UTAH MEDICAID DUR REPORT FEBRUARY 2015 MULTIPLE SCLEROSIS (MS): ORAL DISEASE-MODIFYING DRUGS

Transcription

1 UTAH MEDICAID DUR REPORT FEBRUARY 2015 MULTIPLE SCLEROSIS (MS): ORAL DISEASE-MODIFYING DRUGS Teriflunomide (Aubagio ) Fingolimod (Gilenya ) Dimethyl fumarate (Tecfidera ) Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Melissa Archer, PharmD, Clinical Pharmacist Gary M. Oderda Pharm D, M.P.H, Professor Ekaterina Efimova Pharm D student Chelsea Elise Williams Pharm D student Halee R. Namanny Pharm D student University of Utah College of Pharmacy Copyright 2014 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

2 Contents Introduction... 3 Indications... 4 Methodology... 4 Clinical Guidelines... 4 Clinical Efficacy... 7 Safety... 8 Place in therapy and potential criteria to be reviewed... 9 Utah Medicaid Utilization Data Conclusions Potential clinical criteria Appendix 1 Drug information Appendix 2 Systematic reviews Appendix 4 Additional evidence References

3 Introduction Demyelinating diseases are neurological disorders defined by the destruction of central nervous system (CNS) tissue and are typically immune-mediated conditions. 2,3 Multiple sclerosis (MS) is the most common demyelinating disorder and is characterized by inflammation, demyelination, scarring, and neuronal loss. 2,3 Patients with MS can exhibit benign illness to a debilitating disease resulting in significant changes to one s lifestyle. 2,3 Multiple sclerosis affects nearly 400,000 individuals in the United States and 2.5 million individuals worldwide. 4-6 The average estimated lifetime cost of illness for a patient with MS is estimated to be $1.2 million. 4-7 Prevalence is higher in women than men and the disease is usually diagnosed between the ages of 20 and 50 years. 4,5,7 The cause of multiple sclerosis is not known. 2,3 Both genetic (race and gender) and environmental factors (geographical location, exposure to the sun, birth month) are linked to the disease Immunology also plays a role; MS is thought to be an auto-immune disease mediated by T-cells that compromise the blood brain barrier and allow inflammatory mediators to enter and attack the CNS. Diagnosis of MS is based on clinical symptoms in combination with evidence of lesions on magnetic resonance imaging (MRI). Symptoms vary depending on the location and severity of the CNS lesions and may include sensory loss, optic neuritis, weakness, parasthesias, ataxia, tremor, fatigue, cognitive changes, and bladder dysfunction. 2,3 Multiple sclerosis (MS) is a chronic disease that can progress intermittently or continuously and is divided into four disease courses: relapsing-remitting multiple sclerosis (RRMS), primary-progressive multiple sclerosis (PPMS), secondary-progressive multiple sclerosis (SPMS), and progressive-relapsing multiple sclerosis (PRMS). 2,3 Relapsing-remitting multiple sclerosis is the most common form of MS and is characterized by exacerbations of neurological dysfunction followed by remissions. 11 RRMS may eventually develop into secondary progressive multiple sclerosis which is characterized by a neurologic deterioration with or without relapses. Primary progressive multiple sclerosis occurs in 10-15% of patients with MS and is characterized by disease progression with some minor improvements and without any exacerbations. 10,12 Progressive relapsing multiple sclerosis affects less than 5% of patients and is characterized by disease progression with acute relapses. Most medications used in the treatment of MS are indicated in the treatment of RRMS or SPMS; there are currently no medications labeled for use in PPMS. 2,3 Treatment of MS varies depending on the clinical subset of MS present and individual patient characteristics. 2,3,5,7 In general, treatment may include disease modifying agents in combination with symptomatic treatment. 2,3 Symptomatic treatments include glucocorticoid therapy, benzodiazepines, muscle relaxants, anticonvulsants, antidepressants, and medications used to treat urinary disorders. 2,3 Currently, no curative medication therapies are available in the treatment of MS. 5,7 Disease-modifying agents provide symptomatic relief and reduced disease progression. Currently, there are three oral disease modifying agents available for the treatment of MS; teriflunomide (Aubagio ), fingolimod (Gilenya ), and dimethyl fumarate (Tecfidera ). MS treatment options also include several self-injectable disease modifying agents including glatiramer (Copaxone ), interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), and Peginterferon beta-1a (Plegridy), and infusion agents; mitoxantrone (Novantrone ), and natalizumab (Tysabri ). Fingolimod (Gilenya ), a prodrug of sphingosine 1-phosphate (S1P) receptor agonist, was approved by the FDA in September 2010 and was the first oral disease-modifying medication approved for treatment of multiple sclerosis. 13 Aubagio (teriflunomide), a pyrimidine synthesis inhibitor, is an oral active metabolite of leflunomide that was approved by the FDA in September Tecfidera (dimethyl fumarate), a fumaric acid derivative, was approved by the FDA in March Gilenya and Aubagio are taken once daily and Tecfidera twice daily

