Multiple Sclerosis International Federation December 2018

Transcription

1 MSIF WHO EML APPLICATION Multiple Sclerosis Disease-Modifying Therapies 1. Summary statement of the proposal for inclusion In 2015, an application for widening the indication of azathioprine to cover multiple sclerosis (MS) was submitted to the WHO Essential Medicine List (EML). This application was rejected, but the WHO Expert Committee on Selection and Use of Essential Medicines emphasized the public health relevance of MS and suggested a full review of MS treatments to identify which medicines should be put forward for the WHO EML (1). Multiple Sclerosis International Federation (MSIF), a non-state actor in official relations with WHO, convened a taskforce of global experts in MS research and care to submit an application for Disease-Modifying Therapies (DMTs) for the treatment of MS to be added onto the WHO EML. This taskforce included experts from around the world, national MS organisation, people affected by MS and worked closely with the regional MS clinical networks, i.e. Committees for Treatment and Research for Multiple Sclerosis (TRIMS) and the World Federation of Neurology. The recommendation of the WHO Expert Committee, following the 2015 application, has been taken in to consideration. All approved DMTs used for the treatment of MS are summarized by comparative effectiveness in a variety of clinical settings based on the recently published ECTRIMS/EAN (European Committee for Treatment and Research for Multiple Sclerosis/European Association of Neurology) Guidelines on the pharmacological treatment of people with MS (2). This application is produced in collaboration with University College London National Collaborating Centre for Mental Health (NCCMH), which analysed the data for the ECTRIMS/EAN guidelines. A comparison and consultation were also made with the American Academy of Neurology guidelines on disease modifying therapies in MS (3) to ensure there were no discrepancies. Appendix 1A and 1B contains these 2018 guidelines. Multiple sclerosis is an immune-mediated disorder of the central nervous system (gray and white matter) characterized by inflammation, demyelination, and degenerative changes including neuroaxonal loss and progressive brain and spinal cord atrophy. Approximately 85% of those with MS initially experience relapses and remissions of neurological symptoms, known as relapsing-remitting MS, with relapses often associated with new areas of central nervous system (CNS) inflammation. Gradual worsening in this population, with or without additional inflammatory events, is known as secondary progressive MS. Progressive changes can occur at any time in the disease course, but usually become more prominent over time. Approximately 15% of people diagnosed with MS have a progressive course from disease onset, known as primary progressive MS. Some with primary progressive MS may have typical relapses later in their disease course, after a progressive course has been established (4,5). 0

2 Despite significant research efforts, the exact etiology of MS remains unknown. A number of factors have been identified that contribute to the risk of developing MS. There is a genetic contribution to risk and studies indicate genetic variations within the major histocompatibility complex (MHC) likely contribute the greatest amount of genetic risk, and studies also indicate >100 genetic variants that each contribute a small amount of risk. More recently, environmental factors have been identified as contributors to risk of MS including previous Epstein- Barr virus infection, low serum vitamin D, cigarette smoking, childhood obesity, head injury and solvent exposure (6). Once diagnosed with MS, progression of MS is influenced by several factors including cigarette smoking and certain comorbid conditions. In a large cohort study using the North American Research Committee on Multiple Sclerosis Registry vascular comorbidities appeared to contribute to the risk of MS progression (7). In 1993, interferon beta-1b was the first DMT for multiple sclerosis to receive regulatory approval (Table 1). Since then, more than 15 DMTs have been approved for the treatment of relapsing forms of MS. The approved therapies target various immune cells that contribute to the inflammatory cascade identified in MS. These therapies have been shown in large, well-designed clinical trials to reduce annual relapse rate, limit new areas of CNS damage (measured by MRI), and delay disease progression (measured by sustained change in Expanded Disability Status Score [EDSS]). One therapy has been shown to reduce the risk of progression in primary progressive MS. Table 1 shows the list of MS DMTs and their year of US Food and Drug Administration approval. Table 1 - Year of approval of the different MS DMTs by the US FDA MS disease modifying treatment Approval US Food and Drug Administration Interferon beta-1b (Betaseron ) 1993 Interferon beta-1a (Avonex ) 1996 Glatiramer acetate (Copaxone ) 1996 Interferon beta-1a (Rebif ) 2002 Natalizumab (Tysabri ) 2004 (removed temporarily in 2005 reintroduced in 2006) Interferon beta-1b (Extavia ) 2009 Fingolimod (Gilenya ) 2010 Dimethyl fumarate (Tecfidera )

3 Teriflunomide (Aubagio ) 2012 Interferon beta 1a (Plegridty ) 2014 Alemtuzumab (Lemtrada ) 2014 Glatiramer acetate (Glatopa ) 2015 Ocrelizumab (Ocrevus ) 2017 None of these medications has yet been shown to be curative. All medications may have adverse effects (AEs), which vary from mild to lifethreatening (3). Real world effectiveness varies substantially from one person to another and for each individual over time. The goal of treatment is to control disease activity as quickly and effectively as possible with the aim of preventing irreversible damage in the CNS. The American Academy of Neurology (AAN) 2018 Practice Guideline states that the evidence on the use of MS DMTs in people with relapsing forms of MS can reduce relapses and MRI activity (3). Based upon the evidence, the guideline makes the recommendation that clinicians should offer DMTs to people with relapsing forms of MS, with recent clinical relapses or MRI activity (3). Similarly, European Committee on Treatment and Research in MS (ECTRIMS)/European Academy of Neurology (EAN) guidelines recommend that early treatment with MS disease modifying therapies should be offered to patients with active relapsing remitting MS as defined by clinical relapses and/or MRI activity (2). In addition, the MS Coalition DMT Consensus paper on the use of disease modifying therapies for MS also recommends early and ongoing treatment with a disease modifying therapy (8). MS is a heterogeneous disease and is characterized by highly variable degrees of disease activity in the relapsing phase and by varying rates of worsening during the progressive phases (3). Due to wide variability in response to DMTs, differing mechanisms of action of the available DMTs, the risks of the treatments, contraindication to specific agents, and side effects, access to more than one DMT is essential. Both the AAN and the ECTRIMS/EAN guidelines make specific recommendations for switching therapies based upon several characteristics including MS disease activity contraindications and safety. Access to more than one DMT is essential - selection of three disease-modifying therapies Although there are multiple effective therapies for MS, this application is requesting that three separate medications indicated for treatment of MS be added onto the WHO EML. The three therapies were prioritized based on their efficacy/safety profiles, tolerability/liveability, monitoring needs, route of administration, licensed use in paediatric-onset and primary progressive MS, safety profile in pregnancy, 2

