CLINICAL REVIEW
`
`Application Type NDA
`Application Number 204063
`Priority or Standard Standard
`
`Submit Date 2-27-2012
`Received Date 2-27-2012
`PDUFA Goal Date 3-27-2013
`Division I Office DNP/OND 1/ ODE 1
`
`Reviewer Name Heather Fitter, M.D.
`Review Completion Date 11-08-2012
`
`Established Name BG00012 (BG-12)
`(Proposed) Trade Name Tecfidera
`Therapeutic Class Dimethyl Fumarate
`Applicant Biogen Idee
`
`Formulation Oral
`Dosing Regimen 240 mg bid
`Indication
`
`- - - - .(6)(41
`
`Intended Population Relapsing forms of Multiple
`Sclerosis
`
`Template Version: March 6, 2009
`
`Reference ID: 3214416
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`Biogen Exhibit 2372
`Biogen MA, Inc. v. Forward Pharma A/S
`Interference No. 106,023
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`1 of 114
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`Biogen Exhibit 2003
`Mylan v. Biogen
`IPR2018-01403
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`Page 1 of 114
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 9
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 9
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information ............................................................................................ 9
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 10
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 13
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 13
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 14
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 16
`3.1 Submission Quality and Integrity ...................................................................... 16
`3.2 Compliance with Good Clinical Practices ......................................................... 17
`3.3 Financial Disclosures........................................................................................ 18
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 20
`4.1 Chemistry Manufacturing and Controls ............................................................ 20
`4.2 Preclinical Pharmacology/Toxicology ............................................................... 21
`4.3 Clinical Pharmacology...................................................................................... 23
`4.3.1 Mechanism of Action.................................................................................. 23
`4.3.2 Pharmacodynamics.................................................................................... 23
`4.3.3 Pharmacokinetics....................................................................................... 24
`5 SOURCES OF CLINICAL DATA............................................................................ 25
`5.1 Tables of Studies/Clinical Trials.......................................................................... 25
`5.2 Review Strategy.................................................................................................. 26
`5.3 Discussion of Individual Clinical Trials ................................................................ 26
`5.3.1 Protocol C-1900 .......................................................................................... 26
`5.3.1.1. Efficacy Results Trial C-1900.............................................................................27
`5.3.1.1.1 Trial Population ............................................................................................27
`5.3.1.1.2 Efficacy Analysis ..........................................................................................28
`5.3.2 Protocol 109MS301..................................................................................... 30
`5.3.2.1 Efficacy Results Trial 301....................................................................................48
`5.3.2.1.1 Trial Population ............................................................................................48
`5.3.2.1.2 Efficacy Analysis ..........................................................................................51
`5.3.3 Protocol 109MS302..................................................................................... 64
`5.3.3.1 Efficacy Results Trial 302....................................................................................70
`5.3.3.1.1 Trial Population ............................................................................................70
`5.3.3.1.2 Efficacy Analysis ..........................................................................................74
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`5.3.4 Protocol 109MS303..................................................................................... 87
`5.3.4.1. Efficacy Results Trial 303...................................................................................88
`5.3.4.1.1 Trial Population ............................................................................................88
`5.3.4.1.2 Efficacy Analysis ..........................................................................................88
`6 REVIEW OF EFFICACY......................................................................................... 90
`6.1 Indication ........................................................................................................... 90
`6.1.1 Methods ...................................................................................................... 90
`6.1.2 Demographics ............................................................................................. 90
`6.1.3 Subject Disposition...................................................................................... 92
`6.1.4 Analysis of Primary Endpoints..................................................................... 94
`6.1.5 Analysis of Secondary Endpoints................................................................ 95
`6.1.5.1 Number of New or Newly Enlarging T2 Hyperintense Lesions ...........................95
`6.1.5.2 Number of Gd-enhancing lesions at 2 years.......................................................96
`6.1.5.3 New T1 hypointense lesions ...............................................................................97
`6.1.5.4 Annualized relapse rate/proportion relapsing......................................................98
`6.1.5.5 Disability progression ..........................................................................................99
`6.1.6 Other Endpoints ........................................................................................ 101
`6.1.7 Subpopulations ......................................................................................... 102
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations ... 105
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................ 106
`6.1.10 Discussion of the Presence of Withdrawal Effects .................................. 107
`6.1.11 Additional Efficacy Issues/Analyses ........................................................ 108
`7 REVIEW OF SAFETY........................................................................................... 113
`
`8 POSTMARKET EXPERIENCE............................................................................. 113
`
`9. APPENDICES......................................................................................................... 113
`9.1 Labeling Recommendations ........................................................................... 113
`9.2 Advisory Committee Meeting.......................................................................... 113
`
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`
`Table of Tables
`
`Table 1: Table of currently available treatments for proposed indications..................... 11
`Table 2: Financial disclosure trial 301, earnings over $100,000 and enrollment ≥ 5 ..... 19
`Table 3: Financial disclosure trial 302, earnings over $100,000 and enrollment ≥ 5
`subjects, with one exception. ......................................................................... 20
`Table 4: List of BG-12 trials that contributed to efficacy analysis .................................. 26