4 Indications Fingolimod (Gilenya) is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. 13 Teriflunomide (Aubagio) is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). 14 Dimethyl fumarate (Tecfidera) is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). 15 Methodology A Cochrane Library literature search for systematic reviews was conducted. Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), the American Academy of Neurology (AAN) website, the FDA website (including product labeled information), Micromedex and Lexicomp were searched for safety information, systematic reviews, clinical trials, and guidelines. As per the hierarchy of evidence, high quality systematic reviews and evidence based guidelines were searched for first. After review of the sources, the following were examined: (a) Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines (2002), (b) National Institute for Health and Care Excellence (NICE) Guidance (c) NHS England Clinical commissioning policy (d) Recommendations from the Canadian Agency for Drugs and Technologies in Health 16, (f) Recommendations from the National Multiple Sclerosis Society 17 (g) product labels, (h) Immunization and MS: A summary of published evidence and recommendations (2002) 18, (i) Oregon Health & Science University Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis 19 (j) Four Systematic Reviews from the Cochrane Library (Appendix 2), and University of Utah Drug Reviews for the P&T Committee (Fingolimod & Teriflunomide; March 2013). Clinical Guidelines Currently, there are no consensus guidelines. Guideline on disease modifying therapies (February 2002; Current guideline. Reaffirmed October 17, 2003 and July 19, 2008.) 20 The agents included in this report were approved by the FDA more recently and were therefore not included in the abovementioned guideline. Additional Guidance documents: National Multiple Sclerosis Society released a Clinical Bulletin in 2012 The National Multiple Sclerosis Society released a Clinical Bulletin in 2012 providing recommendations for treatment strategies, symptom management, and a ranking for the disease modifying treatments. Based on these recommendations, the differentiation was made between first- and second-line therapies. Appropriate first-line therapies included interferon-β medications, Copaxone, and Fingolimod while the others (Tysabri, Novantrone) were considered additional or second-line options. The bulletin was released in 2012 and therefore did not include the newer medications for the treatment of multiple sclerosis. 17 4

5 Canadian Drug Expert Committee (CDEC) Recommendation for drug therapies for relapsing-remitting multiple sclerosis (2013). 16 Glatiramer acetate or IFN-β 1b is recommended as initial therapy for patients with relapsing-remitting multiple sclerosis (RRMS). Both of these medications should be tried before initiating a different therapy. If failure occurs or patients have contraindications to both of these medications, initiation of dimethyl fumarate, fingolimod, or natalizumab is recommended. It is advised that these selections should be based on cost and safety concerns. NICE guidance Fingolimod for the treatment of highly active RRMS (NICE technology appraisal guidance 254) 21 Fingolimod is recommended as an option for the treatment of highly active relapsing remitting multiple sclerosis 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, and the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme. Teriflunomide for treating RRMS (NICE technology appraisal guidance 303) 22 Teriflunomide is recommended as an option for treating adults with active RRMS (normally defined as 2 clinically significant relapses in the previous 2 years), only if they do not have highly active or rapidly evolving severe relapsing remitting multiple sclerosis and the manufacturer provides teriflunomide with the discount agreed in the patient access scheme. 22 Dimethyl fumarate for treating RRMS (NICE technology appraisal guidance 320) 22 Dimethyl fumarate is recommended as an option for treating adults with active RRMS (normally defined as 2 clinically significant relapses in the previous 2 years), only if: they do not have highly active or rapidly evolving severe relapsing-remitting multiple sclerosis and the manufacturer provides dimethyl fumarate with the discount agreed in the patient access scheme. In 2002, the UK Department of Health agreed a risk-sharing scheme with manufacturers to ensure that the disease-modifying treatments be made cost effective for the NHS to provide to patients (DH Health Service Circular HSC 2002/004). 22 In April 2013 NHS England published a clinical commissioning policy outlining use of these treatments, including criteria for commencement and stopping of these disease-modifying therapies. 22 It is stated that the criteria for starting and stopping these treatments are based upon the Association of British Neurologists (ABN) Guidelines. 23 Please refer to the complete document as this is a brief abstract from the policy and it states that the criteria must be used in conjunction with definitions in the original document. 23 Fingolimod for highly active relapsing remitting MS Starting Criteria Fingolimod is recommended for the treatment of highly active relapsing remitting MS in adults, only if the following criteria are met: Patients have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon* or glatiramer acetate, As an alternative to natalizumab for those patients receiving natalizumab who are at high risk of developing progressive multifocal leukoencephalopathy (PML) as defined by the following: o JCV exposure indicated by anti-jcv antibody positive status o Receiving an immunosuppressant prior to receiving natalizumab 5