4 availability of generic and/or biosimilar substitutes, and to ensure that at least one therapy would be appropriate for the majority of persons with MS. The proposed medications have been selected based on extensive clinical and post-marketing data, which support their use across the varied disease courses of individuals diagnosed with MS and include treatments considered safe during pregnancy and the paediatric and primary progressive MS populations. MSIF and the taskforce strongly believe that in an ideal world all people with MS should have access to the full repertoire of approved DMTs. MS is a complex disease and the disease course can be very different due to a number of variables, e.g. age at disease onset, disease activity, sex and personal circumstances. The WHO EML is a limited list of medicines and the taskforce recognises that at present not all DMTs can be listed. This application of three DMTs is based on the hope of acknowledging that MS has an unmet need in terms of treatment and increasing the number of countries with reasonable access to treatment where these treatments are not readily available. Rationale a) For reasonable care for people with MS (pwms) there needs to be a choice of DMTs. As a minimum one DMT should be available in each of these categories: 1. Moderate efficacy/high safety (i.e. IFN, glatiramer acetate) 2. Moderate to high efficacy oral therapy (i.e. dimethyl fumarate, teriflunomide, cladribine and fingolimod) 3. High efficacy monoclonal therapy (i.e. natalizumab, alemtuzumab, ocrelizumab) b) Within these categories we considered the following criteria: 1. Risk of adverse events (includes tolerability and liveability) and feasible monitoring needs (important in resource-poor environments). 2. Different populations of pwms: ensuring we cover main sub-populations of pwms, e.g. use in pregnancy, family planning, use in paediatrics and potential for PPMS. 3. Price: if there is no clear advantage on the other criteria, we considered price; including patent status, available and/or emerging generics/biosimilars and off-label alternatives currently in use and supported by evidence published in peer-reviewed journals. Summary It is proposed that the Expert Committee members consider the addition of glatiramer acetate, fingolimod and ocrelizumab to the complementary list in a new section dedicate to multiple sclerosis. Glatiramer acetate is recommended based upon Phase III trial results and subsequent MRI trial (see Table 5). Glatiramer acetate has more than 20 years of established safety evidence, with no emergence of serious side effects or risks. In addition, there have been no risks 3

5 associated with conception or fetal development. Glatiramer acetate requires minimal post-dose monitoring. Head-to-head comparison trials of glatiramer acetate and interferons demonstrated similar efficacy in relapse reduction. Neutralizing anti-drug antibodies have not been shown to be a problem with glatiramer acetate, which are a problem with the interferons. Fingolimod is recommended based upon Phase III data demonstrating superiority over placebo and interferon beta 1a (see Table 5). Fingolimod has received regulatory approval for treatment of relapsing forms of MS for individuals 10 years and up. Ocrelizumab is recommended based upon Phase III clinical trials that demonstrated superiority of ocrelizumab over placebo and interferon beta 1a (see Table 5). In addition, ocrelizumab has received regulatory approval for the treatment of primary progressive MS; the only therapy approved for this type of MS. Recent long-term follow-up data has reassuringly shown persistent efficacy (9) without any new safety signals (10). The treatment of MS has been revolutionised in the last 30 years. The positive impact of effective immunomodulation is supported by reduction in relapse rates, and by prolonged time from onset to development of disability. Treatment may also be associated with an improvement in quality of life, and the potential for personal and financial benefit. At present, there are no medications listed on the WHO EML to treat MS. Given that MS is one of the few neurological diseases with highly effective treatment, we suggest that the present application is timely and with the rising incidence and prevalence in low- and middle-income countries addresses an important unmet need. 2. Name of the focal point in WHO submitting or supporting the application (where relevant) - WHO Secretariat of the Selection and Use of Essential Medicines - WHO Department of Mental Health and Substance Abuse - WHO Gender, Equity and Human Rights 4

6 3. Name of the organization(s) consulted and/or supporting the application This application is submitted by Multiple Sclerosis International Federation (MSIF). The following organisations were represented on the MSIF EML taskforce or consulted during the drafting of the application: Regional organisations: World Federation of Neurology (WFN) European Committee for Treatment and Research for Multiple Sclerosis (ECTRIMS) American Committee for Treatment and Research for Multiple Sclerosis (ACTRIMS) Latin-American Committee for Treatment and Research for Multiple Sclerosis (LACTRIMS) Middle East North Africa Committee for Treatment and Research for Multiple Sclerosis (MENACTRIMS) Pan Asian Committee for Treatment and Research for Multiple Sclerosis (PACTRIMS) Russian Committee for Treatment and Research for Multiple Sclerosis (RUCTRIMS) National MS organisations: National MS Society, United States MS Society of Canada MS Ireland Iranian MS Society All-Russian MS Society 4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine INN: glatiramer acetate [Copaxone ], ATC: L03AX13 INN: fingolimod [Gilenya ], ATC: L04AA27 INN: ocrelizumab [Ocrevus ], ATC: L04AA36 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) 5

