August Horizon Scanning Research & 2016 Intelligence Centre Ozanimod for relapsing remitting multiple sclerosis NIHR HSRIC ID: 8099 Lay summary Ozanimod is a new drug that is taken by mouth to treat patients with 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 and concentration, emotions, sight, speech and swallowing, arm or leg sensation and movement, bladder and bowel function and balance. More than 8 out of every 10 people with MS are diagnosed with the ‘relapsing remitting’ form of disease. This means that the patient will have ‘attacks’ of new or worsening symptoms, known as ‘relapses’. Some studies have suggested that ozanimod may be able to reduce the number of ‘relapses’ 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): relapsing remitting. TECHNOLOGY DESCRIPTION Ozanimod (RPC-1063) is an orally bioavailable, small molecule that acts directly and through its metabolites to selectively activate sphingosine-1-phosphate (S1P) receptor 1 and 5 (S1PR1 and S1PR5). S1P is a soluble signalling molecule involved in a wide range of immunological, cardiovascular, and neurological processes, acting through its interaction with G-protein-coupled receptors S1PR1, S1PR2, S1PR3, S1PR4, and S1PR51. Modulation of S1P receptors with ozanimod may decrease inflammatory cell infiltration of the central nervous system (CNS) leading to a reduction in disease activity in patients with MS1. Furthermore, modulation of S1PR on microglia, oligodendrocytes, astrocytes, and neurons is proposed to have direct beneficial effects. Ozanimod is administered orally at 0.25mg on days 1-4, 0.5mg on days 5-7 and then 0.5mg or 1mg daily thereaftera. Ozanimod does not currently have Marketing Authorisation in the EU for any indication. INNOVATION and/or ADVANTAGES If licensed, ozanimod will offer an additional treatment option for patients with relapsing remitting MS. DEVELOPER Celgene. 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. This results in the wide variety of symptoms and reduced or absent neurological function, which depends upon the part or parts of the CNS that are affected4. Patients with MS typically develop symptoms any time from 20 to 50 years of age, experiencing cognitive, visual and sensory disturbances, limb weakness, gait problems, and a Company provided information. Horizon Scanning Research & Intelligence Centre bladder and bowel dysfunctionb,5. They may initially have partial recovery, but over time about 80% of patients start to develop progressive disabilityb. MS has an unpredictable course with variable disease severity and progression. The most common pattern of disease is relapsing remitting MS (RRMS), where periods of stability (remission) are followed by episodes when there are exacerbations of symptoms (relapses)6. About 80-85% of people with MS have RRMS at onset and around two-thirds of these patients will subsequently develop secondary progressive MS, where there is a gradual accumulation of disability unrelated to relapses, which become less frequent or stop completely6. Approximately 10 to 15% of people with MS present with primary progressive MS where symptoms gradually develop and worsen over with no distinct relapses and remissions6. 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 36% of patients with MS have RRMS, which in England equates to approximately 31,500 patients8. Approximately half of patients with RRMS have highly active disease and around 39% (approximately 12,200 patients) are eligible for treatment with currently available drugs8. MS is generally diagnosed between the ages of 20 and 50 years, with women outnumbering men in a ratio of approximately 3:1b,3. MS is the most common cause of non-traumatic neurological disability in young adultsb, and causes high levels of disability and impaired quality of life for prolonged periods9. 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 adulthood11. Approximately 25% of patients with MS are in employment12. 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. Expert opinion notes that hospital admissions for MS are grossly underestimatedb. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • NICE technology appraisal in development. Daclizumab for treating relapsing-remitting multiple sclerosis [ID827]. Expected publication date January 2017. • 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. b Expert personal communication. 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 treating of highly active relapsing‐ remitting multiple sclerosis (TA254). April 2012. • NICE technology appraisal. Natalizumab for the treating of highly active relapsing‐ remitting multiple sclerosis (TA127). August 2007. • 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. 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. • Joint Accreditation Committee, ISCT, EBMT. International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration. 201518. • Joint Accreditation Committee, ISCT, EBMT. Position statement for patients, families and carers considering HSCT for severe autoimmune disease. 201519. • European Group for Blood and Marrow Transplantation. Haematopoietic SCT in severe autoimmune diseases. 201220. • 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. 200821. • 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. 200522. CURRENT TREATMENT OPTIONS In the individual patient, MS remains a fundamentally unpredictable condition. There are many factors that influence prognosis and disease course, including presenting symptoms and initial MRI characteristics, type and frequency of subsequent relapses, age, sex, MRI lesion load, and spinal cord involvement16. 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 therapists6. In MS, the majority of pharmacological treatments, physical therapies, and