Descriptive Epidemiology of Multiple Sclerosis (MS) Multiple Sclerosis.
MSIF WHO EML APPLICATION Multiple Sclerosis Disease … · Multiple Sclerosis International...
Transcript of MSIF WHO EML APPLICATION Multiple Sclerosis Disease … · Multiple Sclerosis International...
Multiple Sclerosis International Federation December 2018
0
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).
Multiple Sclerosis International Federation December 2018
1
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®) 2013
Multiple Sclerosis International Federation December 2018
2
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 life-
threatening (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,
Multiple Sclerosis International Federation December 2018
3
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
Multiple Sclerosis International Federation December 2018
4
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
Multiple Sclerosis International Federation December 2018
5
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)
Multiple Sclerosis International Federation December 2018
6
Table 2 - Drug Formulation, dosing schedule and indication
Drug classification Agent, Dose and administration Disease classification(s)
Glatiramer acetate immunomodulator (glatiramer acetate)
Glatiramer acetate 20mg subcutaneous injection qd Glatiramer acetate 40mg subcutaneous injection tiw No dosing adjustment required for paediatric MS
Clinically isolated syndrome (CIS) Relapsing multiple sclerosis
Sphingosine 1-phosphate receptor modulator (fingolimod hydrochloride)
Fingolimod 0.25mg – 0.5mg orally qd Fingolimod 0.25 mg for patients < 40 kg
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 500-1000mg 2 weeks apart than every 6 months 500 -1000 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).
Multiple Sclerosis International Federation December 2018
7
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 2023. A secondary patent family, expiring 2029, is granted in China and South Africa, and
Multiple Sclerosis International Federation December 2018
8
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
Multiple Sclerosis International Federation December 2018
9
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
Multiple Sclerosis International Federation December 2018
10
- 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).
Multiple Sclerosis International Federation December 2018
11
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 $23,444.88 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
Multiple Sclerosis International Federation December 2018
12
fingolimod who were natalizumab-naïve is low with an estimated risk of 0.069/1,000 (95% CI: 0.039–0.114), and an estimated incidence rate of 3.12/100,000 patient-years (95% CI: 1.75–5.15) (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).”
Multiple Sclerosis International Federation December 2018
13
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
Multiple Sclerosis International Federation December 2018
14
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 30-60 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, 2017
8. 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 20-50. 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 100 000 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.
Multiple Sclerosis International Federation December 2018
15
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 $24 666 to
$51 678 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).
Multiple Sclerosis International Federation December 2018
16
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
Effect on Gd+ lesions Effect on New or Enlarging T2 lesions
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;45:1268-1276 (59)
Relapses - primary 29% reduction in relapse rate over 24 months+: mean relapse rate -1.68 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
Disability - secondary 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
No MRI outcomes in the
Phase 3 trial
No MRI outcomes in the Phase 3 trial
Multiple Sclerosis International Federation December 2018
17
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 -0.05 ± 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;352:1498-1504 (60)
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%)
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: 0.48-0.98); 21.3 months; 44 mcg (RR=0.62, CI:0.43-0.91, p<0.05 compared to placebo)
MRI outcomes - secondary Median # of active lesions per patient per scan: 2.25 placebo; 0.5 44mcg dose (p<0.0001)
MRI outcomes - secondary Median % change of MRI PD-T2 lesion area at two years: 11% placebo; -3.8% 44mcg dose (p<0.0001)
Interferon beta-1a intramuscular Study: Interferon beta-1a intramuscularly 30 mcg or placebo N=301 Primary outcome- time to sustained progression of disability
Relapses - secondary 18% reduction mean number relapses per patient year: 0.82 placebo; 0.67 treated (p=0.04)
Primary Endpoint - Progression of disability Proportion with progres- sion 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 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 T2 lesion volume from study entry to year 2: -6.5% placebo; -13.2% treated (this was not found to be statistically significant)
Multiple Sclerosis International Federation December 2018
18
Annals of Neurology 1996;39(3):285-294 (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):655-61 (62)
Relapses - primary Annualized relapse rate at 2 years: 1.27 placebo; 1.17- 1.6
MIU; 0.84- 8MIU; (p=
0.0001 for placebo vs
8MIU; 0.01 for placebo vs
1.6 MIU; 0.0086 for 8 MIU
vs 1.6 MIU)
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)
No Gd MRI outcome measurements in the Phase III study
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.
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 36% reduction annualized relapse rate at 48 weeks: 0.397 (CI 0.33-0.48) placebo; 0.256 (CI 0.21-0.32) treated every 2 weeks(p=0.0007), RR=0.64 (CI 0.50-0.83) and treated every 4 weeks 0·288 (CI 0·234-0·355)
Disability - secondary Proportion of patients who had had 12 weeks of sustained disability progression at 48 weeks was 0·105 (SE 0·0142) in the placebo group and 0·068 (SE 0·0119) in both intervention groups
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 Mean number new or newly enlarging T2 lesions at 48 wks: 10.9 (CI: 9.6-12.5) placebo; 3.6 (CI: 3.1-4.2) treated (p<0.0001)
Multiple Sclerosis International Federation December 2018
19
(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 endpoint-proportion of patients who had relapse by 2 years NEJM 2012;367(12):1098-107) (64) Study 2 24-month DMF 240 mg (2or3 times/day) or placebo or glatiramer acetate (GA) (as a reference comparator) N=1430 Primary endpoint- annualized relapse rate over 2 years NEJM 2012;367(12):1087-1097) (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: 0.31-0.57, p<0.001 and 3 times daily 0.41 (0.30-0.56)) Study 2: 44% reduction in annualized relapse rate at two years: 0.40 (95%CI: 0.33-0.49) placebo; 0.22 (CI: 0.18-0.28) 240 mg DMF twice daily (p<0.001) 0.20 (CI:0.16-0.25) 240 mg DMF 3 times daily and 0.29 (CI:0.23-0.35) 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:0.44-0.87, p<0.005 (3 times daily-HR=0.66; 955 CI:0.48-0.92 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:0.52-1.19)
;13% 240 mg DMF 3 times daily (HR 0.76 (0.50-1.16); 16% daily GA HR 0.93 (0.63-1.37)
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:0.05-0.22, p<0.001) and 0.5 (SD±1.7) 3 times daily (OR: 0.27, 95% CI: 0.15-0.46) 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:0.15-0.46, p<0.001); 0.4 ±1.2 240 mg DMF 3 times daily (OR vs placebo 0.35 CI:0.20-0.59 p<0.001); 0.7±1.8 daily GA (OR vs placebo 0.39 (0.24-0.65 p<0.001)
MRI outcomes - secondary Study 1: mean number new or enlarging T2 lesions at two years: 17 (95% CI:12.9-22.4) placebo; 2.6 (CI: 2.0-3.5) 240mg twice daily ; 4.4 (CI: 3.2-5.9) Study 2: mean number new or enlarging T2 lesions at two years: 17.4 (95% CI:13.5-22.4) placebo; 5.1 (CI:3.9-6.6) 240mg DMF twice daily dose ; 4.7 (3.6-6.2) 240 mg DMF 3 times daily; 8.0 (6.3-10.2) 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:
Multiple Sclerosis International Federation December 2018
20
mg or 1.25 mg daily or placebo. N=1272 Primary endpoint- Annualized relapse rate
