Siponimod for Secondary Progressive Multiple Sclerosis

August Horizon Scanning Research & 2016 Intelligence Centre

Siponimod for secondary progressive multiple sclerosis

NIHR HSRIC ID: 8562

Lay summary

Siponimod is a new drug that is taken by mouth to treat patients with secondary progressive multiple sclerosis (MS). MS is a condition which can affect the brain and/or spinal cord. It causes a wide range of symptoms, including problems with memory, sight, speech and swallowing, arm or leg sensation and movement, bladder and bowel function, and balance. Some studies have suggested that siponimod may be able to reduce symptoms in patients with MS by decreasing cells that cause inflammation.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Multiple sclerosis (MS): secondary progressive: relapsing and non-relapsing – first line.

TECHNOLOGY

DESCRIPTION

Siponimod (BAF-312) is a selective agonist of the sphingosine-1 phosphate (S1P) receptors 1 and 5 (S1PR1 and S1PR5). S1P is a soluble signalling molecule involved in a wide range of immunological, cardiovascular and neurological processes, and acts through interaction with G-protein-coupled receptors S1PR1, S1PR2, S1PR3, S1PR4 and S1PR51. Siponimod selectively binds S1PR 1 and 5 on circulating lymphocytes, which enables a reversible trapping of a proportion of lymphocytes in the lymph nodes. Modulation of S1P receptors by siponimod may decrease the number of activated T-cells circulating in the bloodstream and central nervous system (CNS), leading to a reduction in disease activity in patients with MS. Siponimod is administered orally at 2mg daily, after a 6 day dose titration from a starting dose of 0.25mga.

Siponimod does not currently have Marketing Authorisation in the EU for any indication.

Siponimod is not currently in phase II or III development for any other indications.

INNOVATION and/or ADVANTAGES

If licensed, siponimod will offer an additional oral treatment option for patients with secondary progressive MS, who currently have few effective therapies available.

DEVELOPER

Novartis Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

MS is an acquired chronic autoimmune inflammatory condition of the CNS2. The precise cause of MS remains unknown but evidence suggests that it is caused by a complex interplay of epigenetic, environmental and genetic factors that provoke an autoimmune inflammatory response3. This results in areas of demyelination, gliosis and secondary neuronal damage throughout the CNS2. The usual flow of nerve impulses along nerve fibres (axons) is interrupted or distorted, resulting in a wide variety of symptoms, depending on the part or parts of the CNS affected4. Patients with MS typically develop symptoms in their late

a Company provided information. Horizon Scanning Research & Intelligence Centre

20s, experiencing cognitive, visual and sensory disturbances, limb weakness, gait problems, and bladder and bowel dysfunction5.

MS has an unpredictable course with variable disease severity and progression. The most common pattern of initial disease is relapsing remitting MS (RRMS), where periods of stability (remission) are followed by episodes when there are exacerbations of symptoms (relapses)6. About 85% of people with MS have RRMS at disease onset. Approximately 10 to 15% of people with MS present with primary progressive MS where symptoms gradually develop and worsen with no distinct relapses and remissions6.

Approximately 50% of patients with RRMS develop secondary progressive MS within 10 years of diagnosis where there is a gradual accumulation of disability unrelated to relapses, which become less frequent or stop completely3. Around 75% of patients with RRMS will eventually develop secondary progressive disease6.

The accepted definition of secondary progressive MS is that a person must have shown continued deterioration for the past six months whether or not they have continued to experience relapses3. Some patients find that the increase or progression of disability is very gradual, whilst for others it can occur more quickly3.

CLINICAL NEED and BURDEN OF DISEASE

In England the prevalence of MS is estimated to be 164 per 100,000 population, which equates to around 89,000 people with MS and there are approximately 4,000 new diagnoses each year7. Approximately 45% of patients with MS have secondary progressive MS, which in England equates to about 40,000 patients8.

MS is generally diagnosed between the ages of 20 and 40 years, with women outnumbering men in a ratio of approximately 3:12. MS is the most common cause of non-traumatic neurological disability in young adults and causes high levels of disability and impaired quality of life for prolonged periods4,9. Approximately 50% of patients require a walking aid within 15 years of disease onset10. The disease is associated with a high rate of unemployment in early adulthood, only 25% of patients with MS estimated to be in employment11,12.