6 and o Natalizumab treatment duration of >2 years The manufacturer provides fingolimod with the discount agreed as part of the patient access scheme. F.2 Stopping Criteria One or more of the following criteria are met: No reduction in frequency or severity of relapses compared with pre-treatment phase following a minimum 3 month period of fingolimod treatment Unacceptable adverse effects of the drug The patient is pregnant, breast feeding or attempting conception Development of secondary progressive disease causing inability to walk for more than 6 months Stopping criteria should be made known to patients and agreed before treatment is begun. 23 Up to Date According to Up to Date, based upon clinical experience, the available clinical data, neutralizing antibody formation, side effect profile, route of administration, and MRI data, the authors suggest Avonex or glatiramer acetate as agents of first choice for patients with RRMS, depending upon the patient's lifestyle and laboratory data. 24 However, it is also stated that it is reasonable to start newly diagnosed patients with RRMS on one of the following disease modifying agents: Interferon beta-1a (Avonex) 30 mcg intramuscular injection weekly; Glatiramer acetate 20 mg subcutaneous injection daily; Interferon beta-1b (Betaseron) 0.25 mg (1 ml) subcutaneously every other day; Interferon beta-1a (Rebif) 22 or 44 mcg subcutaneously three times a week; Dimethyl fumarate delayed-release capsules 120 mg twice daily for one week, then 240 mg twice daily; or Teriflunomide (7 or 14 mg tablet) once daily. 24 The authors suggest oral teriflunomide 7 mg daily for men or postmenopausal women with RRMS who don t want treatment with the better established MS therapies (eg, interferons and glatiramer acetate) that require injection. 24 According to Up to Date, additional data are needed to determine both the risk profile and the optimal dose of oral fingolimod for RRMS. 24 The authors state that based on two large trials (FREEDOMS and TRANSFORMS) oral fingolimod is an effective disease-modifying agent for RRMS, but its use is associated with a risk of varicella-zoster virus infections (potentially fatal) and tumor development. 24 It is also stated that subsequent reports suggest that fingolimod can cause or contribute to paradoxical worsening of MS disease activity, and further support the likelihood that the immunomodulating and lymphocytopenic effects of fingolimod increase the risk of viral infection. 24 There are concerns about fingolimod-linked deaths (4 due to cardiac events and 7 unexplained). 24 It is reported that a preliminary review by the FDA concluded that the contribution of fingolimod to these deaths is unclear, and that the number of reported deaths due to cardiovascular or unknown origin did not appear to be higher than in patients with MS who were not taking fingolimod. 24 The authors commented on the clinical use of fingolimod that even before concerns arose about the fingolimod-linked deaths discussed above, some experts believed that fingolimod should be reserved for patients who have an inadequate response to treatment with beta interferons or glatiramer acetate, at least until long-term safety data are available for fingolimod. 24,25 6

7 Clinical Efficacy Appendix 2 contains abstracts from systematic reviews focusing on these agents. The Oregon Drug Class review compared the effectiveness and safety of disease-modifying drugs for the treatment of multiple sclerosis, but did not include the oral agents. The review included glatiramer acetate (Copaxone ), interferon beta-1a (Avonex, Rebif ), interferon beta-1b (Betaseron, Extavia ), mitoxantrone (Novantrone ), and natalizumab (Tysabri ). 19 Fingolimod (Gilenya) Roskell et al. (2012) compared the annualized relapse rates after treatment with beta interferon, glatiramer acetate and fingolimod in patients with MS in a study funded by Novartis Pharmaceuticals. The variation of definitions of relapse and use of indirect comparisons are noted as limitations. According to the University of York Centre for Reviews and Dissemination (CRD), the authors conclusions that treatment with fingolimod was associated with significant reductions in relapse when used as first line treatment in patients with relapse remitting multiple sclerosis compared with beta interferon and glatiramer acetate are likely to be reliable. 26 In March 2013, the University of Utah College of Pharmacy prepared a Fingolimod (Gilenya ) Drug Review (AHFS 92:20, Biologic Response Modifiers) for the P&T Committee. Clinical data evaluating the efficacy of fingolimod in the treatment of MS were limited. The report stated that in comparative clinical trials, relapse rate is significantly improved with fingolimod compared to either interferon beta or placebo. No additional clinical benefit was demonstrated with fingolimod at doses greater than 0.5 mg. Data from follow-up trials indicate sustained efficacy and no increases in adverse events for 36 months. Limited data from a subgroup analysis indicate efficacy of fingolimod treatment across patients with a wide range of clinical features. Limited comparative clinical evidence suggests fingolimod is more effective than placebo and has similar efficacy as interferon beta. Teriflunomide (Aubagio) A 2012 Cochrane review (He et al.) found low level evidence for the use of teriflunomide as a diseasemodifying therapy for MS due to the limited quality of the available RCTs. It is reported that the authors were unable to give clear recommendations because of study quality limitations, short duration of studies, and potential bias. 27 In March 2013, the University of Utah College of Pharmacy prepared a Teriflunomide (Aubagio ) Drug Review (AHFS 92:20, Biologic Response Modifiers) for the P&T Committee. Clinical data evaluating the efficacy of teriflunomide in the treatment of MS were limited. The report stated that in comparative clinical trials, improvements in lesions seen on an MRI scan are significantly improved with teriflunomide therapy compared to placebo. Some evidence suggests improvement in relapse rate with teriflunomide therapy as well. Data from follow-up trials indicate sustained efficacy and no increases in adverse events. Limited clinical evidence suggests teriflunomide in combination with interferon beta is more effective than interferon beta alone. Dimethyl fumarate (Tecfidera) A 2014 systematic review of the efficacy and safety of dimethyl fumarate (Kawalec et al.) included two trials (DEFINE and CONFIRM), and showed that dimethyl fumarate taken as 480 mg in two divided doses or as 720 mg in three divided doses is effective in the treatment of RRMS compared to placebo in terms of reduced proportion of patients who had a relapse by 2 years, the rate of disease disability progression, and the mean number of brain lesions at 2 years. 28 One group of the patients in the confirm trial (third group), received glatiramer 20 mg daily and it was reported that dimethyl fumarate could potentially be more effective than glatiramer. 28 7