NEJM 2010 Feb4;363(5):387-401) (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 Lancet Neurology 2014;13:545-56. (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):402-15. (68)
over two years+: 0.40 (CI:0.34-0.47) placebo; 0.18 (CI:0.15-0.22) 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: 0.34-0.48) placebo; 0.21 (CI:0.17-0.25) 0.5mg dose (p<0.0001)) Study 3: annualized relapse rate over 12 months+: 0.33 (CI:0.26-0.42) IFN; 0.16 (CI: 0.12-0.21) 0.5mg dose (p<0.001)
confirmed at 3 months 17.7% 0.5mg; 16.6% 1.25 mg and 24.1% with placebo (NEJM 2010 Feb4;363(5):387-401. Study 2: confirmed disability progression (hazard rate 0.83 with fingolimod 0.5 mg vs placebo; 95% CI 0·61–1·12; p=0·227) S tudy 3: % with absence of disability progression at three months: 92.1% (CI:89.4-94.7) IFN; 94.1% (CI: 91.8-96.3) 0.5mg dose (p=0.25)
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) 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)
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) 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)
Multiple Sclerosis International Federation December 2018
21
Teriflunomide Study 1: 2-year study teriflunomide 7 mg or 14 mg or placebo N=1088 Primary endpoint Annualized relapse rate NEJM 2011;365:1293-303. (69) Study 2: 2 -year study teriflunomide 7 mg or 14 mg or placebo N=1169 Primary endpoint: Annualized relapse rate (number of relapses per patient year) Lancet Neurology 2014 Mar;13(3):247-56. (70)
Relapses – primary Study 1: 31% reduction in annualized relapse rate over two years+: 0.54 (95% CI: 0.47-0.62) placebo; 0.37 (CI: 0.32-0.43) for 7mg and 0.37 (CI: 0.31-0.44) 14mg doses (p<0.001) Study 2: Annualized relapse rate over two years+: 0.50 (CI: 0.43-0.58) placebo; 0.39 (CI: 0.33-0.46) for 7mg dose (p<0.0183) and 0.32 (CI: 0.27-0.38) for 14 mg dose (p<0.0001)
Disability – secondary Study 1: Proportion with confirmed disability progression ≥12 weeks: 27.3% (95% CI: 22.3-32.3) placebo; 21.7% (CI:17.1-26.3) 7mg dose (N.S.); 20.2% (CI:15.6-24.7) 14mg dose (p=0.03) Study 2: Risk of sustained accumulation of disability compared to placebo: HR 0.95 [0.68-1.35; log-rank p=0.7620 7mg dose (N.S.); HR 0.68 (95% CI 0.47-1.00; log-rank p=0.0442 14mg dose (p=0.04)
MRI outcomes – secondary Study 1: Estimated number Gd+ lesions per scan: 1.33 (95% CI: 1.06-1.67) placebo; 0.57 (CI: 0.43-0.75) 7mg dose (p<0.001); 0.26 (0.17-0.41) 14mg dose (p<0.001) Study 2: No MRI outcomes
MRI outcomes – secondary Study 1: Volume of T2 lesions change from baseline (ml) 1.67 ±6.47 placebo; 0.81±6.18 p=0.04 7 mg dose; 0.39±6.90 p<0.001 14 mg dose. Study 2: No MRI outcomes
Oral cladribine Study: 96-week trial cladribine 3.5 or 5.25 mg/kg or placebo N=1326 Primary endpoint: Relapse rate at 96 weeks NEJM 2010;362(5)416-26 (71)
Relapses - primary Annualized relapse rate 96 weeks 0.33 (CI: 0.29-0.38) placebo; 0.14 (CI: 0.12-0.17) 3.5mg/kg (p<.001); 0.15 (CI: 0.12-0.17) 5.25mg/kg (p<0.001)
Disability - Secondary Relative reduction in risk of 3-month sustained progression of disability 33% reduction Cladribine 3.5-mg/kg (HR: 0.67; 95% CI, 0.48 to 0.93; P=0.02); 31% reduction cladribine 5.25-mg/kg (HR:
MRI outcomes – secondary Mean number Gd lesions 0.91 placebo;0.12 3.5 mg/kg ; 0.11 5.25 mg/kg
MRI outcomes – secondary Mean number of active T2 lesions 1.43 placebo; 0.38 3.5 mg/kg; 0.33 5.25 mg/kg
Multiple Sclerosis International Federation December 2018
22
0.69; 95% CI, 0.49 to 0.96; P=0.03)
Alemtuzumab
Study 1: Alemtuzumab 12 mgday or interferon beta-1a SC three timew weekly (Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months) N=563 Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug Lancet. 2012 Nov 24;380(9856):1819-28 (72) Study 2: 2-year Ifn beta 1a three times weekly or alemtuzumab 12 mg/day or alemtuzumab 24 mg/day N=628.
Relapses - primary Study 1: 55% risk reduction in annualized relapse rate over two years+: 0.39 (CI:0.29-0.53) IFN; 0.18 (CI: 0.13-0.23) alemtuzumab (p<0.0001) Study 2: 49% risk reduction in annualized relapse rate over two years: 0.52 (95% CI:0.41-0.66) IFN; 0.26 (CI: 0.21-0.33) alemtuzumab
Disability - primary Study 1: sustained disability accumulation confirmed over six months: 11.12% (95% CI: 7.32-16.71) IFN; 8% (CI: 5.66-11.24) alemtuzumab (p=0.22) HR=0.70 (CI: 0.40-1.23) Study 2: sustained disability accumulation confirmed over six months: 21.13% (CI: 15.95-27.68) IFN; 12.71% (CI:9.89-16.27) alemtuzumab ) HR: 0.58
MRI outcomes - secondary Study 1: Patients with Gd lesions at 24 months: 34/178 (19%) IFN; 26/366 (7%) alemtuzumab p<0.0001 Study 2: Patients with Gd lesions at 24 months: 44/190 (23%) IFN; 38/410 (9%) alemtuzumab p<0.0001
MRI outcomes - secondary Study 1: patients with new or enlarging T2 lesions: 99/172 (58%) IFN; 176/363 (48%) alemtuzumab p=0.04 Study 2: patients with new or enlarging T2 lesions: 127/187 (68%) IFN; 186/403 (46%) p<0.0001
Multiple Sclerosis International Federation December 2018
23
Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. NOTE: 24 mg per day group was discontinued to aid recruitment Coprimary endpoints: were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a Lancet. 2012 Nov 24;380(9856):1829-39 (73)
(0.38-0.87) (42% risk reduction -p=0.0084)
Natalizumab Study: Natalizumab 300 mg IV infusion or placebo infusion every 4 weeks for 2 years N=942 Primary endpoints: relapse rate at 1 year and rate of sustained disability progression at 2 years.
Relapses - primary 1 year: 0.78 (CI:0.64-0.94) placebo; 0.27 (CI: 0.21-0.33) natalizumab (p<0.001) 2 year: 0.73 (CI: 0.62-0.87) placebo; 0.23 (CI: 0.19-0.28) treated (p<0.001)
Disability - primary Cumulative probability of sustained progression at 2yrs: 29% placebo; 17% treated (HR=0.58, 95% CI: 0.43-0.77) (p<0.001)
MRI outcomes - secondary Mean # Gd+ lesions at two years: 1.2 (±3.9) placebo; 0.1 (±1.4) natalizumab
MRI outcomes - secondary Mean # new or enlarging T2 lesions at two years: 11.0 (±: 15.7) placebo; 1.9 (±: 9.2) treated
Multiple Sclerosis International Federation December 2018
24
NEJM 2006;354(9):899-910. (74)
Ocrelizumab Study 1 and 2 in relapsing MS: intravenous ocrelizumab 600 mg every 24 wks or interferon beta 1a three times weekly for 96 weeks. N=821; N=835 Primary endpoint Study 1 and 2: Annualized relapse rate NEJM 2017; 376:221-234 (25) Primary Progressive MS Study: Intravenous ocrelizumab 600 mg or placebo every 24 weeks for at least 120 wks Primary endpoint: Percentage of patients with disability progression confirmed at 12 weeks in time-to-event analysis
Relapses - primary Study 1: Annualized relapse rate at 96 weeks: 0.29 (CI: 0.24-0.36) IFN; 0.16 (CI: 0.12-0.20) ocrelizumab (p<0.001) Study 2: 0.29 (CI:0.23-0.36) IFN; 0.16 (CI: 0.12-0.20) ocrelizumab (p<0.001) Primary Progressive MS: Relapses not a reported outcome measurement
Disability - secondary Study 1: 12.2% IFN;7.6% ocrelizumab HR 0.57 (95% CI 0.37-0.90)p<0.001 Study 2: 15.1% IFN;10.6% ocrelizumab HR 0.63 (CI: 0.42-0.92) p=0.02 Primary progressive MS: Confirmed disability progression for ≥12 wks: 96/244 (39.3%) placebo; 160/487 (32.9%) HR 0.76 (95% CI:0,59-0.98) p+0.03
MRI outcomes – secondary Mean # of T1 Gd+ lesions per scan: Study 1: 0.29 IFN (CI: 0.20-0.41); 0.02 ocrelizumab (CI: 0.01-0.03):RR: 0.06 (CI 0.03-0.10) p<0.001) Study 2: 0.42 IFN (95% CI: 0.31-0.56); 0.02 ocrelizumab (CI: 0.01-0.04): RR 0.05 (CI 0.03-0.09 (p<0.001) Primary progressive MS: Gd not a reported outcome measurement
MRI outcomes - secondary Mean # of new and/or enlarging T2 lesions per scan: Study 1: 1.41 (CI: 1.12-1.78) IFN; 0.32 (CI:0.26-0.41) ocrelizumab: RR 0.23 (CI: 0.17-0.30) (p<0.001) Study 2: 1.90 (CI: 1.54-2.36) IFN; 0.33 (CI: 0.26-0.41) ocrelizumab: RR 0.17 (CI 0.13-0.23) (p<0.001) Primary progressive MS: Adjusted geometric mean % change in volume of T2 lesions from baseline to week 120: 7.43 (95% CI 4.97-9.94) placebo; -3.37 % (CI:-4.99 to -1.72)p<0.001 Secondary outcome – brain volume: Mean % change in brain volume from week 24 to 120: -1.09 (CI: -1.24 to -0.95) placebo; -0.90 (CI: -1.00 to -0.80) treated (p=0.02)
Multiple Sclerosis International Federation December 2018
25
NEJM 2017;376:209-20 (75)
Table 6 – Head-to-head trial Summaries
Study Agents Findings
REGARD (76) Glatiramer acetate vs. IFNB-1a tiw No significant difference between GA and INFB 1a relapse rate (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64) or the number and change in volume of T2 active lesions or volume of gadolinium-enhancing lesions.
