GetReal - Project No

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1 GetReal - Project No WP1: Deliverable 1.5 (Case Study Review: Multiple Sclerosis) Lead Organisations: NICE, Novartis IMI GetReal Deliverable 1.5: Case Study on MS Disease and Treatment Overview 1 of 68

2 1 Executive summary A key objective of Work Package 1 of GetReal is to develop a framework for incorporating real world data (RWD) in decision-making. To this end, the Work Package is using case studies to explore how RWD could be used to help demonstrate relative effectiveness of new drugs. This report relates to a case study in multiple sclerosis (MS). MS was selected as a pilot case study for GetReal work package 1 because a number of MS medicines have received marketing authorisation and subsequently gone through Health Technology Assessment (HTA). The disease area is complex and the medicines have experienced challenges in both the regulatory and HTA processes. The report provides a summary of the disease and its treatment options. It also identifies sources of data relating to efficacy and effectiveness of MS treatments. Additionally, it summarises the observed challenges in establishing effectiveness of MS treatments, as documented in regulatory and HTA assessment documents. In this regard, publically available documents written in English for each medicine considered herein were identified by searching the websites of the European Medicines Agency (EMA) and several European HTA bodies including the Haute Autorite de Sante (HAS), the National Institute for Health and Care Excellence (NICE),the Scottish Medicines Consortium (SMC) and the Zoorginstitut Nederlands (ZIN). No proprietary information was included or used in the making of this document. The challenges and uncertainties relating to effectiveness of MS treatments described in this document were discussed by stakeholders during workshops in 2015, and potential realworld data solutions were identified and discussed. A summary of the workshop discussions is detailed in a separate document, IMI GetReal Deliverable D1.6: Multiple Sclerosis Case Study. IMI GetReal Deliverable 1.5: Case Study on MS Disease and Treatment Overview 2 of 68

3 Contents 1 Executive summary... 2 Contents Multiple sclerosis and its treatment options Epidemiology: Pathogenesis and Aetiology: Clinical Symptoms: Disease Subtypes: Natural History: Diagnosis: Treatment: Disease-Modifying Therapies (DMTs) Newer DMTs A review of efficacy and effectiveness data for disease-modifying MS treatments Pivotal randomised controlled trials (RCTs) Real-world data search strategy Description of identified sources of real-world data A review of challenges in demonstrating relative effectiveness of disease-modifying MS treatments in Europe Sections summarise the regulatory and HTA milestones for each medicine. The sections highlight the key challenges, as identified by the regulatory and HTA agencies themselves, in establishing relative effectiveness during their assessments. The publication dates of key real-world data studies (identified in the literature review described in Section 3) are indicated in graphical form to provide the reader with an indication of what RWD was available relative to the clinical development milestones of each medicine Natalizumab (Tysabri; Biogen Idec) Fingolimod (Gilenya; Novartis): Teriflunomide (Aubagio; Sanofi-aventis) Interferon betas (Avonex Biogen Idec; Betaferon Bayer; Extavia Novartis; Rebif Merck Serono): Glatiramer acetate (Copaxone; Teva): Overall Conclusions: Relative effectiveness challenges for disease-modifying MS therapies in Europe Population: uncertainty in subgroup analyses Comparators: uncertainty in indirect analyses and comparator selection Endpoints: long-term extrapolation of short-term data Natural history modelling using existing disability measures References Appendix A: Pivotal randomised controlled trials for disease-modifying MS treatments Appendix B: Sources of real-world data for disease-modifying MS therapies Appendix C: A summary of the literature search undertaken in the preparation of this report IMI GetReal Deliverable 1.5: Case Study on MS Disease and Treatment Overview 3 of 68

4 2 Multiple sclerosis and its treatment options Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disorder of the central nervous system (CNS) that can manifest as debilitating physical and cognitive impairment resulting from myelin degradation and axonal degeneration in patients (1). Clinical symptoms often manifest early in life ranking MS as one of the most common causes of neurological disability in young adults and a serious public health concern in European populations where prevalence is highest (2). 2.1 Epidemiology: The World Health Organization (WHO) estimates the global prevalence of MS to be 30 per 100,000 people, with an annual incidence rate of about 2.5 per 100,000 individuals worldwide (2). The highest rates are reported in higher income countries, particularly in Europe (prevalence: 80 per 100,000; incidence 3.8 per 100,000), while the lowest global regional estimates are found in Africa (prevalence: 0.3 per 100,000; incidence 0.1 per 100,000). Aside from regional differences in disease rates, MS also exhibits a global gender disparity with about 2 women having the disease for every 1 man (2). Recent evidence also suggests that female incidence is increasing (3). 2.2 Pathogenesis and Aetiology: Pathology in MS patients results from an autoimmune inflammatory response characterised by the activation of myelin-reactive T cells and macrophages that damage myelin sheaths surrounding axons of the central nervous system (CNS). These events precipitate demyelination and subsequent axonal and neuronal damage leading to neurodegeneration and the clinical manifestations of the disease (4). In the majority of cases axonal demyelination is the target of injury and is generally followed by periods of remission characterised by oligodendrocyte mediated axon remyelination. Less commonly, however, oligodendrocyte depletion in some cases prevents subsequent axonal remyelination from occurring, contributing to the heterogeneity of disease pathogenesis (5). The factors that contribute to triggering an autoimmune response and the onset of MS are not completely understood. However, a combination of genetic and non-genetic factors and their interaction may modulate disease onset (6). Environmental factors that may increase MS susceptibility include certain viral infections, and it has been proposed that lack of sun exposure may increase susceptibility (1). The notion that shared genetic risk factors also play a role in disease aetiology is supported by familial clustering of MS in about 15-20% of patients and a higher frequency of certain genetic anomalies in these patients (1, 4). 2.3 Clinical Symptoms: Disease course in MS patients is characterised by recurrent neurological attacks, known as relapses, and neuronal degeneration associated with disease progression (4). Relapses are characterised by periods of acute or subacute neurological abnormality and physical debilitation with concomitant worsening of symptoms present for at least 24 hours in the absence of fever or infection (2). Relapses may last from several hours to weeks before partial or complete remission occurs (4, 7) and, on average, occur 0.4 to 0.6 times per year with frequency waning observed in later years (1). Conversely, progression refers to steady neurodegeneration and irreversible worsening of symptoms over a 6 month period (7). At the molecular level, relapses correlate with disseminated and recurrent inflammation characterised by gadolinium-enhancing (GdE) lesions in magnetic resonance imaging (MRI), while chronic and progressive axonal loss characterizes disease progression (7, 8). IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 4 of 68