8 Safety In addition to the information provided in this section, please also refer to the Systematic review section and appendix 1. Fingolimod (Gilenya) The most common adverse events reported with fingolimod therapy include headache, influenza, elevated liver enzymes, diarrhea, back pain, and cough. 13 Serious adverse events associated with fingolimod therapy include cardiovascular abnormalities (bradycardia and atrioventricular (AV) block). Fingolimod therapy is associated with first-dose bradycardia occurring within 6 hours of the first dose and it is only available through specialty pharmacies or the manufacturers First Dose Program. Patients at higher risk of cardiac effects were excluded from the FREEDOMS and TRANSFORMS studies. 29 Fingolimod is metabolized by the CYP4F2 isoenzyme and has not demonstrated induction or inhibition of any of the major CYP P450 enzymes or interactions with any of the major P-glycoproteins or other transporters. Several monitoring requirements are recommended (refer to appendix 1). Natalizumab to fingolimod switching: It has been reported that internationally, fingolimod has now become the drug of choice for patient MS on natalizumab who are JCV seropositive and are at high-risk of developing PML. 23 However, it has also been reported that there is a risk of carry-over PML when switching from natalizumab to fingolimod. 23 The NHS Clinical commissioning policy states that neurologists have implemented various protocols with variable washout periods, and it is recommended that patients who are switched from natilizumab to fingolimod have a wash out period of at least 8 weeks. 23 The assumption is that by allowing CNS immune reconstitution to occur, postnatalizumab, this would limit the risks of PML occurring on fingolimod. It has also become clear that a prolonged natalizumab washout is associated with rebound disease activity. 23,30-33 It is also important to note that elimination of fingolimod takes approximately 2 months, and women of childbearing potential should use effective contraception to avoid pregnancy during and for 2 months after discontinuing treatment (Pregnancy Category C). 34 Teriflunomide (Aubagio) The most common adverse events include elevated ALT, alopecia, headache, diarrhea, and nausea. Due to potential hepatotoxicity, Aubagio is contraindicated in severe hepatic impairment and concomitant use of Aubagio and hepatotoxic drugs should be avoided. Although hepatic side-effects are rare 35, baseline bilirubin and ALT levels should be obtained within 6 months before starting therapy and monitored at least monthly for the first 6 months of therapy. Aubagio is contraindicated in pregnancy (should be excluded prior to initiating Aubagio) and it is contraindicated in women of childbearing age that are not using reliable contraception. 14,36 8

9 Teriflunomide (Aubagio) black box warning: Hepatotoxicity: Severe liver injury, including fatal liver failure, has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of teriflunomide with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of teriflunomide therapy. Monitor ALT levels at least monthly for 6 months after starting teriflunomide. If drug-induced liver injury is suspected, discontinue teriflunomide and start an accelerated elimination procedure with cholestyramine or charcoal. Teriflunomide is contraindicated in patients with severe hepatic impairment. Patients with preexisting liver disease may be at an increased risk of developing elevated serum transaminases when taking teriflunomide. Risk of teratogenicity: Based on animal data, teriflunomide may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting teriflunomide. Teriflunomide is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during teriflunomide treatment or prior to the completion of an accelerated elimination procedure after teriflunomide treatment. 1 Teriflunomide may remain in serum for up to 2 years, and it is also found in semen. 24,37 It is recommended that men and women who wish to conceive a child should discontinue teriflunomide and undergo an accelerated drug elimination procedure using cholestyramine or activated charcoal powder for 11 days, and that pregnancy should be avoided until the serum concentration of teriflunomide is <0.02 mg/l. 24 Dimethyl fumarate (Tecfidera) The most common adverse events include flushing, abdominal pain, diarrhea, and nausea. 15 Flushing and gastrointestinal symptoms are common in the first 4-6 weeks and persist in approximately 5% of patients thereafter. Tecfidera could cause lymphopenia, and CBC with lymphocyte count should be measured; at baseline, within 6 months of starting treatment, then every 6 to 12 months thereafter and as clinically indicated is recommended. 15,35 In November 2014, the FDA announced that a patient with MS and a low lymphocyte count who had been taking Tecfidera (dimethyl fumarate) for four years, developed progressive multifocal leukoencephalopathy (PML) and later died. 38 It is reported that this patient was not taking any other drugs that affect the immune system or drugs that are thought to be associated with PML. 38 This is the only confirmed case of PML in a patient taking Tecfidera and the information has been added to the Tecfidera drug label. 15,38 PML is a rare and serious brain infection caused by the John Cunningham (JC) virus. The JC virus is a common virus that is harmless in most people but can cause PML in some patients who have weakened immune systems. Symptoms of PML are diverse and may include progressive weakness on one side of the body, clumsiness, vision problems, confusion, and changes in thinking, personality, memory, and orientation. The progression of deficits can lead to severe disability or death. 38 Place in therapy and potential criteria to be reviewed Factors and limitations to consider when considering the oral MS disease modifying agents place in therapy: Neurologist involvement and coordination of care: It is recommended to refer people suspected of having MS to a consultant neurologist. 39 Also, it is recommended to involve professionals who can best 9

