msif who eml application multiple sclerosis …multiple sclerosis international federation december...

Multiple Sclerosis International Federation December 2018

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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).

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


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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.


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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

Teriflunomide (Aubagio®) 2012

Interferon beta 1a (Plegridty®) 2014

Alemtuzumab (Lemtrada®) 2014

Glatiramer acetate (Glatopa®) 2015

Ocrelizumab (Ocrevus®) 2017


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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, 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


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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 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


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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. Relevant WHO technical department and focal point

- WHO Secretariat of the Selection and Use of Essential Medicines

- WHO Department of Mental Health and Substance Abuse

- WHO Gender, Equity and Human Rights

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) and Anatomical Therapeutic Chemical (ATC) code of the medicine


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INN: glatiramer acetate [Copaxone®], ATC: L03AX13

INN: fingolimod [Gilenya®], ATC: L04AA27

INN: ocrelizumab [Ocrevus®], ATC: L04AA36

5. Dose forms(s) and strength(s) proposed for inclusion; including adult and age-appropriate

paediatric dose forms/strengths (if appropriate)

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).


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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 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.


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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 representative of a pharmacological

class

■ 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 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,


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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).


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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

- Sjogren’s

Syndrome

- CNS lupus

- Sarcoidosis

- Behçet’s disease

- CNS vasculitis

- 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

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.


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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).

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,


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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 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


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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).”


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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


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Ocrelizumab Indication: Relapsing forms of MS Primary progressive 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 manage severe reactions such as serious infusion reactions.

Hepatitis B screening Administration of all immunizations at least 6 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 min prior to each infusion with IV methylprednisolone 100 mg 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


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8. Information supporting the public health relevance

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.

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


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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).

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.


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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 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)

No MRI outcomes in the

Phase 3 trial

No MRI outcomes in the Phase 3 trial

Interferon beta-1a subcutaneous Study: Interferon beta 1a SC (44mcg or 22 mcg) three times weekly or placebo. N=560

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

Disability - secondary Time to sustained progression (defined as an increase in EDSS of at least 1 point sustained over

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)


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Primary endpoint – mean number of relapses at 2 years

Lancet 1998;352:1498-1504 (60)

placebo was 27% (95% CI 14–39%)

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)

Interferon beta-1a intramuscular Study: Interferon beta-1a intramuscularly 30 mcg or placebo N=301 Primary outcome- time to sustained progression of disability Annals of Neurology 1996;39(3):285-294 (61)

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 progression of disability by 104 weeks estimated from Kaplan- Meier curves was 34.9% in placebo recipients and 21.9% in interferon beta-la recipients (p=0.02)

MRI outcomes - secondary 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)

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

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.


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(placebo vs 8 MIU p=0.161)

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). (63)

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)

Dimethyl fumarate (DMF Phase III Studies: Study 1 24-month DMF 240 mg twice

Relapses - Primary Study 1: 49% reduction in proportion relapsing

Disability - secondary Study 1: 38% decrease in risk of disability

MRI outcomes - secondary Study 1: mean number Gd+ lesions at two years:

MRI outcomes - secondary Study 1: mean number new or enlarging T2 lesions at two years: 17


3

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)

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

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)

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)

(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 mg or 1.25 mg daily or placebo. N=1272 Primary endpoint- Annualized relapse rate

Relapses - primary Study 1: 54% reduction in annualized relapse rate 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

Disability - secondary Study 1: Probability of disability progression 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.

MRI outcomes - secondary Study 1: mean number T1 Gd+ lesions at month 24: 0.2 (SD: 1.1) placebo; 0.2 (SD: 0.8) 0.5mg dose (p<0.001)

MRI outcomes - secondary Study 1: mean # new or newly enlarging T2 lesions over 24 months: 9.8 (SD: 13.2) placebo; 2.5 (SD:7.2) 0.5mg dose (p<0.001)


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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) Study 4: 2 year oral fingolimod 0.5 mg/day(0.25 mg/day for patients ≤ 40 kg) or interferon beta-1a 30 mcg/week intramuscularly in patients 10-17 years of age

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) Study 4: annualized relapse rate: 0.67 (CI:0.52-0.89) IFN; 0.12 (CI: 0.08-0.19) fingolimod. Between group difference 0.55 (CI:0.36-0.74)(p<0.001)

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) Study 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) Study 4: disability was a post-hoc analysis

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) Study 4: adjusted mean number Gd+ lesions: 1.28 (CI: 0.93-1.76) IFN; 0.44 (CI: 0.31-0.61) fingolimod

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) Study 4: annualized rate or new or newly enlarged T2 lesions 9.27 (CI:7.66-11.21) IFN; 4.39 (CI: 3.62-5.37) fingolimod. Between group difference: 4.88 (CI: 2.91-6.84) (p<0.001).