7 Table 2 - Drug Formulation, dosing schedule and indication Drug classification Agent, Dose and administration Disease classification(s) Glatiramer acetate immunomodulator (glatiramer acetate) Sphingosine 1-phosphate receptor modulator (fingolimod hydrochloride) Glatiramer acetate 20mg subcutaneous injection qd Glatiramer acetate 40mg subcutaneous injection tiw No dosing adjustment required for paediatric MS Fingolimod 0.25mg 0.5mg orally qd Fingolimod 0.25 mg for patients < 40 kg Clinically isolated syndrome (CIS) Relapsing multiple sclerosis Relapsing forms of multiple sclerosis in adults and children 10 years of age and older. CD20 monoclonal antibody (ocrelizumab) Rituximab off-label Ocrelizumab First dose 300 mg IV day one followed by 300 mg IV on day 14. Then 600mg intravenous infusion, every six months Paediatric dosing has not been established Rituximab Induction mg 2 weeks apart than every 6 months mgs (11). For paediatrics, doses of 750 mg/m2 per infusion, to a maximum of 1000 mg 2 weeks apart. Ocrelizumab - CD20-directed cytolytic antibody indicated for the treatment of patients with relapsing or primary progressive forms of multiple sclerosis. Rituximab an alternative CD20 directed antibody, licensed for a number of diseases, is used off-label for relapsing forms of multiple sclerosis in many regions (12), and in pediatric MS (13). 6

8 International availability - sources of possible manufacturers and trade names Glatiramer acetate 20mg and 40mg (trade name COPAXONE ) is registered in many high and middle-low income countries. The manufacturer of glatiramer acetate is Teva Pharmaceutical Industries Inc. Generic options are available for this drug; dosage, price and availability of glatiramer acetate products will vary globally. Fingolimod 0.25mg and 0.5mg (trade name GILENYA ) is registered in many high and middle-low income countries. The manufacturer of fingolimod is Novartis International AG (Basel, Switzerland) price and availability will vary globally. Generic options are available for this drug; dosage, price and availability of fingolimod products will vary globally. Ocrelizumab 600mg (trade name OCREVUS ) is registered in 68 high and middle-income countries. The manufacturer of ocrelizumab is F. Hoffmann-La Roche AG (Basel, Switzerland). Rituximab (500mg 1,000mg (trade name RITUXAN ) Rituximab is registered for non-ms indications in high and middle-low income countries and the manufacturer is F. Hoffmann-La Roche AG (Basel, Switzerland). Biosimilar options are available for rituximab; dosage, price and availability of rituximab will vary globally. Patent landscape and follow-on products patent information courtesy of the Medicines Patent Pool Full patent landscape can be found in Appendix 2. Generic versions of glatiramer acetate are available in some countries for example, in the US, Russian Federation and India. Secondary patents concerning glatiramer acetate are active in some jurisdictions (generally, method-of-use patents expiring in 2030), but these may not be blocking generic entry (14,15). The main product patent on fingolimod appears not to have been filed in the low and middle income country (LMIC) jurisdictions surveyed and expires between 2016 and 2018 in some European countries and 2019 in the USA. However, two formulation patent families, expiring in 2024 and 2032, have been widely granted, with the exceptions of ARIPO [African Regional Intellectual Property Organization], OAPI [Organisation Africaine de la Propriété Intellectuelle], and Vietnam. Several of the secondary patents have been challenged in the US by generic companies. Further consultation would be necessary to establish whether the secondary patents on fingolimod represent a true block to generic market entry. This may depend on whether it is possible to develop non-infringing alternative formulations while achieving bioequivalence. There are several follow-on products currently available in different countries. Ocrelizumab is protected by a product patent expiring in 2023 in many jurisdictions (please see table in Appendix 2). It has generally been filed or granted in the countries/regions surveyed except in ARIPO, OAPI, and Guatemala. It is likely that biosimilar ocrelizumab cannot enter the market where this patent has been granted before A secondary patent family, expiring 2029, is granted in China and South Africa, and 7

9 pending in Brazil and Thailand, but has not been filed in other LMIC jurisdictions that were surveyed. It is not possible yet to comprehensively assess coverage by a secondary patent family expiring 2035/36 and further consultation would be necessary to establish whether these represent a true block to generic market entry. This may depend on the practical enforceability of method-of-use patents in each jurisdiction. Biosimilar versions of rituximab have been approved in numerous countries, including, for example, the European Union, South Korea, Bolivia, Chile, Peru, India, and Australia. Secondary method of use patents concerning rituximab have been filed or granted in some jurisdictions, including in China, Malaysia, Mexico, and South Africa (expected to expire in 2019). Apart from these, there do not appear to be active patents covering the intravenous formulation of rituximab. Secondary formulation patents for a subcutaneous administration form of rituximab have been filed or granted in some jurisdictions, including Canada, the US, and European Union, China, Morocco, Ukraine or Vietnam (expected to expire in 2030) (16). Please note that MSIF believes that people with MS should have access to safe and effective treatments which meet high standards of proof for quality. The development of generics and biosimilars is an important process that can make treatments available more widely at a more affordable cost to health systems and people with MS. Exchange between biological medicines requires adequate clinical monitoring, detailed record-keeping for traceability (product and batch), clear and balanced information and consent by the person with MS. MSIF believes that all treatments (proprietary, generic or biosimilar) need to meet, and be able to demonstrate, stringent safety and efficacy data and be properly assessed by independent regulators. MSIF does not support the use of substandard medicines or copies that have not passed stringent tests for quality, efficacy and safety. 6. Whether listing is requested as an individual medicine or as an example of a therapeutic group Individual medicine 7. Treatment details (requirement for diagnosis, treatment and monitoring) Diagnosis of MS There is no single diagnostic test for multiple sclerosis and the diagnosis remains essentially clinical, supported by MRI, cerebrospinal fluid analysis and other paraclinical tests. The key requirements for the diagnosis are at least two neurological events, each of which is consistent with a demyelinating attack, supported by objective findings, that are disseminated in space (i.e. involving more than one region of the central nervous system) and time (arbitrarily defined as either new episodes of neurological impairment separated by more than 30 days; or progressive neurological impairment sustained over 6 months). The diagnosis of MS was reliably ascribed using these clinical criteria, aided by the presence 8