5 Fatigue and urinary bladder dysfunction are reported by about 90% of patients and are the most prevalent clinical symptoms of MS (9). Other symptoms include a variety of physical, physiological, psychological and even psychiatric conditions as outlined below (10): Physical Physiological Psychological/Psychiatric Urinary tract infections Bladder dysfunction Cognitive impairment Weakness and cardio-respiratory fitness Bowel problems Emotionalism Contractures at joints Sensory losses Depression Ataxia and tremors Visual impairments Anxiety Pain: musculoskeletal and/or neuropathic Swallowing difficulties Pressure ulcers Speech impediments Spasticity and spasms Sexual dysfunction Fatigue Clinical disability from MS is gauged using the Kurtzke disability status scale (known as DSS) (11), or more commonly the expanded DSS (EDSS) (12), which are ordinal scales ranging from 0, representing a normal neurological examination and function, to 10, which represents death from MS. A key clinical milestone frequently referenced in clinical studies is an EDSS value of 6.0, which marks the point in disability progression when a patient is no longer ambulatory (i.e. requires a walking aid). While widely used, the EDSS has been criticised for shortcomings that include high inter- and intra-rater scoring variability and an emphasis on ambulation at higher values that gives little weight to the cognitive disability progression also experienced by patients (1). 2.4 Disease Subtypes: The majority of MS patients can be classified as having one of the four following disease subtypes as described by Goldenberg, 2012 (9): Relapsing remitting MS (RRMS): the most common form, affecting about 85% of MS patients. It is marked by relapses of symptoms followed by periods of remission, when symptoms improve or disappear. Secondary progressive MS (SPMS): may develop in some patients with RRMS. For many patients, treatment with disease-modifying agents helps delay such progression. The disease course continues to worsen with or without periods of remission or levelling off of symptom severity (plateaus). Primary progressive MS (PPMS): affects approximately 10% of MS patients. Symptoms continue to worsen gradually from the beginning. There are no relapses or remissions, but there may be occasional plateaus. This form of MS is more resistant to the drugs typically used to treat the disease. Progressive-relapsing MS (PRMS): a rare form, affecting fewer than 5% of patients. It is progressive from the start, with intermittent flare-ups of worsening symptoms along the way. There are no periods of remission IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 5 of 68

6 The European Medicines Agency (EMA) also broadly includes the following disease subtypes under the heading of relapsing MS (RMS): RRMS, SPMS and superimposed relapses and patients with clinically isolated syndromes (CIS) who show dissemination of lesions in time and space on MRI scans (13). The EMA describes patients with CIS as those with a first clinical event that can be attributed to a demyelinating event that does not comply with the diagnostic criteria for definite MS i.e. dissemination of demyelinating events in time and place either clinically or radiographically (13). A highly active variant of RRMS given focus in this briefing document is referred to as rapidly evolving severe relapsing remitting multiple sclerosis (RES-RRMS). RES-RRMS is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous recent MRI (14). 2.5 Natural History: The natural history of disease refers to its uninterrupted clinical course and is essential for assessing treatment efficacy. The chronic nature of MS means that natural history studies face logistical and ethical hurdles related to the long-term follow-up of untreated patients, with the most highly cited studies having been undertaken (or started) before the use of MS disease-modifying therapy was mainstream (15). The main natural history studies of MS have been conducted on patient cohorts from Canada, France and the USA, with one of the earliest and most highly cited being the London, Ontario cohort, a population and clinic-based study that followed 1099 RMS and PPMS patients from (with two subsequent updates) in London, Ontario, Canada (16). The high proportion of PPMS patients (20%) in this study may have reduced the estimated time to sustained progression (15.0 years) in these patients relative to cohorts in subsequent studies which reported times for the same endpoint upwards of 20 years (15). The average global age of onset of MS is estimated at 29.2 years and can range from 20 to 45 years of age with occasional presentation in childhood or late middle age. Late-onset MS is defined as disease onset at 50 years or older (9, 15). The majority of patients presenting with RRMS continue on this disease course for about 20 years before disease progression to SPMS; with most patients having a lifespan of about 10 years less than the general population (15). The median time following disease onset before a patient requires a walking aid, an important clinical milestone (EDSS 6), ranges from years in RRMS and 6-21 years for patients with PPMS in most major natural history studies, with men generally progressing to this stage more quickly than women (1, 15). 2.6 Diagnosis: The current diagnostic criteria for MS, often referred to as the McDonald criteria, have undergone two revisions (in 2005 and 2010) since their development in 2001 to supersede the older Poser (1983) and Schumacher (1965) diagnostic criteria following advances in MRI techniques (2). Diagnosis relies on the integration of a patient s medical history with clinical evidence of the dissemination of CNS lesions in time and space as assessed by magnetic resonance imaging (MRI) and, when appropriate, evidence of chronic CNS inflammation in sampled cerebral spinal fluid (CSF) (9). Presence of gadolinium enhancing (GdE) lesions and change int2-weighted lesion volume are used as markers of MS on MRI and represent active inflammation coupled to blood-brain barrier disruptions and disease burden, respectively (17, 18). A diagnosis of MS, possible MS or not MS is made depending on how well the Criteria are fulfilled in the absence of an alternative disease diagnosis (19). 2.7 Treatment: Treatment options for MS fall under three therapeutic approaches which aim to i.) shorten the duration and/or severity of acute relapses and prevent their sequelae ii.) moderate symptoms of the disease, or iii.) modify the natural course of MS (13) (Figure 1). IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 6 of 68

