Novartis receives European licence for Mayzent®▼(siponimod), the first oral treatment for secondary progressive multiple sclerosis (SPMS) with active disease

• Licence based on Phase III EXPAND trial data showing siponimod delayed disease progression, slowed the advance of physical symptoms and positively impacted cognition in a broad SPMS patient population [i]^,[ii],[iii]

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

• Until now, there have been limited management options available following an SPMS diagnosis[vii]

London, UK, January 20, 2020 – Novartis today announced that the European Medicines Agency (EMA) has granted a licence for the use of 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. Siponimod, a once-daily tablet, is the first and only oral disease-modifying therapy for this patient population.

SPMS is characterised by a progressive accumulation of disability over time⁴. In addition to this, people living with ‘SPMS with active disease’ experience relapses or new inflammatory activity, demonstrated by changes on MRI scans⁴. While MS progression is different for each person and influenced by multiple factors, studies have shown that between 24% and 40% of people with relapsing remitting MS (RRMS) progress to SPMS within 10 years from diagnosis^{[viii],[ix],[x]}. Currently, once an SPMS diagnosis is received, management options available to patients become limited⁷.

“Siponimod has been shown to delay disability progression for people with SPMS with active disease, reducing the decline of both cognitive and physical abilities and thereby helping them to maintain independence for longer,” said Dr Martin Duddy, Clinical Director and Consultant Neurologist at Newcastle upon Tyne Hospitals NHS Foundation Trust. “The MS clinical community welcomes today’s news, which provides us with a new treatment to support a group of patients who, to-date, have had few options available to help delay the worsening of this often devastating condition.”

“The MS Trust are delighted that siponimod, the first oral treatment for people with secondary progressive MS with active disease, has been granted a European licence. Secondary progressive MS can have a devastating impact on all aspects of people’s lives,” said David Martin, Chief Executive Officer, Multiple Sclerosis Trust. “The approval of siponimod will give hope to a group of people who have previously had very few options for treatment for this life-changing condition. We hope that the availability of this treatment for this type of MS will lead to a renewed focus on the needs of all people with progressive MS and improve their access to services.”

“Our work to deliver a new treatment that has the potential to redefine what it means to live with SPMS demonstrates our commitment to reimagining care for people living with MS," said Haseeb Ahmad, Managing Director UK, Ireland and Nordics, Novartis Pharmaceuticals & Country President UK. “We’re proud to be providing a much needed, generally well tolerated and effective treatment option for SPMS with active disease, and our continued focus now is to work closely with regulatory bodies in the UK to make sure this new treatment is made widely available for those who it could benefit.”

Initial decisions from the National Institute for Health and Care Excellence (NICE) and the Scottish Medicine Consortium (SMC) on siponimod for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease are expected in the first half of 2020. Novartis will work closely with all stakeholders to ensure eligible patients can start benefitting from this treatment as quickly as possible. A bespoke patient support programme and range of resources are also being developed in order to provide as much support as possible to patients and healthcare professionals.

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

Siponimod has been studied in the Phase III EXPAND study, a randomised, double-blind, placebo-controlled trial comparing the efficacy and safety of siponimod versus placebo in in 1,651 people with SPMS with varying levels of disability (Expanded Disability Status Scale [EDSS] scores of 3.0 to 6.5)¹. Siponimod was shown to have a safety profile that was overall consistent with the known effects of S1P receptor modulation¹. Results showed that siponimod reduced the risk of three-month confirmed disability progression (CDP) by a statistically significant 21%  versus placebo (26% of patients in siponimod group vs 32% in placebo group had 3-month CDP; hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.65–0.95; p=0.013; primary endpoint)¹. Specifically, in the post hoc analysis of the SPMS with active disease subgroup (n=779), results demonstrated that siponimod reduced the risk of three- and six-month CDP by 31% (HR 0.69, 95% CI 0.53–0.91; p=0.0094) and 37% (HR 0.63, 95% CI 0.47–0.86, p=0.0040) respectively versus placebo[xvi]. CDP was defined as a 1-point increase in EDSS if the baseline score was 3.0 to 5.0, or a 0.5-point increase if the baseline score was 5.5 to 6.5.

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^5,[xvii]. 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^[xviii]. 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)^[xix]. There are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)^[xx].

SPMS is characterised by gradual worsening of neurological function over time⁴. This leads to a progressive accumulation of disability, which can severely affect patients’ ability to carry out everyday activities⁴. SPMS can be active (with relapses or evidence of new MRI activity) or non-active⁴. There remains a high unmet need for effective treatments to help delay disability progression in SPMS^[xxi].

About Novartis in Multiple Sclerosis 
The Novartis multiple sclerosis (MS) portfolio includes Gilenya^® (fingolimod, an S1P modulator), which is licenced 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

[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] 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.

[iii] 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.

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

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

[vi] 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 December 2019.

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

^[xii] 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.

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

[xiv] 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.

[xv] 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.

[xvi] 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.

[xvii] 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 December 2019.

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

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

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

[xxi] 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.