TRANSFORMS (68) Fingolimod vs. INFB-1a weekly A prospective, 12-month, double-blind, randomized trial of 1153 RRMS patients demonstrated superior efficacy in favour of fingolimod with respect to relapse rate (p<0.001) and MRI outcomes (p<0.001).
OPERA I and II (25) Ocrelizumab vs. IFNB-1a tiw Demonstrated the superiority of ocrelizumab in annualized relapse rate and MRI outcomes, as well as disability progression (pooled analysis).
PARADIGMS (24) Fingolimod vs. INFB-1a weekly Among pediatric patients (10-17 years, mean age 15.3 years) with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse (p<0.001) and less accumulation of lesions on MRI (p<0.001) over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events.
Multiple Sclerosis International Federation December 2018
26
Identification of clinical evidence (search strategy systematic reviews identified, reasons for selection/exclusion of particular data)
The evidence outlined above was identified as part of a systematic review and meta-analysis, conducted to inform the ECTRIMS/EAN Guideline
on the pharmacological treatment for people with multiple sclerosis (2). To identify systematic reviews and clinical trials of disease modifying
therapies for MS, the following databases were searched (inception – December 2015): Central, Embase, MEDLINE and PsychINFO. Terms used
included ‘multiple sclerosis or myelitis’, ‘Disease modifying agents or immunosuppressants’, and known drug names. Appendix 3A (RRMS) and
3B (PPMS) contains the GRADE tables from the analysis.
Summary of available data: appraisal of quality, outcome measures, summary of results
The quality appraisal process was conducted using the Cochrane collaboration's’ tool for assessing risk of bias in randomised trials (77). The
GRADE approach was used to assess the quality of evidence for each outcome, taking into account the following items: study design, risk of bias,
inconsistency, indirectness, and imprecision (78).
Injectable
Summary of available data: Glatiramer Acetate
RRMS Three trials (N=3217) compared glatiramer acetate with placebo with length of follow up ranging from 52 to 104 weeks (59,65,79).
Compared to placebo, glatiramer acetate lowers annualized relapse rates for follow ups of 52-96 weeks (MD=-0.14, 95% CI: -0.21 to -0.06,
moderate quality evidence, n=2117, K=2) and results in more patients free from relapse at 1-2 years follow up (RR=1.17, 95% CI: 1.10-1.24,
moderate quality evidence, n=2360, K=3). Glatiramer acetate was also shown to result in a lower number of cumulative gadolinium enhancing
(GAD) lesions (MD=-0.73, 95% CI: -1.15 to -0.31, high quality evidence, n=1325, K=1) and new or newly enlarging T2 lesions at 6 and 12 months
follow up (MD=-1.94, 95% CI: -3.03 to -0.85, high quality evidence, n=1325, K=1)). Low quality evidence showed a non-statistically significant
effect on disability at 2 years follow up (RR=0.86, 95% CI: 0.66 to 1.11, n=964, K=2).
Multiple Sclerosis International Federation December 2018
27
Number of participants relapse free 52-104 weeks follow up
Annualized relapse rate 52-96 weeks follow up
Multiple Sclerosis International Federation December 2018
28
Comparative effectiveness. Glatiramer acetate was compared to interferon in 4 trials (76,80–82). At 2 years’ follow up, the number of
participants free from relapse did not significantly differ (RR=0.98, 95% CI: 0.90-1.06, moderate quality meta-analysis, n=2175, K=3), nor did
extent of disability worsening (RR=1.07, 95% CI: 0.83-1.31, K=1).
PPMS One trial compared glatiramer acetate to placebo for patients with primary-progressive MS (n=970) (83). There was a non-significant
effect on the number of participants with disability worsening (RR=0.87, 95% CI: 0.75-1.02) and longer time to disability worsening (HR=0.87,
95% CI: 0.71-1.07) in the glatiramer acetate group.
Oral
Summary of available data: Fingolimod
RRMS Two trials compared fingolimod with placebo, with two years follow up (66,67). A larger proportion of patients were free from relapse at
two years in the fingolimod arm (RR=1.44, 95% CI: 1.28-1.63, moderate quality evidence, n=2355, K=2). Annualised relapse rate was also lower in
the fingolimod arm (MD=-0.21, 95% CI: -0.25 to -0.16, moderate quality evidence, n=2355, K=2). Fingolimod put participants at a lower risk of
disability worsening compared to placebo (RR=0.71, 95% CI: 0.56-0.90, moderate quality evidence, n=2355, K=2). Patients also had fewer new or
newly enlarged T2 lesions (RR=2.16, 95% CI: 1.77-2.63, moderate quality evidence, n=1192, K=2) and fewer GAD lesions (MD=-0.87, 95% CI: -1.10
to -0.64, moderate quality evidence, n=1216, K=2) at two years follow up. According to one study, fingolimod reduced percent change in brain
volume at 1-2 years follow up (MD=0.3, 95% CI: 0.16-0.44, moderate quality evidence n=685, K=1).
Number of participants relapse free: 104 weeks follow up
Multiple Sclerosis International Federation December 2018
29
Annualized relapse rate: 104 weeks follow up
Comparative effectiveness One trial compared fingolimod with interferon (68). Moderate quality evidence showed that participants in the
fingolimod arm had lower annualized relapse rates (MD=-0.17, 95% CI: -0.26 to -0.08, moderate quality meta-analysis, n=860), and more
participants were free from relapse at 1 year (RR=1.19, 95% CI: 1.11-1.29, moderate quality meta-analysis, n=860) than the interferon group.
Fingolimod was also associated with fewer new or newly enlarged T2 lesions (MD=-0.90, 95% CI: -1.62 to -0.18, moderate quality meta-analysis,
n=733) and GAD lesions (MD=-0.28, 95% CI: -0.50 to -0.06, moderate quality meta-analysis, n=728). There was no significant difference in extent
of disability progression between fingolimod and interferon in the trial.
A phase III trial PARADIGMS, investigating the safety and efficacy of fingolimod vs. interferon beta-1a, in children and adolescents (ages 10 to 17)
with multiple sclerosis found that fingolimod significantly reduced annualized relapse rates by 82% (p<0.001) over a period of up to two years
compared to interferon beta-1a; reduced the number of new or newly enlarged T2 lesions up to 24 months by 53% (p<0.001) and reduced the
average number of gadolinium-enhancing T1 (Gd+) lesions per scan at 24 months by 66.0% (p<0.001) (24).
PPMS One trial compared fingolimod with placebo (84) in patients with primary-progressive multiple sclerosis (n=970). There was no difference
in disability progression at 156 weeks follow up between fingolimod or placebo (RR=0.93, 95% CI: 0.80-1.08, moderate quality evidence).
Multiple Sclerosis International Federation December 2018
30
Infusion
Summary of available data: Ocrelizumab
RRMS There were no trials that met the inclusion criteria comparing ocrelizumab with placebo. The main exclusion criteria of Kappos et al. study
was insufficient follow-up of 48 weeks as it switched both arms to ocrelizumab after 24 weeks (85).
Comparative effectiveness Two trials compared Ocrelizumab with interferon with follow up of two years (25). Participants receiving Ocrelizumab
showed a significantly lower annualized relapse rate compared to interferon (MD=-0.13, 95% CI: -0.18 to -0.08, high quality meta-analysis,
n=1656, K=2). The Ocrelizumab group had fewer participants with disability progression confirmed at 12 weeks (RR=0.65, 95% CI: 0.49-0.86, low
quality evidence, n=1578, K=2), and mMore participants on Ocrelizumab showed a disability improvement, confirmed at 12 weeks (RR=1.32,
95% CI:1.04-1.68, moderate quality meta-analysis, n=1242, K=2).
PPMS One trial compared Ocrelizumab to placebo in patients with primary progressive MS (75). The Ocrelizumab group had a greater time to
disability progression at 120 weeks follow up when confirmed at both 12 weeks (HR=0.76, 95% CI:0.59-0.98, high quality evidence, n=732) and
24 weeks (HR=0.75, 95% CI: 0.58-0.97, high quality evidence, n=732).
