Horizon Scanning Centre July Ocrelizumab for relapsing-remitting multiple sclerosis SUMMARY NIHR HSC ID: 3711

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1 Horizon Scanning Centre July 2014 Ocrelizumab for relapsing-remitting multiple sclerosis SUMMARY NIHR HSC ID: 3711 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. Ocrelizumab is a second generation, fully humanised anti-cd20 monoclonal antibody. The antibody is designed to selectively target the CD20 surface antigen on B-cells; once bound to the target antigen, ocrelizumab recruits the immune system to attack and destroy marked B-cells. Ocrelizumab is intended for the treatment of relapsing-remitting multiple sclerosis (RRMS). It is administered via intravenous (IV) infusion at 600mg every 24 weeks on a continuing basis (dual infusions of 300mg on day 1 and 15 of cycle 1, followed by single infusions of 600mg on day 1 of each subsequent cycle). Ocrelizumab has the potential to reduce relapse rate, and disease activity as measured by brain lesions and clinical disease activity, defined by absence of both EDSS disability progression and clinical relapse and if licenced will offer an alternative treatment option for patients with RRMS. MS is a chronic immune-mediated condition of the central nervous system characterised by demyelination and axonal degeneration. Resultant damage leads to a wide spectrum of symptoms and signs, potentially including difficulties with weakness, sensory disturbance balance and vision. In MS, the immune system damages the myelin sheath, which is formed of outgrowths of glial cells insulating the axons of neurones, thus allowing rapid conduction of electrical signals. Damage to the myelin sheath disrupts the transfer of these nerve signals leading to MS related symptoms. Relapsingremitting MS describes the clinical situation where a patient experiences neurological events (relapses), representing bouts of central nervous system inflammation, which are typically followed by periods of recovery and relative neurological stability (remissions). The prevalence of MS in England is approximately 0.16%, equivalent to approximately 85,600 affected people in England. Approximately 35.5% of patients have relapsing-remitting disease. Ocrelizumab is currently undergoing two phase III clinical trials evaluating its effect on clinical relapse rate compared to interferon beta-1a. These trials are both expected to be complete by January A phase II clinical trial evaluating the effect of ocrelizumab on disease activity as measured by brain lesions compared with interferon beta-1a was published in 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. NIHR Horizon Scanning Centre, University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Multiple sclerosis (MS): relapsing-remitting (RRMS). TECHNOLOGY DESCRIPTION Ocrelizumab (2H7v114; 2H7v16; PRO 70769; RG1594; R 1594; rhumab 2H7) is a second generation, fully humanised anti-cd20 monoclonal antibody. The antibody is designed to selectively target the CD20 surface antigen on B-cells; once bound to the target antigen, ocrelizumab recruits the immune system to attack and destroy marked B-cells. Ocrelizumab is intended for the treatment of RRMS. It is administered via intravenous (IV) infusion at 600mg every 24 weeks on a continuing basis (dual infusions of 300mg on day 1 and 15 of cycle 1, followed by single infusions of 600mg on day 1 of each subsequent cycle). Ocrelizumab does not currently have Marketing Authorisation in the EU for any indication. Ocrelizumab is also currently in phase III clinical trials for primary progressive MS. INNOVATION and/or ADVANTAGES If licensed, ocrelizumab will offer an additional treatment option for patients with RRMS. The company state that ocrelizumab has the potential to reduce relapse rate, and disease activity as measured by brain lesions and clinical disease activity, defined by absence of both EDSS disability progression and clinical relapse. DEVELOPER Roche Products Ltd. AVAILABILITY, LAUNCH OR MARKETING Currently in phase III clinical trials. PATIENT GROUP BACKGROUND MS is a chronic immune-mediated condition of the central nervous system characterised by demyelination