10 in CSF of oligoclonal bands, prior to the advent of MRI, and remain robust when clinical evaluations are carefully adjudicated (17). Key to the diagnosis of MS is the exclusion of other diagnoses. The differential conditions that may mimic MS have regional implications, most significantly influenced by risk for specific CNS infections, by genetically-defined disorders with population-based differences in frequency and clinical expression, and by other inflammatory demyelinating conditions distinct from MS (Table 3) - the population prevalence of which differs across the world. The McDonald Diagnostic Criteria, revised in 2017, provide criteria for both clinical features and paraclinical tests to expedite a diagnosis of MS (18). The criteria include the ability to render a diagnosis of MS in an individual who has a first neurological event with neurological findings consistent with MS, provided specific magnetic resonance imaging (MRI) features are also present on the baseline MRI scan. Spinal fluid oligoclonal bands may also contribute to MS confirmation. In addition to consideration of infection and genetic aetiologies, clinicians must also consider inflammatory demyelinating conditions that are distinct from MS. A key responsibility is to exclude other aetiologies (see Table 3), as reviewed by an international expert panel (19). Prompt diagnosis is imperative, given the large body of evidence supporting early intervention with disease modifying treatments (18). Table 3 - Summary of common MS mimics - probability of each will vary by patient age and world region Autoimmune/inflammatory conditions CNS infections Metabolic conditions Vascular conditions Other - Neuromyelitis optica spectrum disorder (NMOSD) - Acute disseminated encephalomyelitis (ADEM) - Myelin Oligodendrocyte Glycoprotein (MOG)-related demyelination - CNS Syphilis - Lyme disease - Human T lymphotropic virus (HTLV) - HIV - Vitamin B12 deficiency - Copper deficiency - Mitochondrial disease - Leukodystrophies - Small vessel disease - Stroke - Susac syndrome - CADASIL - Antiphospholipid antibody syndrome (APLAS) - CNS lymphoma - Paraneoplastic myelopathy 9

11 - Sjogren s Syndrome - CNS lupus - Sarcoidosis - Behçet s disease - CNS vasculitis Investigation of individuals manifesting with incident CNS demyelination typically includes neuroimaging of the brain, and when indicated, of the spine and optic nerves. Spinal fluid analysis to exclude infection, malignancy, and paraneoplastic syndromes is performed as indicated, and for the detection of oligoclonal bands (present in over 95% of adults with MS). Serological testing for antibodies against aquaporin 4 (AQP4) assist in the identification of patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Other evaluations, based upon the history, presenting symptoms, patient characteristics and other factors should be individually determined to exclude other possible diagnoses. Treatment of MS The AAN guidelines (3) conducted a systematic review similar to the EAN guidelines (2), to establish efficacy of DMTs in the treatment of multiple sclerosis, please see Appendix 1A and 1B. Glatiramer acetate (20mg or 40mg) is recommended as treatment for relapsing multiple sclerosis, including patients who have experienced a single demyelinating event and have lesions typical of multiple sclerosis on brain MRI (known as clinically isolated syndrome or CIS). Based on its favorable safety profile, glatiramer acetate is used off-label as treatment option in special populations including pediatric multiple sclerosis (20,21) and pregnant women (22). Although interferon preparations were considered for the moderate efficacy/low risk for long-term risk category, due to the requirement for liver function monitoring, as well as the common experience of flu-like side effects, interferon therapies were not selected. Fingolimod is proposed based on its efficacy, as shown in the AAN and EAN guidelines and its concurrent relevance in treatment in paediatric populations (23,24). 10

12 Several other oral therapies were considered. At present, neither dimethyl fumarate nor teriflunomide are approved across the age-span, and teriflunomide has a black box warning in the USA due to its potential risks to the fetus. Both the AAN and EAN guidelines recommend ocrelizumab for the treatment of multiple sclerosis, both for primary-progressive MS (as the only DMT to shown to alter disease progression) and its demonstrated benefits in relapsing remitting MS (25). Due to significant safety concerns and monitoring requirements, both natalizumab and alemtuzumab were not considered for inclusion of this application. Both of these disease modifying therapies have increased safety concerns associated with their use, which require ongoing strict clinical, laboratory and neuroimaging data to monitor for PML (progressive multifocal leukoencephalopathy -particularly for natalizumab), hepatic dysfunction, other autoimmune conditions or malignancies, which require additional resources and financial costs to health care systems and patients (26). Pertaining to PML, the AAN guidelines state that due to its risk of PML (3), natalizumab should only be recommended when there is a reasonable chance of benefit compared to the low but serious risk of PML. The known risk factors of natalizumab-induced PML is highest for patients with anti-jcv antibody-positive status; prior treatment with an immunosuppressant (regardless of duration or point in time); and treatment with natalizumab for <24 months. The estimated incidence for natalizumab-induced PML in patients with all three risk factors is 11/1,000 (27). Monitoring recommendations for patients treated with natalizumab include testing anti-jcv antibody index each six-months and after 12 months, annual MRI imaging is recommended. Patients with an anti-jcv antibody positive index requires further monitoring ranging from MRI scans every six months to every 3-4 months, depending on the index (27). Natalizumab is the only DMT listed as Class 1, high potential risk of PML whereas fingolimod and dimethyl fumarate are listed as Class 2 low potential risk for PML, and alemtuzumab, rituximab, mitoxantrone and teriflunomide are listed as Class 3 no or very low risk for PML (28). Comparatively aligned with the AAN guidelines, a Cochrane Review of natalizumab as treatment for relapsing multiple sclerosis suggests that though proven highly effective in managing disease activity, due to significant safety concerns related to PML it should be used only by skilled neurologists in MS centres under national or international surveillance programs (29). Cost and access to medical equipment and expertise in diagnosing PML in low to middle resource countries is unknown. Well-established pharmacovigilance programs in low to middle resource countries are also unknown. This speaks only to resources available to manage monitoring patients for risk of PML. The Institute for Clinical and Economic Review (ICER) 2016 published a Draft Evidence Report: DMTs for RRMS and PPMS reporting the cost associated with PML as an adverse event, is approximately $23, USD (30). As of August 2017, there were 749 cases of confirmed PML in patients treated with natalizumab worldwide. PML is not isolated to treatment with natalizumab, though it carries the highest risk. PML has been reported in patients treated with fingolimod, dimethyl fumarate and ocrelizumab. As of August 2017, 15 cases of PML were reported in patients treated with fingolimod. The risk of PML in patients treated with 11