Summary plots of the remaining DMTs and head-to-head comparisons can be found in Appendix 4.
NOTE: While this application is not formally requesting to expand the current EML indication of rituximab to include treatment of multiple
sclerosis, it should be noted that rituximab is currently used off-label as monotherapy for treatment of multiple sclerosis. In counties without
access to ocrelizumab, rituximab may provide a high efficacy treatment option for patients with multiple sclerosis.
Rituximab
RRMS Rituximab is similar to ocrelizumab, both target CD20 B-cells. Rituximab is a chimeric antibody whereas ocrelizumab is a humanized
antibody (85). Rituximab binds a similar epitope of the CD20 protein and has quite comparable biological effects. The side effect profile is similar
Multiple Sclerosis International Federation December 2018
31
and long-term safety data are available from other autoimmune diseases. Rituximab is not FDA approved for MS as phase III trials do not
currently exist.
A Cochrane review found one trial comparing rituximab to placebo (12). The mean number of total GAD enhancing lesions, the primary endpoint
of this double-blind phase 2 trial, was significantly decreased after 12, 16, 20 and 24 weeks (-5.0, 95% CI: -9.99 to -0.01, n=104). The proportion
of patients with relapses was significantly reduced in the rituximab group, both after 24 weeks (14.5% vs. 34.3% in the placebo group; P=0.02)
and 48 weeks (20.3% vs. 40.0%, P=0.04) (86). A phase-II open label study of 26 patients with RRMS receiving rituximab at baseline and 6 months
found that mean annualised relapse rate reduced from 1.27 to 0.23, and mean number of GAD lesions reduced from 1.31 to 0.05 at week 48 and
0.0 at week 72. Mean number of new or newly enhancing T2 lesions also decreased from 0.92 at week 4 to 0.0 at week 72 (87).
PPMS Rituximab has also been investigated in a RCT of primary progressive MS (PPMS) (88). A total of 439 PPMS patients were randomized (2:1)
to receive two intravenous doses (2 weeks apart) of rituximab (n=292) or placebo (n=147) infusions every 24 weeks, through 96 weeks (a total of
4 courses). Results showed that fewer in the rituximab group (30.2%) experienced 12 weeks CDP during 96 weeks compared to 38.5% in the
placebo group, but the difference did not reach statistical significance (p= 0.14). However, in a predefined subanalysis, RTX showed a significant
effect in patients with active MRI lesions or <51years. This effect was quite comparable with the effect seen in the Ocrelizumab trial, which only
included patients below the age of 55.
Real-world experience from rituximab therapy in MS
The most extensive real-world data on treatment with rituximab in MS came from a study which examined the disease course of 822 MS-
patients, 557 with relapsing remitting MS (RRMS), 198 with secondary progressive MS (SPMS) and 67 with primary progressive MS (PPMS), who
were followed for a mean of 22 months (11). RRMS patients treated with rituximab had a yearly relapse rate of 0.044 during the study period. In
total, 5.2 % of the patients stopped treatment because of side effects or disease activity. The ratio of gadolinium enhancing lesions per MRI
dropped significantly from approximately 3 months after treatment initiation, and was in total 0.054, present in 2.2% of MRIs. Moreover, the
registry data suggest that the treatment efficacy of rituximab in RRMS could exceed the effect of fingolimod, DMF and beta-interferons. In
addition, adherence was higher and side effects were comparable all other drugs (89,90).
Multiple Sclerosis International Federation December 2018
32
10. Reviews of harms and toxicity: summary of evidence of safety
• Estimate of total patient exposure to date
■ Glatiramer acetate - >1 million patient-years of exposure (91) and is approved in 50+ countries worldwide (92)
■ Fingolimod - 231,000 patients in both clinical trials and the post-marketing setting, approximately 536,000 patient-years of
exposure (93)
■ Ocrelizumab 50,000 patients treated globally, 9,474 patient years of exposure and approved in 67 countries (94)
Table 7 - Description of the adverse effects/reactions and estimates of their frequency (table adapted from MS Coalition DMT Consensus 2017
(8))
Estimated frequencies of adverse effects are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100);
rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known. Adverse effects are reported from clinical trial data using prescribing
information for healthcare professionals published on the electronic Medicines Compendium (eMC) (95).
Agent Side Effects Warnings/Precautions
Glatiramer acetate
(Copaxone®)
20mg SC daily
40mg SC three times
weekly
Indication: relapsing
forms of MS/CIS
Pregnancy Cat: B
-injection-site reactions ≥1/10 (96)
-lipoatrophy ≥1/100 to <1/10
-vasodilation, rash, dyspnea ≥1/10
-chest pain ≥1/10
-lymphadenopathy ≥1/100 to <1/10 (97)
-immediate transient post-injection reaction (flushing,
chest pain, palpitations, anxiety, dyspnea, throat
constriction, and/or urticaria) ≥1/1,000 to <1/100
- skin necrosis ≥1/1,000 to <1/100
-potential effects on immune response
Fingolimod (98)
(Gilenya®) 0.5mg PO
daily
Indication: relapsing
forms of MS
Pregnancy Cat: C
-headache ≥1/10
-influenza ≥1/10
-diarrhea ≥1/10
-back pain ≥1/10
-↑hepatic enzymes ≥1/10
-cough ≥1/10
-bradyarrhythmia and/or atrioventricular block following
first dose ≥1/100 to <1/10;
-risk of infections including serious infections
– monitor for infection during treatment and for 2 months
after d/c
Multiple Sclerosis International Federation December 2018
33
-bradycardia during first dose ≥1/100 to
<1/10-macular edema ≥1/1,000 to <1/100
-lymphopenia ≥1/100 to <1/10
-bronchitis ≥1/100 to <1/10
-pneumonia ≥1/1,000 to <1/100
-avoid live attenuated vaccines during treatment and for 2
months after d/c
-PML (not known, 15 cases reported worldwide)
-cryptococcal infections (not known)
-macular edema ≥1/1,000 to <1/100
-posterior reversible encephalopathy syndrome (PRES)
≥1/10,000 to <1/1,000
↓pulmonary function tests (FEV1)
-hepatic injury
-↑BP
-basal cell carcinoma ≥1/100 to <1/10
-fetal risk: women should avoid conception for two months
after treatment d/c
-↓lymphocyte counts for 2 months after drug d/c
-seizures ≥1/1,000 to <1/100 (99)
- Seizures has been reported as a serious adverse event in
children treated with fingolimod (24)
Ocrelizumab (100)
(Ocrevus™) 600mg IV
every 6 months
Indication: relapsing or
primary progressive
forms of MS
Pregnancy Cat: No
category assigned due
to changes to FDA
labeling procedures for
pregnancy and
-infusion reactions ≥1/10
-infections ≥1/10
-possible increased risk of malignancies
(including breast cancer, which occurred in 6
of 781 treated patients and no placebo
patients)
-infusion reactions (potentially life-threatening), which can
include: pruritus, rash, urticaria, erythema, bronchospasm,
throat irritation, oropharyngeal pain, dyspnea, pharyngeal
or laryngeal edema, flushing, hypotension, pyrexia, fatigue,
headache, dizziness, nausea, tachycardia; premedication
and observation period recommended
-infections including respiratory tract infections, herpes
and potentially PML (no cases of PML were reported
during clinical trials; 6 cases reported worldwide as carry-
over from previous drug therapy)
Multiple Sclerosis International Federation December 2018
34
lactation. No human
data: in monkeys,
administration during
organogenesis and
continuing through the
neonatal period
resulted in perinatal
deaths, renal toxicity,
lymphoid follicle
formation in the bone
marrow and severe
decreases in circulating
B lymphocytes in
neonates.
-hepatitis B reactivation (did not occur in ocrelizumab
clinical trials however has been reported in other anti-
CD20 antibodies)
-possible increased immunosuppressive effect if
immunosuppressant used prior to or after ocrelizumab
-administer all vaccinations at least 6 weeks prior to
administration of ocrelizumab; no live-attenuated or live
vaccines during treatment and until B-cell repletion
-malignancies (increased number of malignancies were
observed in clinical trials in patients treated with
ocrelizumab vs control groups; incidence of malignancies
was within the background rate expected for an MS
population).
Pregnancy There are currently no double-blind, placebo-controlled trials in women with multiple sclerosis who are pregnant or wishing to
conceive (2). However, observational evidence has been outlined below.