and axonal degeneration 1. Resultant damage leads to a wide spectrum of symptoms and signs, potentially including difficulties with weakness, sensory disturbance balance and vision a. In MS, the immune system damages the myelin sheath, which is formed from outgrowths of glial cells which insulate the neuronal axons, thus allowing rapid conduction of electrical signals a. Damage to the myelin sheath disrupts the transfer of these nerve signals leading to MS related symptoms 2,3. Relapsing-remitting MS describes the clinical situation where a patient experiences neurological events (relapses), representing bouts of central nervous system inflammation, which are typically followed by periods of a Expert personal communication. 2

3 recovery and relative neurological stability (remissions). Although there is no typical frequency, an average patient might have a relapse every year or so, with good or complete remission in between 1b. After two decades of relapsing remitting disease, a significant proportion of patients (>50%) enter a secondary progressive phase, during which relapses cease or become less frequent, but the patient instead notes a slow progressive increase in their disability 4,b. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to: The Long-Term (Neurological) Conditions National Service Framework (2005). NHS England. 2013/14 NHS Standard Contract for Complex Disability Equipment: Alternative and Augmentative Communication/ Communication Aids (All Ages). D01/S/b. NHS England. 2013/14 NHS Standard Contract for Complex Disability Equipment: Environmental Controls (All Ages). D01/S/c. NHS England. 2013/14 NHS Standard Contract for Neurosciences: Specialised Neurology (Adult). D04/S/a. NHS England. 2013/2014 Clinical Commissioning Policy Statement: Fampridine for Multiple Sclerosis (MS). D04/PS/c. NHS England. 2013/2014 Clinical Commissioning Policy: Disease Modifying Therapies for Patients with Multiple Sclerosis (MS). D04/P/b. CLINICAL NEED and BURDEN OF DISEASE MS is usually diagnosed between the ages of 20 and 40 years 5 with a relatively low incidence but high prevalence 6. The prevalence of MS in England is approximately 0.16%, equivalent to approximately 85,600 affected people in England. Approximately 35.5% of patients have relapsing-remitting disease, equating to around 30,388 people in England and an estimated 38.75% (11,775) of these will be eligible for drug treatment with disease modifying treatments (DMTs) 7. The incident population starting treatment for MS each year in England is approximately 1,600 people. MS has limited impact on longevity; however it causes considerable disability and impacts on employment and quality of life, with walking impairment being the most prominent disability, affecting up to 85% of people with MS 8. Numbness of the face, body, or extremities is also common, and is often the first symptom experienced prior to diagnosis 9, and around 80% will experience tremor or ataxia at some point during their illness. Fatigue and bladder dysfunction are also common, affecting approximately 75% of people with MS 10. Cognitive impairment occurs in up to 65% of patients at any stage of the disease and is usually irreversible 11,12. Bowel dysfunction, including constipation or loss of bowel control, affects up to 50% of patients 13. In there were 38,080 admissions for MS in England, resulting in 58,892 bed days and 40,418 finished consultant episodes 14. In England and Wales, 1,218 deaths due to MS were registered in (ICD10 G35). b Expert personal communication. 3

4 PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis [ID585]. Expected August NICE technology appraisal in development. Laquinimod for treating relapsing-remitting multiple sclerosis (ID560). Suspended May NICE technology appraisal. Alemtuzumab for treating relapsing-remitting multiple sclerosis (TA 312). May NICE technology appraisal. Teriflunomide for treating relapsing remitting multiple sclerosis (TA303). January NICE technology appraisal. Fingolimod for the treatment of relapsing-remitting multiple sclerosis (TA254). April NICE technology appraisal. Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis (TA127). August NICE technology appraisal. Beta interferon and glatiramer acetate for the treatment of multiple sclerosis (TA32). January NICE clinical guideline in development. Management of multiple sclerosis in primary and secondary care. Expected October NICE clinical guideline. Management of multiple sclerosis in primary and secondary care (CG8). November NICE interventional procedure guidance. Percutaneous venoplasty for chronic cerebrospinal venous insufficiency for multiple sclerosis (IPG420). March Other Guidance Gilhus NE, Barnes MP and Brainin M. Acute Relapses of Multiple Sclerosis Association of British Neurologists. Revised (2009) guidelines for prescribing in multiple sclerosis 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 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 National Collaborating Centre for Chronic Conditions (NCC-CC). Multiple Sclerosis: National clinical guideline for diagnosis and management in primary and secondary care CURRENT TREATMENT OPTIONS Current approaches to the management of MS include 16,17,18,19,20.21,25 : Reduction of disease activity (particularly relapse rates) through the use of immunomodulators or DMTs: o Alemtuzumab (Lemtrada) for adults with active relapsing remitting MS. o Teriflunomide (Aubagio) for active relapsing remitting MS only if they do not have highly active or rapidly evolving severe disease. o Interferon beta-1a (Rebif, Avonex) and interferon beta-1b (Betaferon, Extavia) (not recommended by NICE). 4

5 o o o o o Fingolimod (Gilenya) for highly active MS or patients who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon. Glatiramer acetate (Copaxone) (not recommended by NICE). Natalizumab (Tysabri) for the treatment only of rapidly evolving severe relapsing remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI. Dimethyl fumarate (Tecfidera) for adults with relapsing-remitting MS (NICE technology appraisal expected August 2014). Mitoxantrone (unlicensed for this indication) occasionally used in patients with rapidly progressive disease c. o Unlicensed immunosuppressants are sometimes also used, including methotrexate, cyclophosphamide and azathioprine. Treatment of acute exacerbations with corticosteroids. Treatment of chronic symptomatology through pharmacological approaches alongside physiotherapy, speech and language therapy and occupational therapy and occasionally surgery c. EFFICACY and SAFETY Trial OPERA I, NCT ; ocrelizumab vs interferon beta-1a; phase III. OPERA II, NCT ; ocrelizumab vs interferon beta-1a; phase III. NCT ; ocrelizumab vs interferon beta-1a vs placebo; phase II. Sponsor Hoffman-La Roche. Hoffman-La Roche. Hoffman-La Roche. Status Ongoing. Ongoing. Published. Source of information Trial registry 26, manufacturer. Trial registry 27, manufacturer. Publication 28, trial registry 29. Location EU (incl UK), USA and other countries. EU (incl UK), USA, Canada and other countries. EU (incl UK), USA, Canada and other countries. Design Randomised, activecontrolled. Randomised, activecontrolled. Randomised, active- and placebo-controlled. Participants n=821 (planned); aged years; MS; 2 clinical attacks within 2 years of screening or one clinical attack in the year prior to screening (but 30 days prior to screening); neurological stability 30 days; Expanded Disability Status Scale (EDSS) inclusive; disease duration of <10 years in patients with EDSS score 2.0 at screening; no contraindications for MRI. n=835 (planned); aged years; MS; 2 clinical attacks within 2 years of screening or one clinical attack in the year prior to screening (but 30 days prior to screening); neurological stability 30 days; Expanded Disability Status Scale (EDSS) inclusive; disease duration of <10 years in patients with EDSS score 2.0 at screening; no contraindications for MRI. n=220; MS; relapsingremitting; no secondary or primary progressive disease; no previous treatment with rituximab or lymphocyte-depleting therapies; no use of lymphocyte trafficking blockers 24 weeks; no use of β interferons, glatiramer acetate, IV immunoglobulin, plasmapheresis, or immunosuppressive treatments 12 weeks or use of systemic glucocorticoids 4 c Expert personal communication. 5