In 2014-15, there were 49,900 hospital admissions for MS (ICD-10 G35) in England, accounting for 52,235 finished consultant episodes and 57,474 bed days13. In 2014, 1,202 deaths due to MS were registered in England and Wales14.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Beta interferon and glatiramer acetate for treating multiple sclerosis (review TA32) [ID809]. Expected publication date April 2017. • NICE technology appraisal. Dimethyl fumarate for treating relapsing‐remitting multiple sclerosis (TA320). August 2014. • NICE technology appraisal. Alemtuzumab for treating relapsing‐remitting multiple sclerosis (TA312). May 2014.

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• NICE technology appraisal. Teriflunomide for treating relapsing‐remitting multiple sclerosis (TA303). January 2014. • NICE technology appraisal. Fingolimod for the treatment of highly active relapsing‐ remitting multiple sclerosis (TA254). April 2012. • NICE technology appraisal. Natalizumab for the treatment of highly active relapsing‐ remitting multiple sclerosis (TA127). August 2007. • NICE technology appraisal. Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (TA32). January 2002. • NICE clinical guidance. Multiple sclerosis in adults: management (CG186). October 2014. • NICE quality standards. Multiple sclerosis (QS108). January 2016. • NICE interventional procedure guidance. Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis (IPG420). March 2012. • NICE clinical guidance. Multiple sclerosis in adults: management (CG186). October 2014.

NHS England Policies and Guidance

• NHS England. 2013/14 NHS Standard Contract for Neurosciences: Specialised Neurology (Adult). D04/S/a. • NHS England. Clinical Commissioning Policy: Disease Modifying Therapies for Patients with Multiple Sclerosis. NHSCB/D04/P/b. May 2014. • NHS England. Clinical Commissioning Policy: Fampridine for Multiple Sclerosis (MS). NHSCB/D04/PS/c. April 2013.

Other Guidance

• Association of British Neurologists. Position statement on the use of AHSCT. 201615. • Association of British Neurologists. Guidelines for prescribing disease-modifying treatments in multiple sclerosis. 201516. • European Society for Blood and Marrow Transplantation. SCT for severe autoimmune diseases: consensus guidelines for immune monitoring and biobanking. 201517. • Royal College of Physicians, National Council for Palliative Care, British Society of Rehabilitation Medicine. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care. 200818. • European Federation of Neurological Societies. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. 200519.

CURRENT TREATMENT OPTIONS

Care for people with MS should adopt a coordinated multidisciplinary approach involving consultant neurologists, specialist nurses, physiotherapists, occupational therapists, dieticians, social care and continence specialists, and speech and language therapists5. In MS, the majority of pharmacological treatments, physical therapy and psychological therapy is directed at the management of specific symptoms, such as incontinence, fatigue, pain and depression20,21. In addition to management of symptoms, patients with secondary progressive MS with relapse can be treated with high-dose steroids6,22.

Immune modulating disease modifying therapies are used with a view to changing the long- term course of MS and work by reducing the number and severity of relapses2. As a result they have only been found to be effective for people with RRMS and for some people with

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secondary progressive MS who continue to relapse3. Interferon β 1b is licensed in the EU for the treatment of secondary progressive MS with active disease, evidenced by relapses23.

The currently licensed disease-modifying treatments for RRMS include15: • Alemtuzumab. • Natalizumab. • β-interferons. • Glatiramer acetate. • Teriflunomide. • Dimethyl fumarate. • Fingolimod.

EFFICACY and SAFETY

Trial EXPAND, NCT01665144, CBAF312A2304; siponimod vs placebo; phase III. Sponsor Novartis Pharmaceuticals. Status Ongoing. Source of Trial registry24, manufacturer25. information Location USA. Design Randomised, placebo-controlled. Participants n=1,651; aged 18-60 yrs; secondary progressive multiple sclerosis; increase of disability over at least 6 mths; prior history of relapsing remitting multiple sclerosis; Expanded Disability Status Scale (EDSS) of 3.0 to 6.5; no relapse or corticosteroid treatment within 3 mths. Schedule Randomised to siponimod in a dose titration from 0.25mg to 2mg oral once daily; or placebo, oral, once daily. Follow-up Active treatment for a maximum of 84 mths. Primary Time to confirmed disability progression as measured by EDSS. outcome Secondary Worsening of 25 foot walk test; reduced increase in T2 lesion volume on MRI; annual outcomes relapse rate; time to first relapse; inflammatory disease activity and burden of disease as measured by MRI; three month confirmed disability progression; adverse events. Key results Siponimod met its primary endpoint of a reduction in the risk of disability progression, compared with placebo. Expected Study completion date reported as Aug 2017. reporting date

ESTIMATED COST and IMPACT

COST

The cost of siponimod is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

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Impact on Health and Social Care Services

 Increased use of existing services: expert  Decreased use of existing services opinion states that there is currently no proven treatment for secondary progressive MS in the absence of relapses, any new treatment which is shown to work will have a major impact on NHS services. There will be an incredible demand for any such treatment, putting major pressure on nurses and neurology clinicsb.

