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.

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• 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 psychological therapies are directed at the management of specific symptoms and disability such as incontinence, fatigue, pain and depression23,24:

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For patients with RRMS, treatment also focuses on the prevention and management of relapses. It is important to differentiate a relapse from a ‘pseudo-relapse’, which is a temporary worsening of pre-existing symptoms due to concurrent fever, illness or infection3. Expert opinion notes that it is often difficult to differentiate a relapse from a ‘pseudo-relapse’ as there is no specific definition of a relapse that allows a reliable consistent and valid distinctionc. If the symptoms of the relapse are not due to infection and are affecting day to day function, treatment with a short course of high dose steroids, such as methylprednisolone, is recommended3.

Disease modifying therapies reduce the number and severity of relapses and are therefore used with a view to changing the long-term course of RRMS3. However, expert opinion notes that the efficacy of current disease modifying drugs in terms of improving patient outcomes at the level of disability should not be overestimatedc. Eligible patients will normally be ambulant with a maximum Expanded Disability Status Score (EDSS) of 6.516. The currently licensed disease-modifying treatments divide broadly into two classes16:

• Drugs of moderate efficacy: o β-interferons. o Glatiramer acetate. o Teriflunomide. o Dimethyl fumarate. o Fingolimod. • Drugs of high efficacy: o Alemtuzumab. o Natalizumab.

Patients with RRMS who have had two or more clinical relapses in the previous two years are considered to have ‘active’ disease that warrants consideration of disease-modifying treatments16. However, an increasing number of clinicians are also starting treatments in those whose disease is judged ‘active’ because of a single recent relapse and/or MRI evidence of disease activity, and in those with longer established disease who develop new MRI lesions without clinical relapse16. Most patients are likely to start disease-modifying treatment on moderate efficacy drugs16.

Patients may be classified as having more active MS by frequent clinical relapses and/or MRI activity, either when untreated or while on a moderate efficacy disease-modifying drug16. The formal criteria for high-disease activity despite interferon-β or glatiramer therapy requires one relapse in the previous year on interferon-β and either (a) ≥1 gadolinium- enhancing MRI lesions or (b) at least nine T2-hyperintensive lesions on cranial MRI16. Guidelines recommend that patients with high-disease activity receive high efficacy drugs, i.e. alemtuzumab or natalizumab16, which are able to reduce relapse rate by approximately 75%24.

EFFICACY and SAFETY

Trial SUNBEAM, NCT02294058, RADIANCE (Part B), RADIANCE (Part A), RPC01-301, 2014‐002320‐ NCT02047734, RPC01-201 NCT01628393, RPC01-201 27; ozanimod vs beta (Part B), 2012-002714-40; (Part A), 2012-002714-40; interferon; phase III. ozanimod vs beta ozanimod vs placebo; interferon; phase III. phase II. Sponsor Celgene. Celgene. Celgene. Status Ongoing. Ongoing. Complete and published.

c Expert personal communication.

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Source of Trial registry25, Trial registry26, Publication27, trial information manufacturer. manufacturer. registry28, manufacturer. Location EU (incl UK), USA, Canada EU (incl UK), USA, Canada EU (not UK), USA. and other countries. and other countries. Design Randomised, active- Randomised, active- Randomised, placebo- controlled. controlled. controlled. Participants n=1200 (planned); aged n=1200 (planned); aged n=258; aged 18-55 yrs; 18-55 yrs; multiple 18-55 yrs; multiple multiple sclerosis; EDSS sclerosis; EDSS between sclerosis; EDSS between between 0.0 and 5.0; ≥1 0.0 and 5.0; no primary 0.0 and 5.0; no primary relapse within the last 12 progressive multiple progressive multiple mths or ≥1 relapse within sclerosis. sclerosis. the last 24 mths and ≥1 gadolinium-enhanced (GdE) lesion on brain MRI within the last 12 mths; no secondary or primary progressive multiple sclerosis; no prior treatment with lymphocyte-trafficking blockers or lymphocyte depleting therapies; no treatment with other disease modifying therapies within last 3 mths; no systemic corticosteroid or adrenocorticotropic hormone treatment within last 30 days. Schedule Randomised to ozanimod Randomised to ozanimod Randomised to ozanimod 0.5mg oral once daily; or 0.5mg oral once daily; or 0.5mg oral once daily; or ozanimod 1mg oral once ozanimod 1mg oral once ozanimod 1mg oral once daily; or beta interferon daily; or beta interferon daily; or placebo oral once intramuscular injection intramuscular injection daily. once weekly in combination once weekly in combination with placebo oral once with placebo oral once daily. daily. Follow-up Follow-up 30 mths. Active treatment for 2 yrs. Follow-up 24 wks. Primary Annual relapse rate. Annual relapse rate. Total number of new GdE outcome lesions. Secondary MRI outcomes; EDSS MRI outcomes; EDSS Cumulative number of outcomes progression; patient progression; patient new/enlarging T2 lesions; reported outcomes using reported outcomes using annual relapse rate; patient Short Form 36 Health SF36 assessment. reported outcomes using Survey (SF36) SF36 assessment. assessment. Key results - - Mean cumulative number of GdE lesions for 0.5mg ozanimod vs 1mg ozanimod vs placebo groups, respectively were 1.5 vs 1.5 vs 11.1. Adverse - - The most common adverse effects events in the ozanimod (AEs) groups vs placebo group were: nasopharyngitis (6.2% vs 4.7%), headache (3.1% vs 3.1%) and urinary tract infections (3.1% vs 0.8%).