6 Schedule Randomised to ocrelizumab 600mg IV every 24 weeks (dual infusions of 300 mg on day 1 and 15 of cycle 1, single infusion of 600 mg on day 1 of each subsequent cycle) in combination with placebo SC 3 times weekly; or interferon beta-1a (Rebif) SC (8.8µg on weeks 1 and 2; 22µg on weeks 3 and 4; 44µg on week 5 and subsequent weeks) 3 times weekly in combination with placebo IV every 24 weeks (dual infusions on day 1 and 15 of cycle 1; single infusion on day 1 of each subsequent cycle). Randomised to ocrelizumab 600mg IV every 24 weeks (dual infusions of 300 mg on day 1 and 15 of cycle 1, single infusion of 600 mg on day 1 of each subsequent cycle) in combination with placebo SC 3 times weekly; or interferon beta-1a (Rebif) SC (8.8µg on weeks 1 and 2; 22µg on weeks 3 and 4; 44µg on week 5 and subsequent weeks) 3 times weekly in combination with placebo IV every 24 weeks (dual infusions on day 1 and 15 of cycle 1; single infusion on day 1 of each subsequent cycle). Randomised to ocrelizumab 600mg IV (dual infusions of 300 mg on day 1 and 15 of cycle 1, single infusion of 600 mg on day 1 of subsequent 24 week cycles) in combination with placebo IV; or ocrelizumab 2,000mg IV (dual infusions of 1,000 mg on day 1 and 15 of a 24 week cycle followed by 1,000mg IV for the subsequent treatment cycles); or interferon beta- 1a 30µg once weekly for one 24 week cycle; or placebo IV on day 1 and day 15 of a 24 week cycle. Patients in the placebo group and interferon beta- 1a groups switched to ocrelizumab 600mg IV (dual infusions of 300 mg on day 1 and 15 of cycle 1, single infusion of 600 mg on day 1 of subsequent 24 week cycles). Follow-up Active treatment for 96 Primary Annualised protocol-defined outcome/s 2 year relapse rate at 96 Secondary outcome/s Time to onset of sustained disability progression of at least 12 weeks; time to onset of sustained disability progression of at least 24 weeks; proportion of relapse-free patients; change in total T2 lesion volume as detected by brain MRI; total number of new, and/or enlarging T2 hyperintense lesions as Active treatment for 96 Annualised protocoldefined 2 year relapse rate at 96 Time to onset of sustained disability progression of at least 12 weeks; time to onset of sustained disability progression of at least 24 weeks; proportion of relapse-free patients; change in total T2 lesion volume as detected by brain MRI; total number of new, and/or enlarging T2 hyperintense lesions as Patients receiving ocrelizumab or placebo received methylprednisolone 100mg IV to reduce potential infusion-related reactions. Active treatment for 72 Number of gadoliniumenhancing T1 lesions observed on brain MRI scans at weeks 12, 16, 20, and 24. Annualised protocoldefined relapse rate; proportion of relapse-free patients; total number of gadolinium-enhancing T1 lesions to week 24; change in total volume of T2 lesions from baseline to week 24; safety and tolerability of two dose regimen; safety up to 96 No quality of life 6

7 Key results Adverse effects (AEs) detected by brain MRI; change in Multiple Sclerosis Functional Composite Scale (MSFCS) score; change in brain volume as detected by MRI; adverse events AEs; pharmacokinetics; immunogenicity: all at 96 Results are expected in Q detected by brain MRI; change in MSFCS score; change in brain volume as detected by MRI; AEs; pharmacokinetics; immunogenicity: all at 96 Results are expected in Q measurement included in trial outcomes. For ocrelizumab 600mg, ocrelizumab 2,000mg, interferon beta-1a, and placebo, respectively (p values vs placebo): Annualised relapse rates by week 24, 0.13 (p=0.0005), 0.17 (p=0.0014), 0.36 (p=0.07) and 0.64; number (%) patients with relapses by week 24, 3 (5%), 4 (7%), 9 (17%) and 16 (30%); mean total number of gadolinium-enhancing T1 lesions at all time points to week 24, 0.6 (p<0.001), 0.2 (p<0.001), 6.9, and 5.5; mean number of new gadolinium-enhancing T1 lesions to week 24, 0.0 (p<0.001), 0.0 (p<0.001), 1.0 and 2.2; mean change in total volume of T2 lesions, (p=0.2), (p=0.2), (p=0.5), and ; mean total number of new or enlarging T2 lesions at week 24, 0.0 (p<0.0001), 0.0 (p<0.0001), 1.8, 1.4. For ocrelizumab 600mg, ocrelizumab 2,000mg, interferon beta-1a and placebo respectively: AEs to week 24, 62%, 66%, 56% and 70%. Serious infections occurred at similar rates in ocrelizumab and placebo patients. One patient in the 2000mg group died in week 14. At first infusion, more patients given 600mg 35% (95% CI, 22 47) and 2,000 mg, 44% (95% CI, 31 57) ocrelizumab had 7