10 meet the needs of the person with MS and who have expertise in managing MS. 39 Healthcare professionals could include consultant neurologists, MS nurses, physiotherapists and occupational therapists, speech and language therapists, psychologists, dieticians, social care and continence specialists, and GPs. 39 Treatment options: The evidence indicate that some agents may be more effective than others, but it is important to consider study limitations and potential bias, as well as the risk-benefit balance. Cost is another important consideration. It is not possible to recommend the same strategy for all patients because of the variation in the course of the disease as well as the variety of patient disabilities. 24 Modifiable risk factors for relapse or progression of MS: Apart from pharmacological treatment options, it is important to ensure other measures are implemented as well. NICE recommend (1) encouraging people with MS to exercise (regular exercise may have beneficial effects on their MS and does not have any harmful effects on their MS) (2) advising people with MS not to smoke (since it may increase the progression of disability) Special Populations: Fingolimod was not studied in pregnant (category C) or lactating women, children, or adults over 65 years of age. One clinical trial evaluating fingolimod use in Japanese patients confirmed efficacy of fingolimod in this patient population. Teriflunomide is contraindicated in pregnant women (category X) or women of childbearing age who are not using reliable contraception. Teriflunomide was not studied in lactating women, children, or adults over 65 years of age. Dimethyl fumarate was not studied in pregnant (category C) or lactating women, children, or adults over 65 years of age (did not include sufficient number of patients 65 years or older to determine whether they would respond differently from younger patients). 15 Comorbidities: Refer to Appendix 1 Efficacy: Refer to guideline and efficacy sections Administration: MS treatment options include self-injectable, infusion, and oral agents. Adverse effects: Refer to appendices 1 and 2. All disease-modifying medications used in MS are associated with various significant adverse events. Fingolimod has numerous adverse effects and some are less common, but potentially serious i.e. bradyarrhythmia, AV block (potentially fatal), macular edema, diminished respiratory function, infection and tumor development. 24 Refer to teriflunomide black box warning regarding hepatotoxicity and teratogenicity. Also, teriflunomide has numerous adverse effects and several serious adverse effects i.e. Stevens-Johnson syndrome, toxic epidermal necrolysis, neutropenia, liver failure, peripheral neuropathy, raised serum creatinine, and interstitial lung disease. 40 One recent confirmed case of PML in a patient taking dimethyl fumarate (Tecfidera) has been reported. 38 Other serious adverse effects reported for dimethyl fumarate include lymphocytopenia, anaphylaxis, infectious disease, and angioedema. 41 Teriflunomide is considered a hazardous agent and appropriate precautions should be taken for handling and disposal of the drug. Duplication of therapy: Patients are generally treated with one DMD at a time; Worsening disease is sometimes treated with combination DMD therapy, but the decision to escalate immunotherapy is based on limited evidence 42 Fingolimod should be used as monotherapy. There are no published data concerning safety and efficacy of fingolimod as combination therapy in MS. 43 Tecfidera is not recommended to be used concomitantly with other disease-modifying drugs in the treatment of MS. The safety and effectiveness of teriflunomide when used in combination with other disease-modifying MS medications has not been established. Concomitant use of teriflunomide and leflunomide (indicated for treatment of rheumatoid arthritis) is contraindicated. Monitoring: Refer to appendix 1 Economic evaluations: A cost effectiveness study (from a US societal perspective) revealed that Tecfidera was dominant over Gilenya, Aubagio, and IM (IFN)-β 1a over the range of incremental net monetary benefit willingness-to-pay ($0 to $180,000). They concluded that all three oral therapies were favored in the analysis with Tecfidera 10

11 being the dominant therapy for management of RRMS. Aubagio was the most cost-effective therapy (ICER = $7,115) when compared to IFN- β 1a, apart from Tecfidera. 44 A 2011 published study evaluated the cost effectiveness of natalizumab in comparison with fingolimod for the treatment of patients with relapsing multiple sclerosis. 45 The authors concluded that their results suggest that natalizumab was less costly and more effective than fingolimod for treatment for relapsing multiple sclerosis. 45 The CRD s critical appraisal of this study states that the study was based on valid methods, the data sources and results were reported clearly, and the authors' conclusions appear appropriate

12 Utah Medicaid Utilization Data ALL CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Dimethyl Fumarate Tecfidera Delayed Release Capsule 120 MG Dimethyl Fumarate Tecfidera Delayed Release Capsule 240 MG Fingolimod HCl Gilenya Capsule 0.5 MG Teriflunomide Aubagio Tablet 14 MG Teriflunomide Aubagio Tablet 7 MG PHARMACY CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Dimethyl Fumarate Tecfidera Delayed Release Capsule 120 MG Dimethyl Fumarate Tecfidera Delayed Release Capsule 240 MG Fingolimod HCl Gilenya Capsule 0.5 MG Teriflunomide Aubagio Tablet 14 MG Teriflunomide Aubagio Tablet 7 MG MEDICAL CLAIMS GENERIC DESCRIPTION CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Dimethyl Fumarate Tecfidera Delayed Release Capsule 120 MG Dimethyl Fumarate Tecfidera Delayed Release Capsule 240 MG Fingolimod HCl Gilenya Capsule 0.5 MG Teriflunomide Aubagio Tablet 14 MG Teriflunomide Aubagio Tablet 7 MG

13 Number of patients (A) Diagnosis MS ORAL THERAPY AND DIAGNOSIS* ICD TOTAL PATIENTS PERCENT Multiple Sclerosis (MS) % TOTAL UNIQUE PATIENTS ON MS ORAL DRUGS % TOTAL UNIQUE PATIENTS ON ANY MS THERAPY 485 * Diagnosis date within 60 days before or 60 days after receiving MS oral drug. Including self-injectable, infusion, and oral MS drugs Self-injectables: Interferon beta-1a (Avonex and Rebif), Peginterferon beta-1a (Plegridy), Interferon beta-1b (Betaseron and Extavia), or Glatiramer acetate (Copaxone) Infusion: Mitoxantrone (Novantrone), or Natalizumab (Tysabri) Oral: Teriflunomide (Aubagio), Fingolimod (Gilenya), or Dimethyl fumarate (Tecfidera) (B) Age and Sex Age and sex M F 2 0 < >64 Age TOTAL PATIENTS AGE* M F Total < > TOTAL * Age at first fill.

