXPAND study demonstrate that Mayzent has a positive impact on reducing both cognitive and physical decline, offering renewed hope for people living with active SPMS,” said Dr Eli Silber, Consultant Neurologist at King’s College Hospital NHS Foundation Trust. “The CHMP’s positive recommendation heralds a new era of care for people with active SPMS, potentially offering the multiple sclerosis community, for the first time, a much-needed treatment that is proven to delay disability progression.”

“At Novartis, we are committed to reimagining care for patients across the MS spectrum, and today’s positive decision marks a significant step towards building a better future for people living with active SPMS," said Haseeb Ahmad, Managing Director UK, Ireland and Nordics, Novartis Pharmaceuticals & Country President UK. “Mayzent offers the potential to expand possibilities for those living with the condition by delaying the progression of disability. We will continue working closely with regulatory bodies to make sure this new treatment is made available in the UK for those who it could benefit.”

The CHMP positive opinion for Mayzent is based on data from the Phase III EXPAND study, a randomised, double-blind, placebo-controlled trial comparing the efficacy and safety of Mayzent versus placebo in 1,651 people with SPMS with varying levels of disability (Expanded Disability Status Scale [EDSS] scores of 3.0 to 6.5)ⁱ. Mayzent was shown to reduce the risk of disability progression with a safety profile that was overall consistent with the known effects of S1P receptor modulationⁱ. Specifically, in the post hoc analysis of the active SPMS subgroup (n=779), results demonstrated that Mayzent reduced the risk of three- and six-month confirmed disability progression by 31% (p=0.0094) and 37% (p=0.0040) respectively versus placebo^[xii].

Additionally, a sub-group analysis of the EXPAND study showed that Mayzent had functional benefits on cognitive processing speed, the cognitive function most frequently affected by MS^vi,[xiii]. Further analyses have shown that Mayzent may help patients preserve their mobility for over four years longer on average^v, and that it reduced loss of cortical grey matter and thalamic volume – key drivers of disability progression and declining cognitive function in patients with SPMS^[xiv].

The European Commission will now consider this guidance from the CHMP and is expected to deliver its final decision on the marketing authorisation for Mayzent within three months. In March 2019, Mayzent was approved by the U.S. Food and Drug Administration (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. Novartis is committed to bringing Mayzent to patients worldwide, and additional regulatory filings are currently underway with other health authorities worldwide.

About Mayzent (siponimod)
Mayzent is a potent and selective small-molecule agonist of sphingosine-1-phosphate (S1P) receptors S1P₁ and S1P₅^[xv],[xvi]. Mayzent binds to the S1P₁ sub-receptor on lymphocytes, preventing their egress from lymphoid tissues, thereby preventing recirculation to the central nervous system (CNS)ⁱ. Mayzent readily crosses the blood-brain barrier, and findings from pre-clinical studies suggest that Mayzent prevents synaptic neurodegeneration, has the potential to promote remyelination in the CNS, and modulates pathways involved in cell survival with subsequent reduction of demyelination^{i,[xvii],[xviii],[xix]}.

About Multiple Sclerosis
There are approximately 110,000 people with multiple sclerosis (MS) in the UK, and each year around 5,000 people are newly diagnosed with the condition^iii,[xx]. MS is a chronic disorder of the central nervous system (CNS) that disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss^[xxi]. The evolution of MS results in an increasing loss of both physical and cognitive functions (e.g. mobility problems, numbness, bladder and bowel problems, and problems with thinking, learning and planning)^[xxii]. There are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)^[xxiii].

SPMS is characterised by gradual worsening of neurological function over timeⁱⁱ. This leads to a progressive accumulation of disability, which can severely affect patients’ ability to carry out everyday activitiesⁱⁱ. SPMS can be active (with relapses or evidence of new MRI activity) or non-activeⁱⁱ. There remains a high unmet need for effective treatments to help delay disability progression in SPMS^[xxiv].

About Novartis in Multiple Sclerosis 
The Novartis multiple sclerosis (MS) portfolio includes Gilenya^® (fingolimod, an S1P modulator), which is licensed in Europe for the treatment of adults and children aged 10 and older with highly active relapsing remitting forms of MS. Extavia^® (interferon beta-1b for subcutaneous injection) is approved in Europe to treat people with RRMS, people with SPMS with active disease (evidenced by relapses), and people who have had a single clinical event suggestive of MS.