13 fingolimod who were natalizumab-naïve is low with an estimated risk of 0.069/1,000 (95% CI: ), and an estimated incidence rate of 3.12/100,000 patient-years (95% CI: ) (31). As of August 2017, there were five confirmed cases of PML in patients treated with dimethyl fumarate (31). A of September 2018, six cases of PML have been reported in patients treated with ocrelizumab. All cases have been reported as carry-over from previous treatment with natalizumab (five cases) and fingolimod (one case). Due to its relatively recent marketing, PML risk in patients treated with ocrelizumab has not yet been well-established (32). No cases of PML were reported throughout ocrelizumab clinical trials (32). All long-term immunosuppressive therapies are associated with PML and other opportunistic infections. The PML risk with fingolimod and ocrelizumab are very low (less than one case per 10,000 treated patients) in comparison to natalizumab, which has a risk that it is two orders of magnitude higher in patients who are infected with JCV. Many off-label treatments have been promoted and used in multiple sclerosis, these include azathioprine, cyclophosphamide, cyclosporine, leflunomide, fludarabine. methotrexate, mitoxantrone (licensed in some countries), mycophenolate, rituximab and tacrolimus. Apart from the evidence-base for rituximab, supported by data from ocrelizumab a licensed disease-modifying therapy in the same class (anti-cd20), the committee did not feel the data justified including any of these on the EML. Azathioprine was submitted in the past for the treatment of MS to the EML, but as that application was unsuccessful, we did not feel it warranted that it should be proposed again. The following Table 4 provides the approved marketed dose, administration, pre-dose testing and post-dose monitoring for each of the proposed medications based on each medication s product monograph. Depending on the DMT, additional tests may be warranted to assess for infections and immunization status based on local guidelines. The duration for which patients should remain on the prescribed DMT will vary depending on the disease course and several other factors outlined below as per AAN Guidelines: No RCTs have directly addressed the question of whether, when, or why to discontinue DMTs in an individual with relapsing-remitting MS (RRMS) who has no evidence of relapses or disability progression and has stable brain imaging. The natural history of untreated RRMS is for relapses and disability accumulation to occur. Early studies suggest that most individuals with RRMS ultimately advance to secondary progressive multiple sclerosis (SPMS) if observed for long enough intervals, although disease course is highly variable. People with MS who are stable on DMTs may question the continued value of using DMTs. If people with MS on DMTs stop these medications, continued monitoring may show subclinical disease activity or relapse activity that would indicate a possible need for treatment resumption (33). None of the available DMTs is completely effective against relapses and MRI activity. When a patient shows breakthrough disease activity (continued relapses, MRI activity), trying a medication with a different mechanism or efficacy profile may be beneficial. Although all possible clinical scenarios cannot be answered by drug trials, current evidence supports higher efficacy of alemtuzumab, natalizumab, fingolimod, and ocrelizumab compared with previously approved self-injectable DMTs. Tolerability and likelihood of adherence are other factors that are important in decisions about switching DMTs. Physician judgment and patient preferences are critical in this process (33). 12

14 Table 4 Approved marketed dose, administration, pre-dose testing and post-dose monitoring Medicine Dosing Administration Pre-dose testing Post dose monitoring Glatiramer acetate Indication: Relapsing forms of MS including clinically isolated syndrome (CIS) 20mg 40mg Self administered subcutaneous once per day (20mg) or three times weekly (40mg) No routine tests are recommended. No routine tests are recommended. Fingolimod Indication: Relapsing forms of MS 0.5 mg for patients >40 Kg 0.25 mg for patients <40 Kg Oral self-administration Daily Serum VZV IgG CBC Hepatic function Eye exam including macular examination Cardiac evaluation in patients with pre-existing cardiac conditions *Additional screening as appropriate for infectious diseases and to establish immunization status as per local guidelines. First dose: Monitor heart rate and blood pressure hourly for 6 hours after the first dose administration (or if restarting therapy after 14 days or more since last dose) 12-lead EKG prior to and following the first dose or redosing Post-dosing: Skin evaluation yearly for potential malignant lesions Eye exam to evaluate for macular edema 3-4 months after treatment initiation and again if any visual change Periodic monitoring of CBC and hepatic function Regular BP check Medicine Dosing Administration Pre-dose testing Post dose monitoring Ocrelizumab Indication: Relapsing forms of MS First dose: 300 mg day one and 300 mg day 14 Thereafter 600 mg Intravenous every 6 months under close supervision of an experienced healthcare professional with access to appropriate medical support to Hepatitis B screening Administration of all immunizations at least 6 Premedicate 30 min prior to each infusion with IV methylprednisolone 100 mg 13