7 An assortment of corticosteroids are available to target relapses (20) with the current standard of care being daily methylprednisolone administration for 3-5 days to shorten relapse duration (10, 13). Symptomatic treatment of MS generally comprises non-specific therapies used to improve disease symptoms and/or complications with more specific therapies intending to facilitate remyelination or axonal conductivity (13). Disease-modifying therapies (DMTs) aim to modify MS disease course by preventing relapses and reducing disability accumulation; they will be the primary focus of this briefing document. The treatment pathway for RRMS is outlined in Figure 1 Relapsing remitting multiple Acute relapse Disease-modifying therapy (DMT) Disabling Methylprednisolone (corticosteroids) Non-disabling Symptomatic relief Alemtuzumab (RRMS) (adults with active disease defined by clinical or imaging features) IFN-beta (RRMS, SPMS) Glatiramer acetate (RRMS) Teriflunomide (RRMS) Dimethyl fumarate (RRMS) Fingolimod (RES-RRMS) Natalizumab (RES-RRMS) First-line Second-line Figure 1.: Treatment pathway for relapsing-remitting multiple sclerosis (RRMS). SPMS: secondary-progressive multiple sclerosis; RES-RRMS: Rapidly evolving or severe-rrms. Adapted from Pandit and Murthy, 2011 (21) Disease-Modifying Therapies (DMTs) The earliest DMTs approved for MS in Europe in the late 1990s and early 2000s were injectable immune modulating drugs that included the naturally occurring cytokines interferon beta-1a and beta-1b, as well as a mixture of four synthesised amino acids known as glatiramer acetate (Table 1). The beta interferons and glatiramer acetate are firstline treatments for patients with RRMS, with interferon beta-1b also indicated for treating SPMS. These therapies elicit distinct, albeit incompletely understood, immune reactions that reduce relapse and inflammation (9). Their long term effect on disability progression is less certain and is the focus of an ongoing risk-sharing scheme in the UK (22). In 2006, the EMA issued marketing authorisation for natalizumab, a recombinant humanised monoclonal antibody administered intravenously once a month to patients with RRMS. Natalizumab inhibits the migration of leukocytes into the CNS, thereby reducing inflammation and demyelination (23). While substantially reducing relapse, natalizumab has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) in some individuals, and is indicated for patients with severe RRMS (RES), or those who have failed to respond to firstline treatment (9, 14). The first orally administered DMT, fingolimod, received marketing authorisation by the EMA in Fingolimod is a sphingosine 1-phosphate receptor modulator that reduces lymphocyte infiltration into the CNS leading to robust anti-inflammatory effects as seen on MRI and relapses; its mechanism of action is not completely understood (24). Fingolimod is indicated for RRMS patients with high disease activity and incomplete response to treatment with interferon-betas, similar to the indication for natalizumab (23, 24) IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 7 of 68

8 Teriflunomide, is the active metabolite of leflunomide, an immunosuppressant originally indicated for the treatment of arthritis, and was recently (August 2013) approved by the EMA as a therapy for RRMS (9, 25). It is orally administered once a day and confers anti-inflammatory activity through the selective inhibition of the enzyme dihydroorotate dehydrogenase (DHO-DH) (25). DHO-DH activity is required for cellular proliferation and its inhibition by teriflunomide is thought to prevent the proliferation of inflammatory lymphocytes in the CNS; however the precise mechanism of action is not completely understood (25). In two pivotal clinical trials (TEMSO and TENERE) teriflunomide, at its indicated dosage, showed a reduction in relapses versus placebo and was non-inferior to interferon beta for the same endpoint (9, 25). To account for all important identified and potential risks, teriflunomide was approved under the provision of a risk management plan to ensure safety in its use (25). A summary of these medicines as described in the respective European Public Assessment Reports (EPARs) is outlined in Table Newer DMTs Three DMTs have recently gone through the regulatory process with the EMA. Alemtuzumab, an injectable solution of a recombinant DNA-derived humanised monoclonal antibody, received marketing authorisation for the treatment of RRMS in September 2013 (26). Alemtuzumab targets the CD52 surface antigen which is highly expressed on B and T lymphocytes and is believed to confer anti-inflammatory effects through the reduction of lymphocytes in the circulation; the exact mechanism is not completely understood (9, 26). More recently, in January 2014, dimethyl fumarate, an orally administered DMT was approved for use in RRMS (27). While its mechanism of action is not completely understood, dimethyl fumarate is believed to indirectly promote antioxidant activity by inducing Nrf2 and thereby modulating inflammation. In parallel to the approval of dimethyl fumarate, the EMA issued a negative opinion for treatment of RRMS with the immunomodulator laquinimod in January 2014 (28). The regulatory authority cited concerns over a high occurrence of cancers in animals following long-term exposure to laquinimod that could not be excluded in humans, especially in light of a lack of evidence regarding its therapeutic mode of action (28). In February 2014, the EMA began a re-examination of its decision at the request of laquinimod s manufacturer. A summary of these medicines as described in the respective European Public Assessment Reports (EPARs) is outlined in Table 1. IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 8 of 68