14 (C) Prescribers Prescribers Neurologist Nurse Practitioner Physician Assistant Psychiatrist Unknown Geriatric Medicine Osteopath Number of prescribers PRESCRIBER TYPE* TOTAL CLAIMS Osteopath % Geriatric Medicine % Unknown % Psychiatrist % Physician Assistant % Nurse Practitioner % Neurologist % TOTAL CLAIMS 316 * Prescribers of medications dispensed at a pharmacy. 14

15 Conclusions All disease-modifying agents used in the treatment of MS are associated with safety concerns of varying degree, and safety measures and surveillance are therefore important with the use of these products. These products should only be used by neurologists in patients with MS after assessing the risk versus benefit of all available treatment options for each individual patient. It is important to ensure that patients are appropriately monitored. The number of patients that have been treated with these oral agents is low, but it has been increasing over the last few years. There were only pharmacy claims for these oral agents (no medical claims). The majority of patients have been filling prescriptions for Tecfidera, which appears reasonable when considering the adverse effect profiles and monitoring requirements of the oral agents. MS diagnosis codes have been submitted for all patients that have been filling prescriptions for these oral MS drugs. None of the patients that have received these oral products were <18 or >64 years old. Some prescribers other than neurologists have been prescribing these drugs which may indicate collaborative work with neurologists or some minimal off-label use. However, given the lack of RCTs with high methodological quality available, the lack of long-term safety data, and the potential serious adverse effects and monitoring requirements with these agents, you may wish to consider prior authorization approval prior to coverage. 15

16 Potential clinical criteria You may wish to consider the following criteria: Fingolimod (Gilenya) Patient must have a diagnosis of RRMS Must be 18 years of age or older Neurologist consult within 60 days Has a documented failure, contraindication, or intolerance to at least ONE of the other multiple sclerosis immunomodulator agents (see clinical considerations) Clinical considerations could include: Whether patient has previously been treated with an injectable disease-modifying agent (interferon, glatiramir, natalizumab, or mitoxantrone) Patients must be observed for 6 hours after the initial dose and all other doses where the patient has not received the medication for two weeks or longer (with appropriate resuscitative equipment available) Is patient varicella antibody positive, or has the patient been vaccinated? First dose should be withheld for 1 month following immunization in antibody-negative patients Quantity limitations: maximum of a 30 day supply per fill. The recommended dose of Gilenya is 0.5 mg orally once daily. Higher doses are associated with a greater increase of adverse reactions without additional benefit. Cocomitant use: That coverage NOT be provided for concomitant use with other disease-modifying drugs for MS. Teriflunomide (Aubagio) Patient must have a diagnosis of RRMS Must be 18 years of age or older Neurologist consult within 60 days Has a documented failure, contraindication, or intolerance to at least ONE of the other multiple sclerosis immunomodulator agents (see clinical considerations) Clinical considerations could include: Whether patient has previously been treated with an injectable disease-modifying agent (interferon, glatiramir, natalizumab, or mitoxantrone) Teriflunomide is the active metabolite of leflunomide (Arava) Quantity limitations: 30 day supply per fill. The recommended dose of Aubagio is 7 mg or 14 mg daily. Cocomitant use: That coverage NOT be provided for concomitant use with other disease-modifying drugs for MS. That coverage NOT be provided for concomitant use with leflunomide. Dimethyl fumarate (Tecfidera) Patient must have a diagnosis of RRMS Must be 18 years of age or older Neurologist consult within 60 days Has a documented failure, contraindication, or intolerance to at least ONE of the other multiple sclerosis immunomodulator agents (see clinical considerations) Clinical considerations could include: Whether patient has previously been treated with an injectable disease-modifying agent (interferon, glatiramir, natalizumab, or mitoxantrone) 16

17 Evidence of a Complete Blood Count with Differential from the past 6 months Patient does not have active or chronic infection at the time of initiation of therapy with Tecfidera Quantity limitations: 60 capsules per 30 days. The recommended dose of Tecfidera is 120mg twice daily for 7 days, and then 240mg twice daily therafter. Concomitant use: That coverage NOT be provided for concomitant use with other disease-modifying drugs for MS. Patient is NOT on concomitant therapy with antineoplastic, immunosuppressive, or immune modulating therapies. 17