15 Primary progressive MS manage severe reactions such as serious infusion reactions. weeks prior to initiation of ocrelizumab Assess for infection prior to initial and subsequent dosing *Additional screening as appropriate for infectious diseases. and to establish immunization status as per local guidelines. Premedicate min prior to infusion with an antihistamine such as diphenhydramine My also consider an antipyretic prior to infusion Infuse first 2 doses each over 2.5 hours and thereafter infuse over 3.5 hours Observe the patient for at least one hour after infusion for infusion related reactions References: US Product monographs Copaxone 2018, Gilenya 2016, Ocrevus, Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population, likely impact of treatment of disease) In 2013, it was estimated that there were more than 2.3 million people with MS worldwide (34,35). The incidence and prevalence of MS are rising, with studies published and due to be published showing significantly larger numbers than was previously estimated (36 43). Women are disproportionally affected, with female prevalence 2-3 times that for male (35,44). Caucasians of old European origin have been thought to be affected most, having a concentration of genetic risk. However studies show that other racial groups are affected too, and the research shows that MS may be more aggressive (or progressive) in the African-American and British black Caribbean populations (45,46). Although the cause is not fully understood, MS is considered to have complex causality blending genetic risk and environmental factors. People can be diagnosed throughout the age range, though MS is most often diagnosed between the ages of MS is of particular relevance to women due to the higher incidence rate and that MS is diagnosed during the reproductive age. The onset of MS may also occur in childhood, and it is estimated that 3%-10% of all individuals with MS experience their first attack prior to age 18 years (47). The incidence of pediatric-onset MS in North American and European studies has been reported to be between 0.13 to 0.6 cases per children (48). MS produces numerous symptoms based upon the location of CNS damage. Symptoms can be temporary, associated with relapses, or permanent and progressive. Symptoms negatively impact functional abilities and quality of life, and often include overwhelming fatigue, mood and cognitive changes, mobility impairment, sensory impairment, visual disturbances, sexual dysfunction, and impaired bowel and bladder control. 14

16 People with MS report lower health-related quality of life compared to other populations including those with other chronic illnesses. Depression is one of the factors that contributes to a lower health-related quality of life (49). Mood disorders are a significant co-morbidity in MS (50). There is estimated to be 70% prevalence of depression in MS (51). Suicidal ideation and completed suicides are of higher likelihood in the MS population with anxiety plus depression increasing the risk for self-harm (52). Disease modifying therapies limit new inflammation and disease activity and have a favorable impact on health-related quality of life. These effects may have a favorable impact on mood issues in MS. Though there is significant variance globally, a North American study suggested that approximately 60% of people with MS are unemployed (53), accounting for about one third of the total economic burden of MS (54). In addition to a loss in productivity, people with MS will have additional care needs with advancing age and disease severity. The economic burden of MS per patient and year ranges from approximately $ to $ USD (55). These amounts represent direct costs, which include in and out patient care, medications, medical procedures and social services as well as indirect costs related to loss of employment, disability benefits, early pension plans, and loss of productivity for spouses or family members providing informal care and death. Given the most frequent age of presentation (young adults), it is important to note that MS has both physical and cognitive impact, and also impacts the family development of the patients, as well as, determines a socio-economic impact on society as a whole. The Convention on the Rights of Persons with Disabilities states that a person with disabilities should have the ability to live in equal dignity and rights as others. Persons with disabilities include those who have long-term physical, mental, intellectual or sensory impairments, which in interaction with various barriers may hinder their full and effective participation in society on an equal basis with others. Article 25 on Health in section (b) states: Provide those health services needed by persons with disabilities specifically because of their disabilities, including early identification and intervention as appropriate, and services designed to minimize and prevent further disabilities, including among children and older persons; (56). Given the proven positive impact of DMTs on reduction of disability in MS, we respectfully suggest that the present application to the EML addresses a fundamental right of people with MS. Likely impact of treatment of disease is to reduce the long term burden of the disease, i.e. to delay disability progression and to prevent secondary progressive MS (57). Quality of life and socioeconomic burden of MS is very closely linked to disability, therefore, delaying and preventing disability worsening will have a major impact for individuals with the disease and for society (58). 15