9 Table 1: Summary of European Medicines Agency-Approved Disease-Modifying Therapies for Multiple Sclerosis Interferon beta-1a Interferon beta-1b Glatiramer acetate Natalizumab Fingolimod Teriflunomide Dimethyl fumarate Alemtuzumab Mechanism of Action Not completely understood; likely mediated by binding to cell surface receptors and the upregulation of IL-10 Not completely understood; likely mediated by binding to cell surface receptors Likely modifies the immune processes responsible for pathogenesis of MS Blocks interaction of alpha-4 beta-7 integrin with the mucosal address in cell adhesion molecule-1. Reduces lymphocyte migration in the CNS Not completely understood; likely mediated by reduction in the number of lymphocytes Not completely understood; thought to reduce inflammatory responses by activating Nrf2 antioxidant response pathway. Not completely understood; binding to CD52+ lymphocytes inducing antibodydependent cytolysis and complement mediated lysis Approved Indications (Europe) RRMS; SPMS with relapses; single demyelinating event, accompanied by abnormal MRI scans, with lesions typical of MS RRMS; SPMS; single demyelinating event accompanied by at least two clinically silent lesions typical of MS RRMS; single demyelinating event, accompanied by abnormal MRI scans and considered to be at risk of developing CDMS Highly active-rrms Highly active-rrms Adults with RRMS Adults with RRMS Adults with RRMS with active disease defined by clinical or imaging features. Route of Administration IM injection (Avonex) SC injection (Rebif) SC injection (Betaferon, Extavia) SC injection (Copaxone) IV infusion (Tysabri) Oral capsule (Gilenya) Oral capsule (Aubagio) Oral capsule (Tecfidera) IV infusion (Lemtrada) Recommended Dose IM: 30 mcg/week, or SC: 22 mcg or 44 mcg 3 times/week 0.25 mg every other day 20 mg/day 300 mg every 4 weeks 0.5 mg/day 14 mg/day 120 mg bid; after 7 days 240 mg bid 12 mg/day for 5 days; then, 12 mg/day for 3 days 12 months later Contraindications Contraindicated in patients with known hypersensitivity to natural or recombinant interferon, patients with liver disease, pregnant women Contraindicated in patients with known hypersensitivity to natural or recombinant interferon, patients with liver disease, pregnant women Contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol Contraindicated in patients who have had PML, at risk for PML; hypersensitive to this drug or to any ingredient in the formulation or any component of the drug; immunocompromised, including those immunocompromised due to immunosuppressant or antineoplastic therapies, or immunodeficiencies Contraindicated in patients who are hypersensitive to fingolimod, who are at risk for an opportunistic infection (immunocompromised due to treatment or to disease), have hepatic insufficiency, active severe infections, or known active malignancies Contraindicated in patients who are hypersensitive to teriflunomide, who have severe hepatic impairment, are pregnant or breastfeeding, have severe immunodeficiency, active infections, severe renal impairment or severe hypoproteinaemia Contraindicated for patients hypersensitive to dimethyl fumarate; those with low blood cell counts and/or renal or hepatic insufficiency Contraindicated for patients hypersensitive to alemtuzumab; those with HIV infection; Warnings and Precautions (as per EMA Summary of Should be used under supervision of a physician or qualified Caution to patients with history of suicidal ideation, cardiac May cause transient chest pain and immediate post- MRI scan is required for diagnosis of PML. Risk of PML increases Delay treatment in patients with active severe infection. Monitoring before and during treatment of patient's blood May decrease lymphocyte counts;; may cause flushing; May increase the risk of certain autoimmune disorders of the IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 9 of 68

10 Product Characteristics) health care professional. May cause depression and severe liver injury. disease, thyroid disorders, and seizure disorders. May cause hypersensitivity reactions, liver injury, and pancreatitis. injection reactions. with increasing treatment duration, history of previous exposure to immunosuppressive therapy, and presence of anti-jc Virus antibodies. Varicella zoster vaccination recommended. May cause macular oedema and may increase liver transaminases. pressure, alanine aminotransferase and complete blood cell counts based on signs and symptoms should be undertaken patients with serious infections should not start treatment; should not be used in paediatric or adolescent patients platelets, kidneys, thyroid and blood; increased risk of infections and infusion reactions bid = bis in die ( twice daily ); CDMS = clinically definite multiple sclerosis; CNS = central nervous system; IL-10 = immunosuppressive cytokine interleukin-10; IM = intramuscular; IV = intravenous; mg = milligram; MRI = magnetic resonance imaging; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; RRMS = relapsing-remitting multiple sclerosis; SC = subcutaneous; SPMS = secondary-progressive multiple sclerosis; mcg = microgram. Adapted from CADTH, 2013 (17). IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 10 of 68