About Novartis

Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach more than 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 130 000 people of nearly 150 nationalities work at Novartis around the world. Find out more at www.novartis.com.

In the UK, we employ approximately 1,500 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis. Since 2014, Novartis has invested over £200 million in R&D and is a leading sponsor of clinical trials, in the UK. For more information, please visit www.novartis.co.uk

Novartis UK is on Twitter. Sign up to follow @NovartisUK at www.twitter.com/novartisuk

For Novartis multimedia content, please visit www.novartis.co.uk/news/media-library

[i] Kappos L, Cree B, Fox R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018;391(10127):1263-1273.

[ii] National Multiple Sclerosis Society. Secondary Progressive MS (SPMS). https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS. Accessed October 2019.

[iii] MS Trust. Prevalence and incidence of multiple sclerosis. Available at: https://www.mstrust.org.uk/a-z/prevalence-and-incidence-multiple-sclerosis. Accessed November 2019.

[iv] National Institute for Health and Care Excellence, Health Technology Appraisal. Siponimod for treating secondary progressive multiple sclerosis Final scope. Available at: https://www.nice.org.uk/guidance/gid-ta10436/documents/final-scope. Accessed November 2019.

[v] Vermersch P, Gold R, Kappos L, Fox R, et al. Siponimod Delays the Time to Wheelchair in Patients with SPMS: Results from the EXPAND study. Poster presented at the 35^th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.

[vi] Benedict R, Fox R, Tomic D, et al. Effect of Siponimod on Cognition in Patients with Secondary Progressive Multiple Sclerosis (SPMS): Phase 3 EXPAND Study Subgroup Analysis. Poster presented at the 2019 American Academy of Neurology Annual Meeting, May 2019.

[vii] Multiple Sclerosis International Federation. Atlas of MS 2013. Available at: http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf. Accessed November 2019.

[viii] Tremlett H, Yinshan Z, Devonshire V. Natural history of secondary-progressive multiple sclerosis. Mult Scler. 2008; 14: 314-324.

[ix] Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014; 85: 67-75.

[x] Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol. 2006; 5: 343-354.

[xi] MS Trust. Secondary Progressive Multiple Sclerosis. Available at: https://support.mstrust.org.uk/file/SPMS-A5-Booklet-Oct-2018-FINAL-WEB.pdf. Accessed November 2019.

[xii] 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. Poster presented at the 35^th congress of the European Committee for Treatment and Research in Multiple Sclerosis and

24th Annual Conference of Rehabilitation in MS, 11–13 September 2019, Stockholm, Sweden.

[xiii] Chiaravalloti N, DeLuca J. Cognitive impairment in multiple sclerosis. The Lancet Neurology. 2008;7(12):1139-1151.

[xiv] Arnold DL, 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. Poster presented at the 35^th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.

[xv] Gergely P 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):1035-47.

^[xvi] Pan S, Gray NS, Gao W, et al. Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett 2013;4:333-7.

[xvii] Gentile A, Musella A, Bullitta S, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation 2016; 13: 207.

[xviii] Martin E, Urban B, Beerli C, et al. Siponimod (BAF312) is a Potent Promyelinating Agent: Preclinical Mechanistic Observations. Poster presented at the 35^th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 2019.

[xix] O'Sullivan C, Schubart A, Mir AK, et al. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation 2016;13:31.

[xx] MS Society. MS in the UK. Available at: https://www.mssociety.org.uk/what-we-do/our-work/our-evidence/ms-in-the-uk. Accessed November 2019.

[xxi] American Association of Neurological Surgeons. Multiple Sclerosis. Available at: https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Multiple-Sclerosis. Accessed November 2019.

[xxii] NHS. Multiple sclerosis – Symptoms. Available at: https://www.nhs.uk/conditions/multiple-sclerosis/symptoms/. Accessed November 2019.

[xxiii] MS Society. Types of MS. Available at: https://www.mssociety.org.uk/what-is-ms/types-of-ms. Accessed November 2019.

[xxiv] Mehr S.R. and Zimmerman M.P. Reviewing the unmet needs of patients with multiple sclerosis. Am Health Drug Benefits. 2015; 8(6);426-431.