17 9. Review of benefits: summary of evidence of comparative effectiveness Efficacy data for all DMTs: The pivotal trials for the currently approved DMTs were based on primary endpoints that represent measurable clinical disease activity (i.e. time to first relapse and annualized relapse rate), with secondary endpoints that either included other clinical metrics (i.e. time to sustained disability progression), and/or MRI measures of disease burden and accrual of new MRI changes over time. Trial endpoints, both primary and secondary are variable among the trials, which make cross -trial comparisons difficult. Recent studies have also evaluated the concept of no evidence of disease activity (NEDA). Achievement of NEDA requires cessation of all clinical relapses, absence of clinical disease progression, and serial MRI studies demonstrating no new T2-bright or gadolinium-enhancing lesions. Some studies have expanded NEDA to also include normalisation of progressive brain atrophy to less than is considered abnormal for age-expected annual change. Table 5 provides a summary of the Phase III clinical trial data for the disease modifying therapies with indications for MS treatment. The outcome measurements of greatest interest are the primary outcome measurements; however, the secondary outcomes of MRI (gadolinium enhancement and T2 lesions and/or lesion volume) and disability progression are considered important to the understanding of overall disease activity. MRI outcomes generally include gadolinium enhancement, a marker of active inflammation and T2 lesions or lesion volume, a measure of overall disease burden. Disability progression is generally measured using the expanded disability status score (EDSS), a score calculated from individual scores of pyramidal, visual, brainstem, cerebellar, sensory, elimination, and cerebral (mental) function. Table 5 - Summary of Phase III Clinical Trial Data for all Disease Modifying Therapies Indicated for Multiple Sclerosis. Agent Effect on Relapse Rate Effect on Disability Progression Relapses - primary Disability - secondary Glatiramer acetate (GA) Study: GA 20 mg SC injection daily vs placebo injection daily. N=251 Primary endpoint: difference in relapse rate at 24 months Neurology 1995;45: (59) 29% reduction in relapse rate over 24 months + : mean relapse rate placebo; 1.19 GA (p=0.007) Number of relapses during 2-year study placebo 210; GA 161; Annualized relapse rates 0.84 placebo; 0.59 daily GA Proportion of progression free patients at 24 months: 75.4% placebo; 78.4% GA (N.S.)(this was not found to be statistically significant) Proportion of patients with a change in disability between baseline and conclusion: Improved - EDSS GA Effect on Gd+ lesions No MRI outcomes in the Phase 3 trial Effect on New or Enlarging T2 lesions No MRI outcomes in the Phase 3 trial 16

18 24.8%; placebo 15.2%. Unchanged-GA 54.4%; placebo 56%. Worsened- GA 20.8%; placebo 28.8% (p=0.37 categorical repeated measures EDSS change from baseline to Mo24 (mean ± SD) GA ± 1.13; placebo 0.21 ± 0.99 (p=0.023 (repeated measures ANCOVA) Interferon beta-1a subcutaneous Study: Interferon beta 1a SC (44mcg or 22 mcg) three times weekly or placebo. N=560 Primary endpoint mean number of relapses at 2 years Lancet 1998;352: (60) Interferon beta-1a intramuscular Study: Interferon beta-1a intramuscularly 30 mcg or placebo N=301 Primary outcometime to sustained progression of disability Relapses - primary Mean number of relapses at 2 years in the 44mcg dose against placebo was 33% (95% CI 21 44%) and the 22 mcg dose against placebo was 27% (95% CI 14 39%) Relapses - secondary 18% reduction mean number relapses per patient year: 0.82 placebo; 0.67 treated (p=0.04) Disability - secondary Time to sustained progression (defined as an increase in EDSS of at least 1 point sustained over at least 3 months): 11.9 months (RR 1.00) placebo; 18.5 months 22 mcg (RR 0.68 (CI: ); 21.3 months; 44 mcg (RR=0.62, CI: , p<0.05 compared to placebo) Primary Endpoint - Progression of disability Proportion with progression of disability by 104 weeks estimated from Kaplan- Meier curves was 34.9% in placebo recipients and 21.9% in interferon beta-la recipients (p=0.02) MRI outcomes - secondary Median # of active lesions per patient per scan: 2.25 placebo; mcg dose (p<0.0001) MRI outcomes - secondary Proportion of gadolinium positive scans - Treated- 29.9%; placebo- 42.3% (p = 0.05). This group difference persisted at year 2 MRI outcomes - secondary Median % change of MRI PD-T2 lesion area at two years: 11% placebo; -3.8% 44mcg dose (p<0.0001) MRI outcomes - secondary Median % change T2 lesion volume from study entry to year 2: -6.5% placebo; -13.2% treated (this was not found to be statistically significant) 17

19 Annals of Neurology 1996;39(3): (61) Interferon beta-1b Phase III Study: Interferon beta-1b (8 MIU or 1.6 MIU subcutaneous injection every other day vs placebo. N=372 Primary outcome- Annual relapse rate Neurology 1993 Apr;43(4): (62) Peginterferon beta-1a Study: Pegylated interferon beta-1a 125 micrograms subcutaneous injection every 2 weeks or every 4 weeks or placebo N=1512 Primary endpoint: Annualized relapse rate at 48 weeks Lancet Neurology 2014 Jul;13(7):657-65). Relapses - primary Annualized relapse rate at 2 years: 1.27 placebo; MIU; MIU; (p= for placebo vs 8MIU; 0.01 for placebo vs 1.6 MIU; for 8 MIU vs 1.6 MIU) Relapses - primary 36% reduction annualized relapse rate at 48 weeks: (CI ) placebo; (CI ) treated every 2 weeks(p=0.0007), RR=0.64 (CI ) and treated every 4 weeks (CI ) Disability - secondary Disability measured as stable or worsened by 1.0 in EDSS score over baseline (consecutive EDSS measurements separated by 90 days: Confirmed endpoint Stable 88 (72%) placebo ; 90 (72%) 1.6 MIU; 97 (80%) 8 MIU (placebo vs 8 MIU p=0.161) Worsened: 34 (28% placebo; 35 (28%) 1.6 MIU; 25 (20%) 8 MIU (placebo vs 8 MIU p=0.161) Disability - secondary Proportion of patients who had had 12 weeks of sustained disability progression at 48 weeks was (SE ) in the placebo group and (SE ) in both intervention groups No Gd MRI outcome measurements in the Phase III study MRI outcomes - secondary Mean number contrast enhancing lesions at 48 wks: 1.4 (0.17 SE) placebo; 0.2 (0.05 SE) treated (p<0.0001) MRI outcomes - secondary %change in mean MRI lesion area at 2 years: 20% increase placebo; 10.5% increase 1.6 MIU; 0.1% decrease 8 MIU. MRI outcomes - secondary Mean number new or newly enlarging T2 lesions at 48 wks: 10.9 (CI: ) placebo; 3.6 (CI: ) treated (p<0.0001) 18