11 3. A review of efficacy and effectiveness data for disease-modifying MS treatments A literature review was carried out to identify sources of data on efficacy and effectiveness of disease modifying therapies for MS. The purpose of this review was to identify data that could be used in simulation work conducted as part of this case study. 3.1 Pivotal randomised controlled trials (RCTs) While the primary focus of the literature review was to identify sources of real world data relevant to the therapies considered herein, pivotal RCTs were identified from respective European Public Assessment Reports (EPARs) available on the EMA website ( and a recent review of published controlled trials for DMTs in RRMS undertaken by the CADTH (17). HTA review documents were also hand-searched to identify any RCTs completed post-licensing and used to populate the development timelines for each medicine (45, 52). These pivotal studies are summarised in Table A1 in Appendix A. 3.2 Real-world data search strategy Regulatory and HTA documents in the public domain issued by GetReal partnering agencies were hand-searched for references of relevant observational studies (45, 52). The US registry of clinical trials (ClinicalTrials.gov) was also searched using the trade- and non-proprietary names of pertinent DMTs limiting results to observational studies only. The public bibliographic database Medline (via OvidSP) was searched as described below. The Medline database (via OvidSP) was searched using relevant combinations of MeSH headings and free text for each topic. Pertinent search structure from a recent systematic literature review on MS therapies undertaken by the CADTH (2013) (17) was adapted to meet the medicine and observational study specific requirements of the current review. The search was limited to real-world data published in the English language and published subsequently to existing literature reviews undertaken in the HTA submissions described earlier. Results in abstract form, duplicate publications, narrative reviews, editorials and case reports were excluded. Studies evaluating the following diseasespecific endpoints were included: relapse, disability progression, MRI changes, quality of life (QoL), adverse events (AEs) and treatment withdrawal due to adverse events. Only published evidence was included for further consideration. Table C1 in Appendix C illustrates the search strategy used and the number of references identified for each medicine over the indicated timeframe. The literature search was done up to 2 April, Description of identified sources of real-world data A tabular summary of the studies identified in the literature review for each medicine is included in Tables B1-B5 in Appendix B. Published results were generally not available prior to the date of marketing authorisation with the exception of the Confavereux et al. phase II extension study which was published in the year prior to EMA approval of teriflunomide. The publication date of each studied identified relative to other key development milestones for each medicine, is depicted graphically on timelines in the subsequent section (Section 4). Note that while publication date is known, the date of initiation of each study was not available for all studies and therefore not documented here. The studies in Tables B1-B5 are grouped by design based on whether they were comparative (cohorts of individuals administered different treatments) or non-comparative (where patients received the same treatment). IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 11 of 68

12 As expected, the number of published sources of real-world data identified for each medicine correlated with the length of its post-licensing period. In this respect, 25 studies were identified for the interferon betas (collectively) and 14 for glatiramer acetate; the earliest licensed DMTs. Conversely, only one phase II extension study was identified for the most recently licensed DMT considered in this briefing teriflunomide (29). The smallest study, in terms of enrolment, followed a cohort of 11 adult patients administered fingolimod over a 12-month period (30), while the largest was the QUASIMS observational study that compared interferon beta therapies for RRMS in over 4700 patients for two years (31). IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 12 of 68

13 4 A review of challenges in demonstrating relative effectiveness of disease-modifying MS treatments in Europe Publicly available documents relating to the assessment of MS treatments by the EMA, MHRA and four HTA agencies (HAS, NICE, SMC and ZIN) were reviewed with the aim of collating information about uncertainties and challenges in assessing relative effectiveness of the MS treatments included in this report. The dates of European marketing authorisation and health technology assessments for these medicines are summarised in Table 2, below, together with corresponding references for the publically available documents used. Table 2: Key Dates for European Regulatory Approval and HTA Appraisal for Medicines of Interest and key assessment documents Active substance Proprietar y Name a.) Disease Modifying Therapies for Multiple Sclerosis MA holder Regulatory body: MA date; document (reference) NICE: assessment date; guidance report(reference) SMC: assessment date; guidance report (reference) HAS: assessment date; guidance report (reference) ZIN: assessment date; (reference) teriflunomide Aubagio Sanofi-aventis EMA: 26/08/2013; EPAR (25) 22/01/2014; TA303 (39) 07/02/2014; No. 940/14 (40) planned 14/03/2014; (67) fingolimod Gilenya Novartis Europharm EMA: 17/03/2011; EPAR (24) 25/04/ MTA in 2015; TA254 (36) 10/09/2012; No. 763/12 (38) 20/07/2011; CT10252 (37) 23/01/2012; (68) fampridine Fampyr a Biogen Idec EMA: 20/07/2011; EPAR (53) NA NA 11/04/2012; CT11904 (61) 17/12/2012; (69) interferon beta-1b Extavia Novartis Europharm. EMA: 20/05/2008; EPAR (42) NA NA 21/07/2010; CT8731 (62) NA natalizumab Tysabri Biogen Idec [not GetReal] EMA: 27/06/2006; EPAR (14) 22/08/ MTA in 2015; TA127 (34) 10/09/2007; No. 329/06 (23) 17/01/2007; CT3657 (33) 18/12/2006; (70) glatiramer acetate Copaxo ne Teva MHRA: 07/04/2003; PAR (49) 01/ MTA in 2015; TA32 (46) NA 20/11/2002; CT (51) NA interferon beta-1a Rebif Merck Serono Europe EMA: 04/05/1998; EPAR (54) 01/ MTA in 2015; TA32 (46) NA 11/10/2002; CT (63) NA interferon beta-1a Avonex Biogen Idec EMA: 13/03/1997; EPAR (44) 01/ MTA in 2015; TA32 (46) 10/11/2003; No. 58/03 (58) 18/12/2002; CT (64) NA interferon beta-1b Betafer on Bayer Pharma EMA: 30/11/1995; EPAR (41) 01/ MTA in 2015; TA32 (46) 12/02/2007; No. 345/07 (48) 11/09/2002; CT (65) NA b.) Newer Disease Modifying Therapies for Multiple Sclerosis dimethyl fumarate Tecfidera Biogen Idec Nerventr laquinimod a Teva alemtuzuma b Lemtrada Genzyme/Sano fi EMA: 30/01/2014; EPAR (27) EMA: 21/02/2014 (Neg. Response) (28) EMA: 12/09/2013; EPAR (26) 05/2014; TA320 (55) 05/07/2013; No. 886/13 (59) 07/05/2014; CT13005 (66) in progress suspended; ID560 (56) NA NA NA 05/2014; TA312 (57) 12/05/2014; No. 959/14 (60) planned planned NA = not available; MTA = Multiple Technology Appraisal; MA = marketing authorisation; EMA = European Medicines Agency; (E)PAR = (European) Public Assessment Report; MHRA = Medicines and Health Products Regulatory Agency (UK); NICE = National Institute for Health and Care Excellence (England&Wales); SMC = Scottish Medicines Consortium (Scotland); TA = Technology Appraisal; HAS = Haute Autorité de Santé (France);ZIN = Zorginstituut Nederland (Netherlands) IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 13 of 68