5

Primary endpoint: annualized relapse rate NEJM 2018;379(11):1017-27. (24)

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

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

Disability - Secondary Relative reduction in risk of 3-month sustained progression of disability 33% reduction

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


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Primary endpoint: Relapse rate at 96 weeks NEJM 2010;362(5)416-26 (71)

(p<.001); 0.15 (CI: 0.12-0.17) 5.25mg/kg (p<0.001)

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: 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)

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

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

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

MRI outcomes - secondary Study 1: patients with new or enlarging T2 lesions: 99/172 (58%) IFN; 176/363 (48%) alemtuzumab p=0.04


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Study 2: 2-year Ifn beta 1a three times weekly or alemtuzumab 12 mg/day or alemtuzumab 24 mg/day N=628. 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)

relapse rate over two years: 0.52 (95% CI:0.41-0.66) IFN; 0.26 (CI: 0.21-0.33) alemtuzumab

confirmed over six months: 21.13% (CI: 15.95-27.68) IFN; 12.71% (CI:9.89-16.27) alemtuzumab ) HR: 0.58 (0.38-0.87) (42% risk reduction -p=0.0084)

(23%) IFN; 38/410 (9%) alemtuzumab p<0.0001

Study 2: patients with new or enlarging T2 lesions: 127/187 (68%) IFN; 186/403 (46%) p<0.0001

Natalizumab Study: Natalizumab 300 mg IV infusion or placebo infusion every

Relapses - primary 1 year: 0.78 (CI:0.64-0.94) placebo; 0.27 (CI: 0.21-0.33) natalizumab

Disability - primary Cumulative probability of sustained progression at 2yrs: 29% placebo; 17%

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


8

4 weeks for 2 years N=942 Primary endpoints: relapse rate at 1 year and rate of sustained disability progression at 2 years. NEJM 2006;354(9):899-910. (74)

(p<0.001) 2 year: 0.73 (CI: 0.62-0.87) placebo; 0.23 (CI: 0.19-0.28) treated (p<0.001)

treated (HR=0.58, 95% CI: 0.43-0.77) (p<0.001)

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:

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


9

Percentage of patients with disability progression confirmed at 12 weeks in time-to-event analysis NEJM 2017;376:209-20 (75)

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)

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


10

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.


0

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).


0

Number of participants relapse free 52-104 weeks follow up

Annualized relapse rate 52-96 weeks follow up


0

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).


0

Number of participants relapse free: 104 weeks follow up

Annualized relapse rate: 104 weeks follow up


0

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).

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


1

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 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.


2

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).

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).

https://www.medicines.org.uk/emc/about-the-emc


0

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

-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

-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

-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)


1

- 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

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.

-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)

-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).


0

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).

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).


0

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)


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)



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)


1

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



Mortality RR=1, 95% CI: 1-1, K=2, n=1546, non-significant



Risk of Cancer RR=1 95% CI: 0.99-1.01, K=1, n=818, non-significant


Risk of Infection RR=1.16, 95% CI:0.88-1.51, K=1, n=722, non-significant



2

Oral Cladribine

Moderate efficacy

Oral

Versus placebo


Giovannoni 2010 (Cladribine 3.5mg/kg)


Discontinuation for any reason 96 weeks FU: RR=0.72, 95% CI: 0.53-0.99, K=2, n=1327, favours cladribine



Mortality NR

Risk of Cancer Risk Difference: 0.01, 95% CI: 0.00-0.02, K=2, n=1320, non-significant



Risk of Infection RR= 1.41, 95% CI: 0.64-3.13, K=2, n=1320, non-significant



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)



3

Mortality RR=1, 95% CI: 0.99-1.01, K=1, n=761, non-significant


Risk of Cancer RR=1, 95% CI: 0.99-1.01, K=2, n=1482, non-significant



Risk of Infection RR=0.85, 95% CI: 0.75-0.98, K=2, n=1482, (favours teriflunomide)



Fingolimod

High efficacy

Oral

Versus placebo


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)



Mortality NR

Risk of Cancer RR=0.84, 95% CI: 0.21-3.34, K=2, n=1556, non-significant



4


Risk of Infection RR=1.04, 95% CI: 0.99, 1.09, K=2, n=1556, non-significant



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


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


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



5



Risk of Cancer RR= 1, 95% CI: 0.99-1.00, K=1, n=942, non-significant


Risk of Infection RR=1.23, 95% CI: 1.13-1.34, K=1, n=942, favours placebo


Note: NR=not recorded


0

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.


0

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


0

Rituximab is already listed on the WHO EML and part of WHO’s prequalification pilot project on biotherapeutics (110).

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


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.



for the treatment of patients

with relapsing-remitting MS in

1997; approved branded


monotherapy for clinically

isolated syndrome in 2009;

approved branded glatiramer


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


monotherapy for relapsing

forms of MS including

clinically isolated syndrome

in 2001

Approved branded



forms of MS in 2015

Approved generic

glatiramer acetate 20mg

and 40mg as monotherapy

for relapsing forms of MS in

2016 and 2017 respectively.



for relapsing remitting MS

including clinically isolated

syndrome in 2003


acetate 40mg for relapsing

remitting MS including clinically

isolated syndrome in 2014


acetate 20mg as


forms of MS in 1997


acetate 40mg as


forms of MS in 2015

Approved several generic

forms of glatiramer acetate

20mg as monotherapy for

relapsing forms of MS in

2015-2018.


1

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


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



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


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


relapsing or primary

progressive forms of MS in

2017



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



relapsing forms of MS; and

treatment of patients with

primary progressive MS in 2017


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, International

Pharmacopeia)

Pharmacopoeial standards Glatiramer Acetate Fingolimod Ocrelizumab

British Pharmacopoeia Yes Yes Yes

European Pharmacopoeia Yes Yes Yes

United States Pharmacopoeia Yes Yes Yes

International Pharmacopeia No No No


0

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