8 infusion-related adverse events than did those in the placebo group 9%, (95% CI, 2 17). From weeks there was no imbalance in AEs for the treatment groups, and serious AEs were similar. Expected reporting date Estimated study completion date reported as Nov Estimated study completion date reported as Jan No opportunistic infections or clinically relevant abnormal laboratory changes were recorded. - ESTIMATED COST and IMPACT COST The cost of ocrelizumab is not yet known. The cost of selected comparator treatments are as follows: Drug Dose Annual cost 30,31,32 Interferon beta-1a (Rebif) 44mg, SC, 3 times weekly. 8,942 d,35 Interferon beta-1a (Avonex) 30mg, IM, once weekly. 8,502 Fingolimod (Gilenya) 500mg daily. 19,110 Natalizumab (Tysabri) 300mg, IV, 4 weekly. 14,690 Glatiramer acetate (Copaxone) 20mg daily. 5,823 d,35 Alemtuzumab (Lemtrada) Dimethyl Fumarate (Tecfidera) 5 daily consecutive 12mg doses in year 1, followed by 3 daily consecutive 12mg doses 12 months later in year mg oral twice daily; increased to 240mg oral twice daily after 7 days. Yr 1 cost: 35,225 Yr 2 cost: 21, ,192 Teriflunomide (Aubagio) 14mg once daily. 13,492 IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Other: Reduced symptoms or disability: potential for increased periods of clinical remission. No impact identified d Prices from the Cost effective provision of disease modifying therapies for people with multiple sclerosis risk share scheme. Department of Health. Health Service Circular. Cost effective provision of disease modifying therapies for people with multiple sclerosis. London: DOH; February

9 Impact on Health and Social Care Services Increased use of existing services: Re-organisation of existing services Other: as things stand, delivery should be relatively straightforward. All neuroscience centres should be equipped to provide natalizumab and adapting the equipment and personnel to ocrelizumab would not be an issue e. Decreased use of existing services: potential for delayed progression of disease. Need for new services None identified: Impact on Costs and Other Resource Use Increased drug treatment costs Other increase in costs: Other: increase or reduction in drug treatment costs depending on comparator. Reduced drug treatment costs Other reduction in costs: potential for increased periods of clinical remission. None identified Other Issues Clinical uncertainty or other research question identified: expert opinion suggests that the place of ocrelizumab in the treatment pathway will depend upon the results of the phase III clinical trials which will need to be balanced against short and long term side effect profiles and tolerability as none of the comparator treatments provide an optimal balance of therapeutic efficacy versus side effects e. None identified However, it is likely that ocrelizumab will be targeted for second line use, as a potential alternative for alemtuzumab, fingolimod and/or natalizumab. All of these have superior efficacy to first line agents, but have disadvantages: alemtuzumab requires an involved monitoring protocol, fingolimod requires inpatient hospitalisation for cardiac monitoring at the point of initiation, and natalizumab has a well-recognised risk of progressive multifocal leukoencephalopathy. Should ocrelizumab prove at least equally effective to these agents (preferably as effective as alemtuzumab) but have a superior safety profile and convenient dosing regimen (infusions every 24 weeks), this could be a significant advance. This latter aspect could be particularly important e.g. natalizumab requires infusions every 4 weeks e. Expert also states that there are no particular issues of clinical uncertainty at present, as the trial protocols are well described and uncontroversial e. e Expert personal communication. 9