14 Sections summarise the regulatory and HTA milestones for each medicine. The sections highlight the key challenges, as identified by the regulatory and HTA agencies themselves, in establishing relative effectiveness during their assessments. The publication dates of key real-world data studies (identified in the literature review described in Section 3) are indicated in graphical form to provide the reader with an indication of what RWD was available relative to the clinical development milestones of each medicine. 4.1 Natalizumab (Tysabri; Biogen Idec) Regulatory milestones and challenges: Natalizumab was granted marketing authorisation based on evidence presented in two pivotal RCTs: AFFIRM and SENTINEL (described in Table A1). In the AFFIRM trial, natalizumab decreased the annualised relapse rate and the probability of sustained progression compared with placebo in RRMS patients. A post-hoc sub-group analysis was requested during the approval process in patients with rapidly evolving (RES) RRMS in which significant reductions in relapse and sustained progression were also observed. In the SENTINEL study, natalizumab combined with interferon beta-1a reduced relapse and progression to sustained disability after two years compared with patients treated with a combination of interferon beta-1a and placebo (14). An extensive safety review was undertaken for natalizumab and a risk management plan (RMP) was introduced following the discovery of cases of progressive multifocal leucoencephalopathy (PML) in some patients administered natalizumab in clinical trials. Data collected on patients who received natalizumab in clinical trials was sufficient to maintain the original MA with changes to indicate/lessen the risk of PML in patients using the drug (14). Recently the indication for natalizumab was changed to include patients who are non-responsive to glatiramer acetate treatment following the reduction in annualised relapse rate observed in subsets of patients followed in several natalizumab registries or in observational studies (32). Challenges that arose during the regulatory process can be grouped into those related to the initial marketing authorisation and based on the two pivotal RCTs, and those related to the extension of the original indication, which relied principally on registry and observational data. In the former case, the EMA stated that the subgroup analysis in RES patients should be interpreted cautiously as it may not be representative of the general population with RES, given that information regarding severity of relapses was not collected during patient recruitment in the AFFIRM trial (14). In the SENTINEL study, natalizumab efficacy was measured in combination with interferon beta-1b and may not necessarily confer the same absolute effect as monotherapy. Moreover, direct controlled comparisons between natalizumab and interferon-beta were not available to validate this issue. While pivotal RCTs were used to derive conclusions on probability to sustained disability progression, they were of a relative short-term nature (two years) and may not represent the long-term time horizons necessary for accurately assessing disability progression in MS. The extension of the indication to include patients that were recalcitrant to glatiramer acetate treatment relied principally on observational data such as the single arm observational study, TOP, and registry data. A limitation of using single arm studies is a lack of control groups and potential bias arising from their lack of randomisation. Moreover, the TOP study did not stratify patients by previous DMT use and no discrimination was made regarding the specific type of DMT treatment used in other studies. HTA milestones and challenges: Shortly after obtaining marketing authorisation, natalizumab underwent HTA appraisals with HAS, NICE and SMC in 2007 and was approved for the treatment of highly active (HA)-RRMS in patients non-responsive to beta-interferon or those with rapidly evolving severe (RES) RRMS (23, 33, 34). In 2010 and 2013 NICE put forth proposals to review the original appraisal of natalizumab. However, both times the reviews were postponed to coincide with the release IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 14 of 68