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 Cohen J, Arnold D, Comi G et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. The Lancet Neurology 2016;15(4):373-381. 2 National Institute for Health and Care Excellence. Clinical Knowledge Summaries: Multiple sclerosis. www.cks.nice.org.uk/multiple-sclerosis Accessed 1 September 2016. 3 Multiple Sclerosis Trust. MS information for health and social care professionals. www.mstrust.org.uk/health-professionals/practice-resources/ms-information-health-and-social- care-professionals Accessed 1 September 2016. 4 Multiple Sclerosis Society of Canada. Patient group input to CADTH. www.cadth.ca/sites/default/files/pdf/TR0004_PatientInputSubmission_e.pdf Accessed 1 September 2016. 5 National Institute for Health and Care Excellence. Multiple sclerosis. Quality standard QS108. London: NICE; January 2016. 6 National Institute for Health and Care Excellence. Multiple sclerosis in adults: management. Clinical guideline CG186. London: NICE; October 2014. 7 MS Society. MS in the UK. www.mssociety.org.uk/sites/default/files/MS%20in%20the%20UK%20January%202016_0.pdf Accessed 1 September 2016. 8 National Institute for Health and Care Excellence. Beta interferon and glatiramer acetate for the treatment of multiple sclerosis. Technology appraisal TA32. London: NICE; January 2002. 9 Mackenzie I, Morant S, Bloomfield G et al. Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database. Journal of Neurology Neurosurgery and Psychiatry 2014;85:76-84. 10 Antel J, Antel S, Caramanos Z et al. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathologica 2012;123:627-638. 11 Boe Lunde H, Telstad W, Grytten N et al. Employment among patients with multiple sclerosis – a population study. PLoS ONE 2014;9(7):3103317.

b Expert personal opinion.

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12 National Institute for Health and Care Excellence. Dimethyl fumarate for treating relapsing- remitting multiple sclerosis. Technology appraisal TA320. London: NICE; August 2014. 13 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-2015. www.hscic.gov.uk 14 Office for National Statistics. Mortality statistics deaths registered in 2014 (series DR). www.ons.gov.uk 15 Association of British Neurologists. Position statement on the use of AHSCT in MS. www.theabn.org/resources/abn/a/abn-statement-on-autologous-haematopoietic-stem-cell- treatment-of-multiple-sclerosis.html Accessed 1 September 2016. 16 Scolding N, Barnes D, Cader S et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. Practical Neurology 2015;0:1-7. 17 Alexander T, Bondanza A, Muraro P et al. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplant 2015;50(2):173-180. 18 Turner-Stokes L, Sykes N and Silber E. Long-term neurological conditions: management at the interface between neurology, rehabilitation and palliative care. Clinical Medicine 2008;8:186-191 19 Sellebjerg F, Barnes D, Filippini G et al. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. European Journal of Neurology 2005;12(12):939-946. 20 European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis. Committee for Medicinal Products for Human Use. London: EMA; March 2015. 21 Multiple Sclerosis Trust. Treating MS symptoms. www.mstrust.org.uk/a-z/treating-ms-symptoms Accessed 1 September 2016. 22 Multiple Sclerosis Society. Secondary progressive MS. www.mssociety.org.uk/what-is-ms/types- of-ms/secondary-progressive-spms Accessed 1 September 2016. 23 electronic Medicine Compendium. Betaferon. www.medicines.org.uk/emc/medicine/1809 Accessed 1 September 2016. 24 ClinicalTrials.gov. Exploring the efficacy and safety of siponimod in patient with secondary progressive multiple sclerosis (EXPAND). www.clinicaltrials.gov/ct2/show/NCT01665144 Accessed 1 September 2016. 25 Novartis. Novartis announces positive phase III results showing efficacy of BAF312 in patients with secondary progressive MS. www.novartis.com/news/media-releases/novartis-announces- positive-phase-iii-results-showing-efficacy-baf312-patients Accessed 1 September 2016.