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. 3 Horizon Scanning Research & Intelligence Centre • 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 4 Horizon Scanning Research & Intelligence Centre 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