15 of new clinical information; results of the SURPASS study in 2010 (which was terminated), and the UK Risk-Sharing Scheme in 2013 (to be completed in 2015). The issues raised by most of the HTA bodies (NICE, SMC and HAS) that assessed natalizumab, centred around uncertainties relating to subgroup analyses (both the sub-optimal therapy and RES subgroups) and whether they would be generalisable to the overall population with those conditions (23, 33, 34). Uncertainty regarding indirect analyses undertaken in the economic models was also at issue, with specific concern being the large degree of variability around disease progression in patients with highly active MS. Moreover, in the economic evaluation submitted to NICE and SMC, natalizumab was compared with interferon beta for patients with RES, however the comparator data for interferon beta (from a Cochrane review) was not specific to RES patients but to all RRMS patients. The HTA bodies also questioned the validity of the 20 year time horizon used in the long-term extrapolation of study data acquired over a two year period. These issues are further detailed in the clinical development timeline for natalizumab in Table 3a with the key milestones depicted in Figure 2. Natalizumab Jan-11 Mancardi et al Jan-11 Sangalli et al Jan-11 IMSE registry Feb-11 Mattioli et al Feb-11 Belachew et al Aug-11 Maurer et al Sep-11 Halpern et al Mar-13 Fragoso et al Mar-13 Jokubaitis et al Apr-13 Wickstrom et al Jun-13 Portaccio et al Jul-13 Ghezzi et al Nov-01 AFFIRM Jan-02 SENTINEL (C-1802) Jun-04 EMA MA Sep-07 SMC HTA Jan-07 HAS HTA Jan-10 Putzki 2010b Mar-13 Oleen-Burkey et al Mar-12 Kallweit et al Apr-12 Iaffaldano et al Aug-13 Gobbi et al Nov-13 ENER-G study 01/01/ /09/2014 Legend Mar-92 Pivotal RCTs Nov-96 Observational studies Mar-98 Marketing authorisation (MA) Aug-07 NICE HTA Oct-91 Health Technology Assessment (HTA) Jan-10 Putzki 2010a Nov-10 Fernandez 2010 Jan-11 Marrosu et al Mar-11 Horga et al Jun-12 Melin et al May-11 Krysko et al Aug-12 Zivadinov et al Sep-12 Fernandez et al Nov-12 Lanzillo et al Jun-13 TST study Mar-13 Apr-13 TYNERGY study Kornek et al Dec-12 Stephenson et al Figure 2: Timeline of key clinical development milestones for natalizumab and publication dates of identified real-world studies. IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 15 of 68

16 Table 3a: Natalizumab clinical development timeline Regulatory Milestone (EMA) HTA Milestone Relative Effectiveness - Key Issues: 27 June January 2007 Questions Addressed During Regulatory Process: EMA MA granted: RRMS (as second line treatment or for patients with highly active disease e.g. RES, unresponsive to beta interferons ) under additional monitoring of European Risk Management Plan Studies: 1.) AFFIRM 2.) SENTINEL 3.) Three supportive Phase II studies: MS231, MS 201, MS202 Basis for MA: more effective than placebo in reducing the number of relapses; reduction in disability progression over two years vs. placebo; Outstanding issues: -SENTINEL study design did not allow for unambiguous identification of whether Tysabri alone or in combination with interferon beta-1a reduced disability progression and relapses -severe adverse events observed in some patients (e.g. PML) HAS: RES-RRMS (IAB = level III); citing severe adverse effects Issues: lack of real-world evidence on: long-term disability progression, quality of life, relapse frequency 22 August 2007 NICE: RES-RRMS (two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI) Issues: further research into the clinical effectiveness of natalizumab for the treatment of highly active relapsing remitting multiple sclerosis in the suboptimal therapy group is needed Population: 1.) Relatively few patients in subgroup with low lesion load (<9 lesions) could affect robustness of clinical benefit (SENTINEL) 2.) Claim for broader indication (to SPMS with superimposed relapse) limited to small number of patients from phase II studies. Questions Addressed During HTA Reviews: Population: NICE: 3.) No direct evidence about the use of natalizumab among the suboptimal therapy group (SOT: people whose MS failed to respond to treatment with beta interferon). 4.) Limited trial evidence available: Evidence for the RES MS group is based on a subgroup analysis of only one RCT. 5.) Uncertainty regarding the appropriateness of some of the data used to populate the model for the SOT group. 6.) Generalisability of subgroup analysis: Intention to treat (IIT) population from AFFIRM study was assumed by manufacturer to be a suitable proxy for the suboptimal therapy group from SENTINAL study (whose data was not presented in the HTA assessment). 7.) Generalisability of data sources used in cost-effectiveness analyses: Utility and cost data (based on UK MS survey) was not exclusively derived from people with highly active relapsing-remitting MS; due to low response rate survey may not have been representative. SMC: 8.) No data presented for use of natalizumab in suboptimally treated patients (only RES RRMS group) 9.) Generalisability of effectiveness data of beta-interferon: taken from randomised controlled trials of its use in all patients with RRMS, not just the RES sub-group. -induction of natalizumab into Risk Management Plan 10 September 2007 IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 16 of 68 Appropriateness of comparators: NICE: 1.) Uncertainty associated with indirect analyses: the effect of natalizumab compared with active treatments is uncertain indirect comparisons among people with highly active MS show wide confidence intervals that include no benefit around the key outcome of disease progression.