A pregnancy registry maintained by the marketing company of branded glatiramer acetate (Copaxone®) captured over 7,000 pregnancies
exposed to glatiramer acetate did not find an increase in spontaneous abortions, premature births, neonatal complications, or birth defects (22).
No significant differences were observed in birth weight to babies born to mothers exposed to glatiramer during pregnancy compared with
mothers not exposed to glatiramer acetate during pregnancy. Furthermore, a wash-out period is no longer necessary for women treated with
branded glatiramer acetate prior to or following conception. Evidence supports the use of branded glatiramer acetate in pregnant women who
are recommended to remain on treatment to manage disease activity. In 2016 Teva Pharmaceutical Industries Ltd removed the pregnancy
contraindication from the European label for branded glatiramer acetate injection 20 mg/mL (101).
Fingolimod is a teratogen class C agent and should be considered an absolute contraindication in pregnancy and breastfeeding based on its
known teratogenicity in animal studies and post-marketing data (102).
Multiple Sclerosis International Federation December 2018
35
Ocrelizumab, a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins and known to cross the placental
barrier. Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.
There are no adequate data on the developmental risk associated with use of ocrelizumab in pregnant women. There are no data on B-cell levels
in human neonates following maternal exposure to ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been
reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. In clinical trials, the rate of induced abortion
reported was 16.7% (8/48). In the general population worldwide, the overall rate of pregnancies ending in induced abortion is 20% and in MS
patients it is 26.5% as reported in literature. The overall rate of birth defects (defined as any abnormality affecting body structure or function)
was 12.5% (6/48) and the rate of structural malformations was 6.3% (3/48). The background risk of major birth defects and miscarriage for the
indicated population is unknown (103).
Paediatrics While data on paediatric treatment of MS is limited at present, there have been some cohort studies (104). The first randomised
clinical trial, PARADIGMS, has recently been published which demonstrated superior efficacy of fingolimod as compared to interferon-beta 1a
intramuscular injection. The PARADIGMS study randomised 190 patients (mean age 15.3 years) from 101 centres in 26 countries to receive
either fingolimod or interferon beta 1a (23,24). Relapse rate was found to be 80% lower in the fingolimod group at 2-year follow up. This
suggests fingolimod could be even more efficacious in paediatric populations than in adults (105).
Table 8 - Summary of Additional Safety Data from EAN Guidelines (2)
DMT Side effects
Interferon
Moderate efficacy
Injection
Versus placebo
Discontinuation due to side effects 104 weeks FU: RR=1.72, 95% CI: 1.04-2.86, K=4, n=1630 (favours placebo)
Jacobs 1996 IFNb-1a (30 µg)
PRISMS 1998 IFNb-1a (22 µg)
PRISMS 1998 IFNb-1a (44 µg)
Vollmer 2014 IFNb-1a (30 µg)
Discontinuation for any reason 104 weeks FU: RR=0.84, 95% CI: 0.65-1.07, K=3, n=1458 (favours interferon)
PRISMS 1998 IFNb-1a (22 µg)
PRISMS 1998 IFNb-1a (44 µg)
Multiple Sclerosis International Federation December 2018
36
Vollmer 2014 IFNb-1a (30 µg)
Mortality NR
Risk of Cancer NR
Risk of Infection NR
Glatiramer Acetate
Moderate efficacy
Injection
Versus placebo
Discontinuation due to side effects 96-104 weeks FU: RR=2.63, 95% CI: 1.17-5.90, K=2, n=1655 (favours placebo)
Johnson 1995 (Glatiramer acetate 20mg qd)
Fox 2012 (Glatiramer acetate 20mg qd)
Discontinuation for any reason 96-104 weeks FU: RR=0.86, 95% CI: 0.88-1.11, K=2, n=974 (favours glatiramer acetate)
Johnson 1995 (Glatiramer acetate 20mg qd)
Fox 2012 (Glatiramer acetate 20mg qd)
Mortality NR
Risk of Cancer NR
Risk of Infection NR
Dimethyl Fumarate
Moderate efficacy
Oral
Versus placebo
Discontinuation due to side effects 104 weeks FU: RR=0.97, 95% CI: 0.78-1.21, K=2, n=1546, non-significant
Fox 2012 (Dimth Fum 240mg; bid)
Gold 2012 (Dimth Fum 240mg; bid)
Discontinuation for any reason 104 weeks FU: RR=0.97, 95% CI: 0.80-1.16, K=2, n=1546, non-significant
Multiple Sclerosis International Federation December 2018
37
Fox 2012 (Dimth Fum 240mg; bid)
Gold 2012 (Dimth Fum 240mg; bid)
Mortality RR=1, 95% CI: 1-1, K=2, n=1546, non-significant
Fox 2012 (Dimth Fum 240mg; bid)
Gold 2012 (Dimth Fum 240mg; bid)
Risk of Cancer RR=1 95% CI: 0.99-1.01, K=1, n=818, non-significant
Gold 2012 (Dimth Fum 240mg; bid)
Risk of Infection RR=1.16, 95% CI:0.88-1.51, K=1, n=722, non-significant
Fox 2012 (Dimth Fum 240mg; bid)
Oral Cladribine
Moderate efficacy
Oral
Versus placebo
Discontinuation due to side effects 96 weeks FU: RR=1.13, 95% CI: 0.43-2.94, K=2, n=1327, non-significant
Giovannoni 2010 (Cladribine 3.5mg/kg)
Giovannoni 2010 (Cladribine 5.25mg/kg)
Discontinuation for any reason 96 weeks FU: RR=0.72, 95% CI: 0.53-0.99, K=2, n=1327, favours cladribine
Giovannoni 2010 (Cladribine 3.5mg/kg)
Giovannoni 2010 (Cladribine 5.25mg/kg)
Mortality NR
Risk of Cancer Risk Difference: 0.01, 95% CI: 0.00-0.02, K=2, n=1320, non-significant
Giovannoni 2010 (Cladribine 3.5mg/kg)
Multiple Sclerosis International Federation December 2018
38
Giovannoni 2010 (Cladribine 5.25mg/kg)
Risk of Infection RR= 1.41, 95% CI: 0.64-3.13, K=2, n=1320, non-significant
Giovannoni 2010 (Cladribine 3.5mg/kg)
Giovannoni 2010 (Cladribine 5.25mg/kg)
Teriflunomide
Moderate efficacy
Oral
Versus placebo
Discontinuation due to side effects 108 weeks FU: RR=1.33, 95% CI: 1.33, 95% CI: 0.84-2.11, K=1, n=721, non-significant
O'Conner 2011 (Teriflu 14mg)
Discontinuation for any reason 48-108 weeks FU: RR=1, 95% CI: 0.86-1.16, K=2, n=1482, non-significant
Confavreux 2014 (Teriflu 14mg)
O'Conner 2011 (Teriflu 14mg)
Mortality RR=1, 95% CI: 0.99-1.01, K=1, n=761, non-significant
Confavreux 2014 (Teriflu 14mg)
Risk of Cancer RR=1, 95% CI: 0.99-1.01, K=2, n=1482, non-significant
Confavreux 2014 (Teriflu 14mg)
O'Conner 2011 (Teriflu 14mg)
Risk of Infection RR=0.85, 95% CI: 0.75-0.98, K=2, n=1482, (favours teriflunomide)
Confavreux 2014 (Teriflu 14mg)
O'Conner 2011 (Teriflu 14mg)
Multiple Sclerosis International Federation December 2018
39
Fingolimod
High efficacy
Oral
Versus placebo
Discontinuation due to side effects 104 weeks FU: RR=1.42, 95% CI: 0.92-2.17, K=2, n=1556, non-significant
Calabresi 2014b (Fingolimod 0.5mg)
Kappos 2010 (Fingolimod 0.5mg)
Discontinuation for any reason 104 weeks FU: RR=0.75 95% CI: 0.57-0.99, K=2, n=1556 (favours fingolimod)
Calabresi 2014b (Fingolimod 0.5mg)
Kappos 2010 (Fingolimod 0.5mg)
Mortality NR
Risk of Cancer RR=0.84, 95% CI: 0.21-3.34, K=2, n=1556, non-significant
Calabresi 2014b (Fingolimod 0.5mg)
Kappos 2010 (Fingolimod 0.5mg)
Risk of Infection RR=1.04, 95% CI: 0.99, 1.09, K=2, n=1556, non-significant
Calabresi 2014b (Fingolimod 0.5mg)
Kappos 2010 (Fingolimod 0.5mg)
Ocrelizumab
High efficacy
Infusion
Versus Interferon
Discontinuation due to side effects NR
Discontinuation for any reason RR=0.60, 95% CI: 0.48-0.75, K=2, n=1656 (favours ocrelizumab)
OPERA I 2016
OPERA II 2016
Mortality RR=1, 95% CI: 1.00-1.01, K=1, n=1651, non-significant
Multiple Sclerosis International Federation December 2018
40
OPERA I & II 2016 (combined)
Risk of Cancer NR
Risk of Infection RR=1.11, 95% CI: 1.02-1.22, K=1, n=1651, (favours interferon)
OPERA I & II 2016 (combined)
Natalizumab
High efficacy
Infusion
Versus placebo
Discontinuation due to side effects 104 weeks FU: RR=1.26, 95% CI: 0.49-3.21, K=1, n=942, non-significant
Polman 2006 (Natalizumab 300mg q4w)
Discontinuation for any reason 104 weeks FU: RR=0.84, 95% CI: 0.55-1.29, K=1, n=942, non-significant
Polman 2006 (Natalizumab 300mg q4w)
Mortality RR=1, 95% CI: 0.99-1.00, K=1, n=942, non-significant
Polman 2006 (Natalizumab 300mg q4w)
Risk of Cancer RR= 1, 95% CI: 0.99-1.00, K=1, n=942, non-significant
Polman 2006 (Natalizumab 300mg q4w)
Risk of Infection RR=1.23, 95% CI: 1.13-1.34, K=1, n=942, favours placebo
Polman 2006 (Natalizumab 300mg q4w)
Note: NR=not recorded
Multiple Sclerosis International Federation December 2018
41
11. Summary of available data on comparative cost and cost-effectiveness of the medicine
A significant number of cost-effectiveness studies have been undertaken on disease modifying therapies in MS. These have been the subject of a
number of systematic reviews (106–109). The number of studies reviewed in these reviews varied from 23 to 51; in all cases these studies were
confined to high income countries principally in Europe and North America. The studies reported that DMTs (including those drugs covered in
this review) were potentially cost-effective but several studies reported costs which were likely to be above particular countries’ willingness to
pay thresholds. Limitations of these studies noted in these reviews included the lack of head-to-head comparisons between different DMTs,
variation in time-horizons, and variation in end-points. There were no cost-effectiveness studies identified from low or middle-income countries
and therefore no studies which were directly relevant for this review.