10 REFERENCES 1 National Institute for Health and Care Excellence. Multiple sclerosis (2014) final scope. London: NICE; August NHS Choices. Multiple Sclerosis. Available from Accessed18 July Multiple Sclerosis Society. About MS. Accessed 19 June Liu J, Wang LN, Zhan S, Xia Y. Daclizumab for relapsing remitting multiple sclerosis (Review). Cochrane Database Systematic Reviews 2013, Issue 12. Art. No.: CD DOI: / CD pub4. 5 Multiple Sclerosis Society. What is MS? Accessed 19 June Hobart JC, Riazi A, Lamping DL. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome. Health Technology Assessment 2004; 8(9). 7 National Institute for Health and Care Excellence. Costing report: Implementing the NICE guidance on alemtuzumab for treating relapsing remitting multiple sclerosis (TA312). London: NICE; May Harris Interactive. Experiences with Multiple Sclerosis (MS): Perspectives of People with MS and MS Care Partners. Poll commissioned by: Acorda Therapeutics Inc and the National MS Society. March National Multiple Sclerosis Society. MS Symptoms. Diagnosis/MS-Symptoms Accessed 20 June Thompson AJ, Toosy AT, Ciccarelli O. Pharmacological management of symptoms in multiple sclerosis: current approaches and future directions. Lancet Neurology 2010;9(12): Amato MP, Zipoli V, Portaccio E. Multiple sclerosis-related cognitive changes: a review of crosssectional and longitudinal studies. Journal of the Neurological Sciences 2006;245: Kujala P, Portin R, Ruutiainen J. The progress of cognitive decline in multiple sclerosis. A controlled 3-year follow-up. Brain: a journal of neurology 1997;120: NIHR Horizon Scanning Centre. BIIB-017 for relapsing forms of multiple sclerosis. University of Birmingham, September Health and Social Care Information Centre. Hospital episode statistics for England. Admitted patient care, Office for National Statistics. Mortality statistics deaths registered in 2012, series DR National Institute for Health and Care Excellence. Alemtuzumab for treating relapsing remitting multiple sclerosis. Technology appraisal TA312. London: NICE; May National Institute for Health and Care Excellence. Teriflunomide for treating relapsing remitting multiple sclerosis. Technology appraisal TA303. London: NICE; January National Institute for Health and Clinical Excellence. Fingolimod for the treatment of highly active relapsing-remitting multiple sclerosis. Technology appraisal TA254. London: NICE; April National Institute for Health and Clinical Excellence. Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis. Technology appraisal TA127. London: NICE; August National Institute for Health and Clinical Excellence. Multiple sclerosis - beta interferon and glatiramer acetate. Technology appraisal TA32. London: NICE; January National Institute for Health and Clinical Excellence. Management of multiple sclerosis in primary and secondary care. Clinical guideline CG8. London: NICE; November Gilhus, NE, Barnes MP and Brainin M. (2010) Acute Relapses of Multiple Sclerosis, in European Handbook of Neurological Management, Second Edition, Volume 1, Second Edition, Wiley- Blackwell, Oxford, UK. doi: / ch27 23 Association of British Neurologists. Revised (2009) guidelines for prescribing in multiple sclerosis. London: ABN. November 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. March

11 25 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): ClinicalTrials.gov. A study of ocrelizumab in comparison with interferon beta-1a (Rebif) in patients with relapsing multiple sclerosis. Accessed 24 June ClinicalTrials.gov. A study of ocrelizumab in comparison with interferon beta-1a (Rebif) in patients with relapsing multiple sclerosis. Accessed 24 June Kappos L, Li D, Calabresi PA et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. The Lancet 2011; 378: ClinicalTrials.gov. A study of the efficacy and safety of ocrelizumab in patients with relapsingremitting multiple sclerosis. Accessed 24 June British National Formulary (BNF). Accessed 30 June National Institute for Health and Care Excellence. TA312 Multiple sclerosis (relapsing-remitting) alemtuzumab: costing template. London: NICE; May Department of Health. Health Service Circular. Cost effective provision of disease modifying therapies for people with multiple sclerosis. London: DOH; February