17 SMC: HA-RRMS SMC: 1.) Uncertainty regarding indirect analyses: There are no controlled comparative studies of natalizumab with existing therapies such as beta-interferon or glatiramer acetate. Inter- and intra-individual variability is large, particularly in patients with RRMS, and therefore a cautious approach should be made with respect to results related to indirect comparisons. HAS: 1.) Absence of any comparative study with mitoxantrone for the treatment of aggressive forms of RRMS October 2009 Review of MA: maintain, vary or suspend MA in light of PML data Evidence used: studies from manufacturer; expert advice Result: indication maintained with additional updates re: PML 30 May 2013 December 2010 NICE: Review proposal: deferred until 2013 upon provision of SURPASS study results July 2013 Acceptability of endpoints: NICE: 1.) Underlying disease progression in the model is based on data from the AFFIRM trial and should be treated with caution: Intention to treat (IIT) population from AFFIRM study was assumed by manufacturer to be a suitable proxy for the SOT group from the SENTINAL study (whose data was not presented by manufacturer). There is no direct evidence about the clinical effectiveness of natalizumab monotherapy in the SOT group. 2.) Long-term accuracy of extrapolated results: 2-year data from the AFFIRM study was extrapolated to a 20-year time horizon. SMC: 1.) Assumption of long-term effectiveness in the absence of long-term data: (see point 2 from NICE appraisal above) Other: NICE: 1.) Expanded Disability Status Scale (EDSS) instrument has limited responsiveness and inter- and intra-rater variability. Regulatory (EMA): Extension of indication: same as in original MA but also in patients unresponsive to glatiramer acetate NB: negative response to extension of indication to RRMS population with high disease activity and NICE: Review proposal: deferred until completion of UK Risk-Sharing Scheme and joint MTA with IFNBs, glatiramer acetate and fingolimod in early 2015; SURPASS study terminated IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 17 of 68 1.) Lack of control groups and randomised treatment assignment: a limitation of single-arm observational studies like TOP 2.) Most analyses (using data from the observational studies and registries presented) were not designed to discriminate between different prior disease modifying therapies; no stratification for prior DMTs

18 negative for anti-jcv antibodies citing lack of sufficient data used in TOP study Studies: 1.) TOP (Tysabri Observational Program) 2.) IMSE (Swedish Tysabri Registry) 3.) TYSEDMUS (French Tysabri Registry) 4.) GLANCE phase II study 5.) Several independent patient cohort studies: i.) Memon et al ii.) Vokaer et al. 2010; Belachew et al iii.) Putzki et al. 2009a iv.) Putzki et al. 2009b Basis for extension: Natalizumab was associated with significant reductions in the ARR in all subsets of subjects, irrespective of a history of GA only use or IFN-beta only use or switching between these DMTs prior to natalizumab IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 18 of 68

19 4.2 Fingolimod (Gilenya; Novartis): Regulatory milestones and challenges: The results from two randomised double-blind studies were submitted to support the marketing authorisation for fingolimod; TRANSFORMS and FREEDOMS (described in Table A1) (24). Both studies demonstrated a significant reduction in relapse, while the risk of disability progression was shown to be reduced only in the FREEDOMS study. Post-hoc analyses in subgroups of patients from both studies who were unresponsive to DMTs received in the year prior to randomisation were also submitted by the manufacturer. Both subgroups showed a significant reduction in annualised relapse rate versus comparator treatment (interferon beta-1a in TRANSFORMS; placebo in FREEDOMS). A review of the original marketing authorisation for fingolimod was undertaken in light of evidence of a cardiovascular disorder in some trial patients using the medicine that resulted in amendments to the summary of product characteristics to reflect this issue (35). The EMA granted negative approval for fingolimod in the general population with RRMS as examined in the pivotal RCTs; rather fingolimod was approved for subgroups of patients with highly active disease (24). The EMA also noted that the study population excluded elderly patients and therefore might not be generalisable to the population at large. Moreover, the EMA noted that the one-year duration of the TRANSFORMS trial was too short to draw representative conclusions regarding comparative efficacy on secondary endpoints like confirmed disability progression (24). HTA milestones and challenges: HTA assessments have been undertaken for fingolimod by HAS in 2011, and by NICE, SMC and CVZ in 2012 for treatment of highly active relapsing-remitting MS (HA-RRMS) in individuals unresponsive to prior treatment with interferon beta (36-38). NICE recommend fingolimod as an option for the treatment of HA-RRMS in adults only if they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon (36). Recently, a planned review of the original assessment by NICE was postponed to coincide with the release of data on the DMTs included in the UK Risk Sharing Scheme (see section on beta interferons below), and fingolimod will be included in an upcoming NICE MTA together with natalizumab, the beta interferons and glatiramer acetate in In the HTA submission for fingolimod, the manufacturer placed emphasis on assessment of the medicine for treatment in patients who were unresponsive to standard treatment (sub-optimal therapy group SOT) (38). In this regard, a population with rapidly evolving severe MS (RES-MS) (subgroup 2) was included in the HTA submissions with SOT patients further dichotomized into two subpopulations representing 1a) relapsing patients with specific MRI detected lesions, 1b) patients with an equal or greater number of relapses compared to the previous year. The choice of comparator used in the sub-optimal therapy group and the indirect comparisons undertaken, were the focus of the questions raised during the HTA reviews for fingolimod. In the NICE assessment, the assessment group was unclear whether beta interferon was an appropriate comparator for fingolimod in the 1a population as these patients were unresponsive to prior treatment with disease-modifying therapy (DMT) which, in the great majority of cases, was beta-interferon (i.e. they may be resistant to this treatment) (36). Also, as the proportion of study patients who were unresponsive to prior treatment with Avonex (interferon beta-1a) was unknown, the SMC suggested that it may have been more appropriate to allow these patients to be randomised to another betainterferon rather than continue with one which resulted in sub-optimal response (38). In the post-hoc analyses, patient subgroups from the FREEDOMS and TRANSFORMS studies who may not have been receiving DMTs at the time of relapse were included. The impact of including these patients, who did not necessarily correspond to the target population, was not clear (38). Although direct head-to-head data was available for the comparison of fingolimod with Avonex, an indirect analysis was submitted to facilitate use of an existing model in the cost-utility IMI GetReal Case Study 1: Deliverable 1.5 Disease and Treatment Overview 19 of 68