Table 9 - Summary of available data on approximate comparative annual cost within the pharmacological class (USD*) 2017/2018.
Agent
(Brand name only)
United States Canada Argentina Russia Iran Brazil India Norway
Glatiramer acetate
(20mg/40mg)
$86,554/$75,816 $12,360 $46,344
(40mg)
$4,222/$4,630 $3,600** $18,324
(40mg)
$5,051** $10,900/$12,150
Fingolimod $86,966 $23,585 $47,976 $17,024 $9,600 $29,280 Not
available
$ 28,900
Ocrelizumab $65,000 $24,809 Not
available
$11,803-
14981
$32,000*** Data not
available
Not
available
Not available
Rituximab $19,786 $15,000 $10,800 $1,000 -
$3,000
$7,500 $7,000 -
$8,400
$2,260 $3,100
* exchanged to USD
** generic glatiramer available only
***ocrelizumab not available in Iran, patients obtain ocrelizumab from Dubai
Rituximab is already listed on the WHO EML and part of WHO’s prequalification pilot project on biotherapeutics (110).
Multiple Sclerosis International Federation December 2018
42
12. Summary of regulatory status and market availability of the medicine
Table 10 - Summary of regulatory status for glatiramer acetate, fingolimod and ocrelizumab
Agent United States (FDA) Health Canada EMA Australia Russian Federation
Glatiramer
acetate
Approved branded glatiramer
acetate 20mg as monotherapy
for the treatment of patients
with relapsing forms of MS in in
1996; approved branded
glatiramer acetate 20mg as
monotherapy for clinically
isolated syndrome in 2009;
approved branded glatiramer
acetate 40mg as monotherapy
for relapsing forms of MS in
2014
Approved generic formulations
of glatiramer acetate 20mg and
40mg as monotherapy for
treatment of relapsing forms of
MS between 2015 and 2018.
Approved branded glatiramer
acetate 20mg as monotherapy
for the treatment of patients
with relapsing-remitting MS in
1997; approved branded
glatiramer acetate 20mg as
monotherapy for clinically
isolated syndrome in 2009;
approved branded glatiramer
acetate 40mg as monotherapy
for relapsing remitting MS in
2016
Approved non-biological
complex drug glatiramer
acetate 20mg for relapsing
remitting MS including clinically
isolated syndrome in 2017
Approved branded
glatiramer acetate 20mg as
monotherapy for relapsing
forms of MS including
clinically isolated syndrome
in 2001
Approved branded
glatiramer acetate 40mg as
monotherapy for relapsing
forms of MS in 2015
Approved generic
glatiramer acetate 20mg
and 40mg as monotherapy
for relapsing forms of MS in
2016 and 2017 respectively.
Approved branded glatiramer
acetate 20mg as monotherapy
for relapsing remitting MS
including clinically isolated
syndrome in 2003
Approved branded glatiramer
acetate 40mg for relapsing
remitting MS including clinically
isolated syndrome in 2014
Approved branded glatiramer
acetate 20mg as
monotherapy for relapsing
forms of MS in 1997
Approved branded glatiramer
acetate 40mg as
monotherapy for relapsing
forms of MS in 2015
Approved several generic
forms of glatiramer acetate
20mg as monotherapy for
relapsing forms of MS in
2015-2018.
Multiple Sclerosis International Federation December 2018
43
Fingolimod Approved as monotherapy for
the treatment of patients with
relapsing forms of MS in 2010
Approved as monotherapy in
patients with relapsing MS ages
10 years and older in 2018
Approved as monotherapy for
the treatment of patients with
relapsing-remitting MS in 2011
-generally recommended in MS
patients who have had an
inadequate response to, or are
unable to tolerate, one or more
therapies for multiple sclerosis
Approved as monotherapy
for the treatment of
patients with highly active
relapsing-remitting MS who
have already undergone
treatment with beta
interferon, or have a rapidly
evolving severe form of the
condition in 2011
Approved as monotherapy for
the treatment of patients with
relapsing remitting MS and
secondary progressive MS with
superimposed
relapses to delay the
progression of physical
disability and reduce
the frequency of relapse in
2011
Approved as monotherapy for
the treatment of patients
with highly active relapsing-
remitting MS who have
already undergone treatment
with beta interferon or
glatiramer acetate, or have a
rapidly evolving severe form
of the condition in 2010
Ocrelizumab Approved as monotherapy for
the treatment of patients with
relapsing or primary
progressive forms of MS in
2017
Approved as monotherapy for
the treatment of patients with
relapsing remitting MS with
active disease in 2017
Conditionally* approved for
adult patients with early
primary progressive MS in 2017
Approved as monotherapy
for the treatment of
patients with active
relapsing forms of MS and
for patients with early
primary progressive forms
of MS in 2018
Approved as monotherapy for
the treatment of patients with
relapsing forms of MS; and
treatment of patients with
primary progressive MS in 2017
Approved as monotherapy for
the treatment of patients
with relapsing forms of MS
and for patients with primary
progressive forms of MS in
2017
Rituximab Not officially approved for treatment of MS – used off-label for relapsing forms of MS. Rituximab is part of WHO’s prequalification pilot project on biotherapeutics
(110)
13. Availability of pharmacopoeial standards (British Pharmacopoeia, European Pharmacopeia, United Stated Pharmacopoeia)
Pharmacopoeial standards Glatiramer Acetate Fingolimod Ocrelizumab
British Pharmacopoeia Yes Yes Yes
European Pharmacopoeia Yes Yes Yes
United States Pharmacopoeia Yes Yes Yes
Multiple Sclerosis International Federation December 2018
44
14. References 1. Report of the WHO Expert Committee, 2015, (including the 19th WHO Model List of Essential Medicines, and the 5th WHO Model List of
Essential Medicines for Children). WHO Technical Report Series 994: The Selection and Use of Essential Medicines [Internet]. Geneva, Switzerland: World Health Organisation; 2015 [cited 2018 Nov 23]. Available from: http://apps.who.int/medicinedocs/documents/s22190en/s22190en.pdf
2. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, et al. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler J. 2018 Feb 1;24(2):96–120.
3. Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Apr 24;90(17):777–88.
4. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72 Suppl 1:1–5.
5. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain J Neurol. 2009 May;132(Pt 5):1175–89.
6. Zhang T, Tremlett H, Zhu F, Kingwell E, Fisk JD, Bhan V, et al. Effects of physical comorbidities on disability progression in multiple sclerosis. Neurology. 2018 Jan 30;90(5):e419–27.
7. Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269–90.