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Expected Study completion date Study completion date - reporting reported as Nov 2017. reported as June 2017. date

ESTIMATED COST and IMPACT

COST

The cost of ozanimod 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

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services: oral treatment option.

 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: uncertain unit cost compared to  None identified existing treatment.

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion notes that there is clinical uncertainty about whether ozanimod will have an effect on reducing disability in patients with MSd.

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 25 August 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 25 August 2016.

d Expert personal opinion.

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4 Multiple Sclerosis Society of Canada. Patient group input to CADTH. www.cadth.ca/sites/default/files/pdf/TR0004_PatientInputSubmission_e.pdf Accessed 25 August 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 25 August 2016. 8 National Institute for Health and Care Excellence. Alemtuzumab for treating relapsing-remitting multiple sclerosis. Technology appraisal costing report TA312. London: NICE; May 2014. 9 Mackenzie IS, Morant SV, Bloomfield GA 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 HM, Telstad W, Grytten N et al. Employment among patients with multiple sclerosis – a population study. PLoS ONE 2014;9(7):3103317. 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 25 August 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 Joint Accreditation Committee of International Society of Cellular Therapy. Accreditation standards for haematopoietic cellular therapy. www.jacie.org/standards/6th-edition-2015 Accessed 25 August 2016. 19 European Society for Blood and Marrow Transplantation. General information for patients, families and carers considering HSCT for severe autoimmune disease. www.ebmt.org/Contents/Research/TheWorkingParties/ADWP/Documents/ADWP%20website%20 information%20for%20patients_VF.pdf Accessed 25 August 2016 20 Snowden J, Saccardi R, Allex M et al on behalf of the EBMT Autoimmune Disease (ADWP) and Paediatric Diseases (PDWP) Working Parties. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2012;47(6):770-90. 21 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. 22 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. 23 Multiple Sclerosis Trust. Treating MS symptoms. www.mstrust.org.uk/a-z/treating-ms-symptoms Accessed 25 August 2016. 24 NIHR Horizon Scanning Research & Intelligence Centre. Autologous haematopoietic stem cell transplantation for relapsing remitting multiple sclerosis. University of Birmingham, June 2016. www.hsric.nihr.ac.uk/ 25 ClinicalTrials.gov. Phase 3 study of RPC1063 in relapsing MS. www.clinicaltrials.gov/ct2/show/NCT02294058 Accessed 25 August 2016.

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26 ClinicalTrials.gov. Efficacy and safety study of RPC1063 in relapsing multiple sclerosis patients (radiance study). www.clinicaltrials.gov/ct2/show/NCT02047734 Accessed 25 August 2016. 27 Selmaj K, Arnold D, Comi G et al. Safety and tolerability results of the phase 2 portion of the radiance trial: a randomised, double-blind, placebo-controlled trial of oral RPC1063 in relapsing multiple sclerosis. Neurology 2015;84(14):7. 28 ClinicalTrials.gov. Efficacy and safety study of RPC1063 in relapsing multiple sclerosis patients (radiance study). www.clinicaltrials.gov/ct2/show/NCT01628393 Accessed 25 August 2016.

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