18 Appendix 1 Drug information Name Class Labeled indication Teriflunomide (Aubagio ) 1,14,40 Pyrimidine synthesis inhibitor Fingolimod Sphingosine 1- (Gilenya ) 13,40,47 phosphate receptor modulator Relapsing forms of MS Relapsing forms of MS Oral agents MS Dose Adverse reactions Warnings/precautions Special considerations 7-14 mg per mouth Pregnancy risk factor X. once daily 0.5 mg per mouth once daily Headache, alopecia, hypophosphatemia, diarrhea, nausea, neutropenia, increase in ALT, influenza Headache, diarrhea, increase of ALT/AST, back pain, flulike symptoms [US Boxed Warning]: hepatotoxicity and increased risk of birth defects Hyperkalemia, hypertension, infections, interstitial lung disease, malignancy, peripheral neuropathy, transient acute renal failure, rare skin reactions AV block, bradycardia, hepatic effects, hypertension, infections, macular edema, neurotoxicity, respiratory effects, QT prolongation Contraindicated in patients with NYHA class III/IV heart failure in the past 6 months, 2-3 degree AV block, baseline QT >=500 msec Closely monitor in patients with cardiovascular disease or hepatic impairment. Pregnancy risk factor C REMS: To inform healthcare providers of the serious risks associated with fingolimod, including bradyarrhythmia and atrioventricular block when treatment is initiated, infection, macular edema, respiratory or hepatic effects, and fetal risk Dimethyl fumarate (Tecfidera ) 40,48 Fumaric acid derivative (immunomodul ator) Relapsing forms of MS Starting dose: 120 mg per mouth twice daily for 7 days Maintenance dose: 240 mg per mouth twice daily Flushing, abdominal pain, diarrhea, nausea, infection Dermatitis, flushing, GI events, elevation of transaminase, lymphopenia, proteinuria Pregnancy risk factor C

19 MONITORING (from Micromedex Drug Comparisons) 40 Fingolimod reduction in multiple sclerosis relapse rate is indicative of efficacy CBC, including differential, in patients who do not have a recent CBC (within 6 months) varicella zoster virus (VZV) antibody status in those patients without a history of chickenpox or VZV vaccination, before initiation of fingolimod transaminase and bilirubin concentrations before initiation of therapy in those without recent levels (within 6 months); hepatic enzymes levels during therapy in patients who develop symptoms of hepatic dysfunction, or in those with severe hepatic impairment blood pressure during treatment bradycardia (signs and symptoms) for 6 hours after the first dose in all patients; additionally if 6 hours after the first dose the heart rate is less than 45 beats/min, or is at the lowest value; if fingolimod dosing is being reinitiated after being interrupted for 1 day or more during the first 2 weeks of therapy; for more than 7 days during the third or fourth week of therapy; or for more than 14 days after the first month of therapy ECG; baseline and at end of 6-hour postdose observation period after first dose, and if fingolimod dosing has been interrupted for 1 day or more during the first 2 weeks of therapy, for more than 7 days during the third or fourth week of therapy, or for more than 14 days after the first month of therapy and is being reinitiated continuous overnight ECG; in patients with preexisting conditions (eg, uncontrolled hypertension, atrioventricular block, cerebrovascular disease, congestive heart failure, history of cardiac arrest, history of myocardial infarction, history of recurrent syncope, history of symptomatic bradycardia, ischemic heart disease, severe untreated sleep apnea, or sino-atrial heart block), prolonged QT interval or at greater risk for prolonged QT interval (eg, congenital long-qt syndrome, hypokalemia, hypomagnesemia, concurrent QTprolonging medications), or those receiving heart-rate lowering medications (eg, beta blockers, digoxin, heartrate lowering calcium channel blockers such as diltiazem, and verapamil); and after the first dose and upon reinitiation of therapy if fingolimod dosing has been interrupted for 1 day or more during the first 2 weeks of therapy, for more than 7 days during the third or fourth week of therapy, or for more than 14 days after the first month of therapy ophthalmologic examinations (visual acuity) at baseline and 3 to 4 months after staring fingolimod in all patients; additionally, patients experiencing visual disturbances at any time during treatment, those with diabetes or a history of uveitis should have regular follow-up ophthalmologic evaluations Teriflunomide reduction in multiple sclerosis relapse rate is indicative of efficacy pregnancy test prior to treatment and during treatment when pregnancy suspected CBC with differential; within 6 months prior to treatment initiation and during therapy if clinically indicated serum transaminases and bilirubin; within 6 months prior to treatment initiation and then ALT (SGPT) at least monthly for the first 6 months of therapy blood pressure before initiating therapy and periodically thereafter Dimethyl fumarate a reduction in multiple sclerosis relapse rate is indicative of efficacy CBC with lymphocyte count; at baseline, within 6 months of starting treatment, then every 6 to 12 months thereafter and as clinically indicated 19