8. A Consensus Paper by the MS Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence [Internet]. 2014 [cited 2018 Nov 28]. Available from: http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color
9. Hauser S.L., Brochet B., Montalban X., Naismith R.T., Wolinsky J.S., , M. Manfrini, et al. Long-term reduction of relapse rate and confirmed disability progression after 5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis [Internet]. ECTRIMS Online Library; Hauser S. Oct 10 2018; 228434; Vol. Poster 590. 2018 [cited 2018 Dec 4]. Available from: http://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/228434/stephen.l.hauser.long-term.reduction.of.relapse.rate.and.confirmed.disability.html
10. Hauser S.L., Kappos L., Montalban X., Hughes R., Koendgen H., McNamara J., et al. Safety of ocrelizumab in multiple sclerosis: updated analysis in patients with relapsing and primary progressive multiple sclerosis [Internet]. ECTRIMS Online Library; Hauser S. Oct 12 2018;
Multiple Sclerosis International Federation December 2018
45
229069; Vol. Poster 1229. 2018 [cited 2018 Dec 4]. Available from: http://onlinelibrary.ectrims-congress.eu/ectrims/2018/ectrims-2018/229069/stephen.l.hauser.safety.of.ocrelizumab.in.multiple.sclerosis.updated.analysis.html
11. Salzer J, Svenningsson R, Alping P, Novakova L, Björck A, Fink K, et al. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology. 2016 Nov 15;87(20):2074–81.
12. He D, Guo R, Zhang F, Zhang C, Dong S, Zhou H. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2013 Dec 6;(12):CD009130.
13. Salzer J, Lycke J, Wickström R, Naver H, Piehl F, Svenningsson A. Rituximab in paediatric onset multiple sclerosis: a case series. J Neurol. 2016 Feb;263(2):322–6.
14. Drugs@FDA: FDA Approved Drug Products [Internet]. [cited 2018 Nov 27]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
15. Glatiramer acetate: view uses, side effects and medicines | 1mg [Internet]. [cited 2018 Nov 27]. Available from: https://www.1mg.com/generics/glatiramer-acetate-212501
16. Generics and Biosimilars initiative. http://www.gabionline.net/Biosimilars/General/Biosimilars-of-rituximab [Internet]. 2015. Available from: http://www.gabionline.net/Biosimilars/General/Biosimilars-of-rituximab
17. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–31.
18. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162–73.
19. Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler Houndmills Basingstoke Engl. 2008 Nov;14(9):1157–74.
20. Ghezzi A, Banwell B, Boyko A, Amato MP, Anlar B, Blinkenberg M, et al. The management of multiple sclerosis in children: a European view. Mult Scler Houndmills Basingstoke Engl. 2010 Oct;16(10):1258–67.
21. Chitnis T, Tenembaum S, Banwell B, Krupp L, Pohl D, Rostasy K, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2012 Jan;18(1):116–27.
Multiple Sclerosis International Federation December 2018
46
22. Sandberg-Wollheim M, Neudorfer O, Grinspan A, Weinstock-Guttman B, Haas J, Izquierdo G, et al. Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database. Int J MS Care. 2018 Feb;20(1):9–14.
23. Chitnis T, Arnold DL, Banwell BL, Brück W, Ghezzi A, Giovannoni G, et al. PARADIGMS: a randomised double-blind study of fingolimod versus interferon β-1a in paediatric multiple sclerosis. Mult Scler J. 2017 Oct 1;23(3_suppl):977–8.
24. Chitnis T, Arnold DL, Banwell B, Brück W, Ghezzi A, Giovannoni G, et al. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018 Sep 13;379(11):1017–27.
25. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung H-P, Hemmer B, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 19;376(3):221–34.
26. Clerico M, Artusi CA, Di Liberto A, Rolla S, Bardina V, Barbero P, et al. Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017 Aug;16(8):963–72.
27. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870–80.
28. Yukitake M. Drug-induced progressive multifocal leukoencephalopathy in multiple sclerosis: A comprehensive review. Clin Exp Neuroimmunol. 9(S1):37–47.
29. Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD007621.
30. Tice JA, Chapman R, Kumar V, Loos AM, Liu S, Seidner M, et al. Institute for Clinical and Economic Review, 2016 Draft Evidence Report: DMTs for RRMS and PPMS. 2016;197.
31. Berger JR, Cree BA, Greenberg B, Hemmer B, Ward BJ, Dong VM, et al. Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology. 2018 May 15;90(20):e1815–21.
32. Genentech. Ocrelizumab & PML - Progressive Multifocal Leukoencephalopathy. 2018;1.
33. American Academy of Neurology. AAN Guideline Stopping: Recommendation 1 and 2 [Internet]. 2018 [cited 2018 Nov 27]. Available from: https://www.aan.com/Guidelines/home/GetGuidelineContent/900
Multiple Sclerosis International Federation December 2018
47
34. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014 Sep 9;83(11):1022–4.
35. Multiple Sclerosis International Federation. Atlas of MS - Mapping Multiple Sclerosis Around the World [Internet]. 2013 [cited 2018 Nov 23]. Available from: http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf
36. Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology. 2010 Feb 9;74(6):465–71.
37. Mackenzie IS, Morant SV, Bloomfield GA, MacDonald TM, O’Riordan J. Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database. J Neurol Neurosurg Psychiatry. 2014 Jan;85(1):76–84.
38. Benito-León J. Multiple Sclerosis: Is Prevalence Rising and if So Why? Neuroepidemiology. 2011 Dec;37(3–4):236–7.
39. Amankwah N, Marrie RA, Bancej C, Garner R, Manuel DG, Wall R, et al. Multiple sclerosis in Canada 2011 to 2031: results of a microsimulation modelling study of epidemiological and economic impacts. Health Promot Chronic Dis Prev Can Res Policy Pract. 2017 Feb;37(2):37–48.
40. Sahraian MA, Sahebkar M, Dehghani R, Derakhshan-Jazari M, Kazami-Moghaddam V, Kouchaki E. Multiple sclerosis-A disease on a dramatically rising trend in Iran: Review of possible reasons. Iran J Neurol. 2017 Jan 5;16(1):34–40.
41. Chinea A, Ríos-Bedoya CF, Vicente I, Rubí C, García G, Rivera A, et al. Increasing Incidence and Prevalence of Multiple Sclerosis in Puerto Rico (2013-2016). Neuroepidemiology. 2017;49(3–4):106–12.
42. Brola W, Sobolewski P, Flaga S, Fudala M, Jantarski K. Increasing prevalence and incidence of multiple sclerosis in Poland. Neurol Neurochir Pol. 2017 Feb;51(1):82–5.
43. Bezzini D, Policardo L, Profili F, Meucci G, Ulivelli M, Bartalini S, et al. Multiple sclerosis incidence in Tuscany from administrative data. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2018 Nov;39(11):1881–5.
44. Ascherio A, Munger KL. Epidemiology of Multiple Sclerosis: From Risk Factors to Prevention-An Update. Semin Neurol. 2016;36(2):103–14.
45. Koffman J, Gao W, Goddard C, Burman R, Jackson D, Shaw P, et al. Progression, symptoms and psychosocial concerns among those severely affected by multiple sclerosis: a mixed-methods cross-sectional study of Black Caribbean and White British people. PloS One. 2013;8(10):e75431.
Multiple Sclerosis International Federation December 2018
48
46. Piccolo L, Kumar G, Nakashima I, Misu T, Kong Y, Wakerley B, et al. Multiple sclerosis in Japan appears to be a milder disease compared to the UK. J Neurol. 2015;262(4):831–6.
47. Chitnis T. Disease-modifying therapy of pediatric multiple sclerosis. Neurother J Am Soc Exp Neurother. 2013 Jan;10(1):89–96.
48. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014 Sep;13(9):936–48.
49. Feinstein A, Magalhaes S, Richard J-F, Audet B, Moore C. The link between multiple sclerosis and depression. Nat Rev Neurol. 2014 Sep;10(9):507–17.
50. Berrigan LI, Fisk JD, Patten SB, Tremlett H, Wolfson C, Warren S, et al. Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. Neurology. 2016 Apr 12;86(15):1417–24.
51. Marrie RA, Fisk JD, Tremlett H, Wolfson C, Warren S, Tennakoon A, et al. Differences in the burden of psychiatric comorbidity in MS vs the general population. Neurology. 2015 Dec 1;85(22):1972–9.
52. Pompili M, Forte A, Palermo M, Stefani H, Lamis DA, Serafini G, et al. Suicide risk in multiple sclerosis: a systematic review of current literature. J Psychosom Res. 2012 Dec;73(6):411–7.
53. Dobrescu A, Dinh T, Stonebridge C. Multiple Sclerosis in the Workplace: Making the Case for Enhancing Employment and Income Supports. The Conference Board of Canada. 2018;44.