20 (63) Dimethyl fumarate (DMF Phase III Studies: Study 1 24-month DMF 240 mg twice daily or 3 times daily or placebo N=1237 Primary endpointproportion of patients who had relapse by 2 years NEJM 2012;367(12): ) (64) Study 2 24-month DMF 240 mg (2or3 times/day) or placebo or glatiramer acetate (GA) (as a reference comparator) N=1430 Primary endpointannualized relapse rate over 2 years NEJM 2012;367(12): ) (65) Relapses - Primary Study 1: 49% reduction in proportion relapsing within two years + : 46% placebo; 27% treated twice daily and 26% treated 3 times daily (twice daily OR= 0.42, 95% CI: , p<0.001 and 3 times daily 0.41 ( )) Study 2: 44% reduction in annualized relapse rate at two years: 0.40 (95%CI: ) placebo; 0.22 (CI: ) 240 mg DMF twice daily (p<0.001) 0.20 (CI: ) 240 mg DMF 3 times daily and 0.29 (CI: ) daily GA Disability - secondary Study 1: 38% decrease in risk of disability progression at 2 years, confirmed at 12 weeks, 27% placebo; 16% twice daily and 34% in the 3 times daily (twice daily- HR= 0.62, 95% CI: , p<0.005 (3 times daily-hr=0.66; 955 CI: p=0.01) Study 2: Estimated proportion of patients with progression at 2 years (confirmed at least 12 weeks later) 17% placebo; 13% 240 mg DMF twice daily (HR= 0.79, 95% CI: ) ;13% 240 mg DMF 3 times daily (HR 0.76 ( ); 16% daily GA HR 0.93 ( ) MRI outcomes - secondary Study 1: mean number Gd+ lesions at two years: 1.8 (SD:4.2)placebo; 0.1 (SD:0.6) 240mg bid dose (OR= 0.1, 95% CI: , p<0.001) and 0.5 (SD±1.7) 3 times daily (OR: 0.27, 95% CI: ) Study 2: number Gd+ lesions at two years: 2.0 (± 5.6) placebo; 0.5 (±:1.7) 240mg DMF twice daily dose (OR vs placebo : 0.26, 95% CI: , p<0.001); 0.4 ± mg DMF 3 times daily (OR vs placebo 0.35 CI: p<0.001); 0.7±1.8 daily GA (OR vs placebo 0.39 ( p<0.001) MRI outcomes - secondary Study 1: mean number new or enlarging T2 lesions at two years: 17 (95% CI: ) placebo; 2.6 (CI: ) 240mg twice daily ; 4.4 (CI: ) Study 2: mean number new or enlarging T2 lesions at two years: 17.4 (95% CI: ) placebo; 5.1 (CI: ) 240mg DMF twice daily dose ; 4.7 ( ) 240 mg DMF 3 times daily; 8.0 ( ) daily GA Fingolimod Study 1: 24 months Oral fingolimod 0.5 Relapses - primary Study 1: 54% reduction in annualized relapse rate Disability - secondary Study 1: Probability of disability progression MRI outcomes - secondary Study 1: mean number T1 Gd+ lesions at month 24: MRI outcomes - secondary Study 1: mean # new or newly enlarging T2 lesions over 24 months: 19

21 mg or 1.25 mg daily or placebo. N=1272 Primary endpoint- Annualized relapse rate NEJM 2010 Feb4;363(5): ) (66) Study 2: 24 months Oral fingolimod 0.5 mg or 1.25 mg daily or placebo. N=1083 Primary endpoint: Annualised relapse rate at month 24 over two years + : 0.40 (CI: ) placebo; 0.18 (CI: ) 0.5mg dose (p<0.001); 0.16 with 1.25 mg dose (CI: 0.13 to 0.19) p<0.001 Study 2: 48% reduction in annualized relapse rate over two years + : 0.40 (CI: ) placebo; 0.21 (CI: ) 0.5mg dose (p<0.0001)) confirmed at 3 months 17.7% 0.5mg; 16.6% 1.25 mg and 24.1% with placebo (NEJM 2010 Feb4;363(5): Study 2: confirmed disability progression (hazard rate 0.83 with fingolimod 0.5 mg vs placebo; 95% CI ; p=0 227) 0.2 (SD: 1.1) placebo; 0.2 (SD: 0.8) 0.5mg dose (p<0.001) Study 2: mean # T1 Gd+ lesions at month 24: 1.2 (SD: 2.97) placebo; 0.4 (SD: 1.84) 0.5mg dose (p<0.0001) 9.8 (SD: 13.2) placebo; 2.5 (SD:7.2) 0.5mg dose (p<0.001) Study 2: mean # new or newly enlarging T2 lesions over 24 months: 8.9 (SD: 13.86) placebo; 2.3 (SD:7.26) 0.5mg dose (p<0.0001) Lancet Neurology 2014;13: (67) Study 3: 12 months Oral fingolimod 1.25 mg or 0.5 mg or intramuscular interferon beta-1a Primary endpoint: annualized relapse rate NEJM 2010 Feb 4:362(5): (68) Study 3: annualized relapse rate over 12 months + : 0.33 (CI: ) IFN; 0.16 (CI: ) 0.5mg dose (p<0.001) S tudy 3: % with absence of disability progression at three months: 92.1% (CI: ) IFN; 94.1% (CI: ) 0.5mg dose (p=0.25) Study 3: mean # T1 Gd+ lesions at 12 months: 0.51 (SD: 1.86) IFN, 0.23 (SD: 0.97) 0.5mg dose (p<.001) Study 3: mean # new or newly enlarging T2 lesions at 12 months: 2.6 (SD:5.8) IFN, 1.7 (SD: 3.9) 0.5mg dose (p=0.004) 20