20 Appendix 2 Systematic reviews Cochrane review(s) Author/Date Title Objective Main results Author s Conclusion He D, et al. Teriflunomide for (2012) 27 multiple sclerosis To explore the potential benefits of teriflunomide and so expand the available DMT options, the effectiveness and safety of teriflunomide, as monotherapy or combination therapy, were assessed versus placebo or approved DMDs (IFN-β, glatiramer acetate, natalizumab, mitoxantrone, fingolimod) for modifying disease in patients with MS. 27 Two studies involving 1204 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFN-β, versus placebo for adult patients with relapsing forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)) and an entry Expanded Disability Status Scale (EDSS) score of 5.5. Both studies had high attrition bias (26.8% and 36.4% attrition respectively). Teriflunomide 7 or 14 mg alone had potential benefits on reducing relapse rates, and alone or with add-on IFN-β was safe for patients with relapsing forms of MS in the short term. The most common adverse events included nasopharyngitis, headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, back pain, urinary tract infection, and pain in the arms or legs. Four ongoing trials were identified. We found low-level evidence for the use of teriflunomide as a disease-modifying therapy for MS, due to the limited quality of the available RCTs. We did not conduct meta-analysis because of the clinical and methodological diversity of the included studies. Short-term teriflunomide, 7 or 14 mg alone or with add-on IFN-β, was safe for patients with relapsing MS. Both teriflunomide 7 and 14 mg alone had potential benefits for patients with relapsing forms of MS. We are waiting for the publication of ongoing trials. RCTs with high methodological quality and longer periods of observation are needed to assess safety, disability progression, neuroprotection and quality of life. Plain language summary He et al. New disease-modifying therapies (DMTs) with less invasive routes of administration and new modes of action are in development to expand the available DMT options and enhance adherence, thereby improving efficacy. Teriflunomide is an oral disease-modifying drug with immunosuppressive and immunomodulatory properties.the authors of this review assessed the efficacy and safety of teriflunomide in patients with different forms of MS (relapsing-remitting (RRMS), secondary progressive (SPMS) with relapse, and progressive relapsing MS (PRMS)). They took into account the annualised rate of relapse, the proportion of patients free of disability progression, and the number of brain lesions. Among the pertinent literature, two studies met the inclusion criteria. They involved a total of 1204 patients and evaluated the efficacy and safety of teriflunomide alone or with add-on IFN-β, respectively, versus placebo. The authors were unable to give any clear recommendations for the use of teriflunomide as a DMT for MS because the studies had limited quality, were of short duration and were funded by a pharmaceutical company. As far as safety is concerned, common adverse events included headache, diarrhoea, fatigue, elevated alanine aminotransferase levels, nausea, hair thinning or decreased hair density, influenza, and urinary tract infection. Future studies are needed with higher methodological quality, a better evaluation of the adverse events, and a longer period of teriflunomide administration. Other review(s) - Database of Abstracts of Reviews of Effects/DARE abstracts Authors Title Objective Main results Author s Conclusion / CRD Kawalec P, et al. (2014) 28 The effectiveness of dimethyl fumarate monotherapy in the treatment of To assess the efficacy and safety of dimethyl fumarate ((BG-12, Tecfidera ) in the treatment of RRMS Two trials, DEFINE and CONFIRM involved patients and compared dimethyl fumarate taken either two or three times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients received glatiramer acetate. The overall results of the meta-analysis showed that summary Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinical disease parameters and other measures of disease activity in RRMS. The safety CRD commentary DARE Provisional Abstract (Systematic review that meets the criteria for inclusion on DARE.)

21 Roskell NS, et al. (2012) 26 relapsingremitting multiple sclerosis: a systematic review and meta analysis Annualized relapse rate of first line treatments for multiple sclerosis: a meta analysis, including indirect comparisons versus fingolimod To compare the annualised relapse rates after treatment with beta interferon, glatiramer acetate and fingolimod in patients with multiple sclerosis. BG-12 (at both dosages) given to patients with RRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who had a relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years. The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be more effective in the treatment of RRMS. Fourteen trials (6,717 participants, range 50 to 1,345) were included in the review. Ten trials reported allocation concealment and 12 studies used intention to treat analyses. Most studies were reported to be appropriately blinded. Baseline characteristics for the treatment groups were described as similar across the studies.results of the mixed treatment comparison found that fingolimod administered at 0.5mg conferred significantly greater benefits than all comparators, with lower annualised relapse rates (ARR) compared to interferon beta 1a 30mcg (6 MIU) (ARR 1.67, 95% CI 1.32 to 2.10), interferon beta 1a 22mcg (ARR 1.55, 95% CI 1.26 to 1.90), interferon beta 1a 44mcg (ARR 1.93, 95% CI 1.59 to 2.34), interferon 1b 250mcg (ARR 1.51, 95% CI 1.22 to 1.860) and glatiramer acetate (ARR 2.32, 95% CI 1.95 to 2.77).Covariate analyses showed significant effects of baseline Expanded Disability Scale Scores (ARR 1.63, 95% CI 1.04 to 2.56; 13 trials) and year of publication (ARR 0.96, 95% CI 0.94 to 0.98). Repeat mixed treatment analyses with adjustments for each covariate found no differences between actual relative treatment effects for the unadjusted models. There were no significant differences in results from the mixed treatment comparison model and those from head to head comparisons. Estimates provided by the reduced Χ² statistic indicated a reasonably good fit for both the adjusted and unadjusted models. Informal assessment of the model fit showed that the mixedtreatment comparison derived relative rates closely matched to rates from head to head trials. profile of the study agent was acceptable. Authors' conclusions: Treatment with fingolimod was associated with significant reductions in relapse when used as first line treatment in patients with relapse remitting multiple sclerosis compared with beta interferon and glatiramer acetate. CRD summary This review found that first line treatment in patients with multiple sclerosis with fingolimod was associated with significant decreases in relapse rates compared to beta interferon and glatiramer acetate. The results were derived from indirect comparisons between the treatments but the authors' cautious conclusions are likely to be reliable. 49 The review outlined a defined question and criteria for the inclusion of studies in the review were outlined. The search was comprehensive; various appropriate databases were searched for relevant studies and attempts were made to identify unpublished studies. The search was performed without language restrictions but articles in languages other than English were excluded from the review and this may have introduced language bias. Steps were taken to minimise errors and bias during study selection and data extraction but were not reported for the assessment of methodological quality. The reviewers assessed study quality using sensible criteria and the quality of the included trials was generally good. The authors acknowledged limitations of the review due to variation of definitions of relapse across the trials and use of indirect comparisons to provide estimates of efficacy. The study was funded by Novartis Pharmaceuticals (manufacturer of fingolimod). The authors' cautious conclusions reflected the evidence presented 21