54. Dinh T. Multiple Sclerosis in the Workplace: Supporting Successful Employment Experiences. The Conference Board of Canada. 2016;94.
55. Ernstsson O, Gyllensten H, Alexanderson K, Tinghög P, Friberg E, Norlund A. Cost of Illness of Multiple Sclerosis - A Systematic Review. PloS One. 2016;11(7):e0159129.
56. United Nations. Convention on the Rights of Persons with Disabilities [Internet]. United Nations; 2008 [cited 2018 Nov 28]. Available from: http://www.un.org/disabilities/documents/convention/convoptprot-e.pdf
57. Giovannoni G, Butzkueven H, Dhib-Jalbut S, Hobart J, Kobelt G, Pepper G, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5–48.
58. Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J, MSCOI Study Group, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler Houndmills Basingstoke Engl. 2017 Jul;23(8):1123–36.
Multiple Sclerosis International Federation December 2018
49
59. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995 Jul;45(7):1268–76.
60. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet Lond Engl. 1998 Nov 7;352(9139):1498–504.
61. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996 Mar;39(3):285–94.
62. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993 Apr;43(4):655–61.
63. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J, et al. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 Jul;13(7):657–65.
64. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098–107.
65. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1087–97.
66. Kappos L, Radue E-W, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):387–401.
67. Calabresi PA, Radue E-W, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545–56.
68. Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):402–15.
69. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293–303.
Multiple Sclerosis International Federation December 2018
50
70. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247–56.
71. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):416–26.
72. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet Lond Engl. 2012 Nov 24;380(9856):1819–28.
73. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet Lond Engl. 2012 Nov 24;380(9856):1829–39.
74. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar 2;354(9):899–910.
75. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 19;376(3):209–20.
76. Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008 Oct;7(10):903–14.
77. Higgins JP, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions - version 2005 [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 20015 [cited 2018 Nov 30]. Available from: http://doi.wiley.com/10.1002/9780470712184
78. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924–6.
79. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013 Jun;73(6):705–13.
80. Cadavid D, Wolansky LJ, Skurnick J, Lincoln J, Cheriyan J, Szczepanowski K, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009 Jun 9;72(23):1976–83.
Multiple Sclerosis International Federation December 2018
51
81. Calabrese M, Bernardi V, Atzori M, Mattisi I, Favaretto A, Rinaldi F, et al. Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Mult Scler Houndmills Basingstoke Engl. 2012 Apr;18(4):418–24.
82. O’Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009 Oct;8(10):889–97.
83. Wolinsky JS, Narayana PA, O’Connor P, Coyle PK, Ford C, Johnson K, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007 Jan;61(1):14–24.
84. Lublin F, Miller DH, Freedman MS, Cree BAC, Wolinsky JS, Weiner H, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2016 Mar 12;387(10023):1075–84.
85. Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet Lond Engl. 2011 Nov 19;378(9805):1779–87.
86. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb 14;358(7):676–88.
87. Bar-Or A, Calabresi PAJ, Arnold D, Arnlod D, Markowitz C, Shafer S, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol. 2008 Mar;63(3):395–400.
88. Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009 Oct;66(4):460–71.
89. Granqvist M, Boremalm M, Poorghobad A, Svenningsson A, Salzer J, Frisell T, et al. Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis. JAMA Neurol. 2018 Mar 1;75(3):320–7.
90. Alping P, Frisell T, Novakova L, Islam-Jakobsson P, Salzer J, Björck A, et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016 Jun;79(6):950–8.
91. Boster AL, Ford CC, Neudorfer O, Gilgun-Sherki Y. Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2015 Jun;15(6):575–86.
92. Teva to Present New Data Across Multiple Therapeutic Areas at 70th Annual Meeting of the American Academy of Neurology [Internet]. [cited 2018 Nov 23]. Available from:
Multiple Sclerosis International Federation December 2018
52
https://www.tevapharm.com/news/teva_to_present_new_data_across_multiple_therapeutic_areas_at_70th_annual_meeting_of_the_american_academy_of_neurology_04_18.aspx
93. Novartis announces FDA approval of Gilenya® as the first disease-modifying therapy for pediatric relapsing multiple sclerosis [Internet]. Novartis. [cited 2018 Nov 23]. Available from: https://www.novartis.com/news/media-releases/novartis-announces-fda-approval-gilenyar-first-disease-modifying-therapy-pediatric-relapsing-multiple-sclerosis
94. Genentech: Press Releases | Monday, Oct 1, 2018 [Internet]. [cited 2018 Nov 23]. Available from: https://www.gene.com/media/press-releases/14748/2018-10-01/genentech-to-present-five-year-ocrevus-o
95. About the eMC - electronic Medicines Compendium (eMC) [Internet]. [cited 2018 Nov 28]. Available from: https://www.medicines.org.uk/emc/about-the-emc
96. Copaxone 20mg/ml, Solution For Injection, Pre-Filled Syringe - Summary of Product Characteristics (SmPC) - (eMC) [Internet]. [cited 2018 Nov 27]. Available from: https://www.medicines.org.uk/emc/product/183/smpc
97. Copaxone® (glatiramer acetate) [prescribing information]. [Internet]. Overland Park, KS: Teva Neuroscience, Inc.; 2018 [cited 2018 Nov 23]. Available from: https://www.copaxone.com/resources/pdfs/prescribinginformation.pdf
98. GILENYA® (fingolimod) [prescribing information]. [Internet]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018 [cited 2018 Nov 23]. Available from: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/gilenya.pdf
99. GILENYA (fingolimod) [prescribing information] [Internet]. [cited 2018 Dec 4]. Available from: https://medsafe.govt.nz/profs/Datasheet/g/gilenyacap.pdf
100. OcrevusTM (ocrelizumab) [prescribing information] [Internet]. South San Francisco, CA: Genentech, Inc; 2018 [cited 2018 Nov 23]. Available from: https://www.gene.com/download/pdf/ocrevus_prescribing.pdf
101. Teva Receives Positive Outcome for COPAXONE® Label in Europe [Internet]. 2016 [cited 2018 Nov 23]. Available from: https://www.businesswire.com/news/home/20161205005399/en/Teva-Receives-Positive-Outcome-COPAXONE%C2%AE-Label-Europe
102. Alroughani R, Altintas A, Al Jumah M, Sahraian M, Alsharoqi I, AlTahan A, et al. Pregnancy and the Use of Disease-Modifying Therapies in Patients with Multiple Sclerosis: Benefits versus Risks. Mult Scler Int. 2016;2016:1034912.
103. Roche Canada: Product Monograph including patient medication information OCREVUSTM [Internet]. Mississauga, Ontario: Hoffmann-La Roche Limited; 2018 [cited 2018 Nov 23]. Available from:
Multiple Sclerosis International Federation December 2018
53
http://www.rochecanada.com/content/dam/roche_canada/en_CA/documents/Research/ClinicalTrialsForms/Products/ConsumerInformation/MonographsandPublicAdvisories/Ocrevus/OCREVUS_PM_E.pdf
104. Ghezzi A, Amato MP, Makhani N, Shreiner T, Gärtner J, Tenembaum S. Pediatric multiple sclerosis: Conventional first-line treatment and general management. Neurology. 2016 Aug 30;87(9 Suppl 2):S97–102.
105. Rostásy K, Bajer-Kornek B. Paediatric multiple sclerosis and other acute demyelinating diseases. Curr Opin Neurol. 2018 Jun;31(3):244–8.
106. Sharac J, McCrone P, Sabes-Figuera R. Pharmacoeconomic considerations in the treatment of multiple sclerosis. Drugs. 2010 Sep 10;70(13):1677–91.
107. Hawton A, Shearer J, Goodwin E, Green C. Squinting through layers of fog: assessing the cost effectiveness of treatments for multiple sclerosis. Appl Health Econ Health Policy. 2013 Aug;11(4):331–41.
108. Thompson JP, Abdolahi A, Noyes K. Modelling the cost effectiveness of disease-modifying treatments for multiple sclerosis: issues to consider. PharmacoEconomics. 2013 Jun;31(6):455–69.
109. Hernandez L, O’Donnell M, Postma M. Modeling Approaches in Cost-Effectiveness Analysis of Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: An Updated Systematic Review and Recommendations for Future Economic Evaluations. PharmacoEconomics. 2018 Oct;36(10):1223–52.
110. WHO | Pilot Procedure for Prequalification of Biotherapeutic Products and Similar Biotherapeutic Products [Internet]. WHO. [cited 2018 Nov 26]. Available from: http://www.who.int/medicines/regulation/biotherapeutic_products/en/