`Table 5: Study C-1900 summary of key efficacy results (efficacy evaluable population)
`....................................................................................................................... 29
`Table 6: Laboratory criteria requiring withholding or permanent discontinuation of
`blinded study treatment.................................................................................. 35
`Table 7: Blinded study treatment dosing regimen ......................................................... 37
`Table 8: Trial 301 study activities, visit 1-12, chart 1/3.................................................. 38
`Table 9: Trial 301 study activities: visits 13-25, chart 2/3 .............................................. 39
`Table 10: Trial 301 study activities with premature study withdrawal visit and
`unscheduled relapse visit, chart 3/3............................................................... 39
`Table 11: Disposition of subjects in trial 301 ................................................................. 49
`Table 12: Summary of number of subjects and reasons for exclusion from the per-
`protocol population (trial 301) ........................................................................ 50
`Table 13: Baseline MRI evaluation- MRI cohort Trial 301 ............................................. 51
`Table 14: Summary of the proportion of subjects relapsed (INEC confirmed relapses) at
`2 years -ITT ................................................................................................... 52
`Table 15: Summary of proportion of subjects relapsed (INEC confirmed) at 2 years -
`sensitivity analysis reassigning status of patients that reported an unknown
`relapse status-ITT population ........................................................................ 53
`Table 16: Results of sensitivity analyses of the primary endpoint (trial 301) ................. 54
`Table 17: Number of new or newly enlarging T2 lesions at 2 years compared to
`baseline-MRI cohort (trial 301)....................................................................... 55
`Table 18: Number of Gd enhancing lesions at 2 years-MRI cohort (trial 301)............... 55
`Table 19: Summary of ARR (INEC confirmed) at 2 years- ITT population .................... 56
`Table 20: Summary of time to confirmed progression of disability as measured by an
`increase in EDSS (12 week confirmation)-ITT (trial 301) ............................... 57
`Table 21: Change of MSFC z score from baseline to 2 years- ITT (trial 301) ............... 59
`Table 22: MSFC: Change of actual scores from baseline to 2 years- ITT population (trial
`301)................................................................................................................ 60
`Table 23: Subgroup analyses (trial 301)........................................................................ 63
`Table 24: Key demographic and baseline characteristics- MRI cohort and non-MRI
`cohort (trial 302)............................................................................................. 74
`Table 25: Summary of ARR (INEC confirmed) at 2 years-ITT (trial 302)....................... 76
`Table 26: MRI: Number of new or newly enlarging T2 lesions at 2 years compared to
`baseline- MRI cohort (trial 302)...................................................................... 77
`Table 27: Number of new T1 hypointense lesions at 2 years compared to baseline- MRI
`cohort (trial 302)............................................................................................. 78
`Table 28: Summary of time to confirmed disability progression at 2 years- per protocol
`population (trial 302) ...................................................................................... 81
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`Table 29: MSFC: Change of raw scores from baseline to 2 years- ITT (trial 302)......... 82
`Table 30: ARR with 95% CI for subjects randomized to placebo then active study
`treatment (trial 303)........................................................................................ 90
`Table 31: Demography in terms of distribution of regions between trials and treatment
`groups............................................................................................................ 91
`Table 32: Trial subject disposition ................................................................................. 92
`Table 33: Efficacy results of ARR and proportion relapsing- ITT (trials 301 and 302)... 94
`Table 34: Number of new and newly enlarging T2 hyperintense lesions at 2 years
`compared to baseline (trial 301 and 302)....................................................... 96
`Table 35: Number of Gd enhancing lesions at 2 years- MRI cohort (trials 301, 302) .... 97
`Table 36: Number of new T1 hypointense lesions over 2 years- MRI cohort (trial 301
`and 302)......................................................................................................... 98
`Table 37: Disability progression in trial 301, 302 and pooled analysis ........................ 101
`Table 38: Summary of ARR (INEC confirmed) at 2 years by EDSS score (trials 301 and
`302 pooled).................................................................................................. 103
`Table 39: Summary of proportion of subjects relapsed (INEC confirmed) at 2 years by
`region- ITT (trial 301) ................................................................................... 104
`Table 40: Summary of ARR (INEC confirmed) at 2 years by region- ITT (trial 302)... 105
`Table 41: Estimated proportion of relapsing patients based on the presence of the
`adverse event of flushing (trial 301)............................................................. 108
`Table 42: Estimated ARR based on the presence of the adverse event of flushing (trial
`302).............................................................................................................. 108
`Table 43: Summary of proportion of subjects relapsed (INEC confirmed) at 2 years by
`dose reduction/interruption status (trial 301)................................................ 110
`Table 44: Summary of ARR (INCEC confirmed) at 2 years by dose
`reduction/interruption status (trial 302)......................................................... 110
`Table 45: Summary of the proportion of subjects relapsed (INEC confirmed) at 2 years
`by the presence of minimum post baseline lymphocyte count <LLN (trial 301)
`..................................................................................................................... 112
`Table 46: Summary of ARR (INEC confirmed) at 2 years by the presence of minimum
`post baseline lymphocyte count <LLN (trial 302) ......................................... 112
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`
`Table of Figures
`
`Figure 1: Mean (+/- S.E.) number of new Gd-enhancing lesions (observed values) from
`scans at week 12 to week 24: efficacy-evaluable population......................... 29
`Figure 2: Study design trial 301..................................................................................... 32
`Figure 3: Time to first relapse (INEC confirmed relapses) -ITT population.................... 52
`Figure 4: Time to confirmed progression of disability as measured by increase in EDSS
`(12 week confirmation)-ITT (trial 301) ............................................................ 57
`Figure 5: Time to discontinuation of study drug- ITT population (trial 302).................... 71
`Figure 6: Patient disposition trial 302 ............................................................................ 71
`Figure 7: Summary of ARR (INEC confirmed) at 2 years-ITT population...................... 75
`Figure 8: Time to first relapse (INEC confirmed relapses) - ITT population (trial 302)... 79
`Figure 9: Time to confirmed progression of disability (12 week confirmation) as
`measured by increase in EDSS- ITT population (trial 302) ............................ 80
`Figure 10: Summary of number of relapses requiring IV steroid therapy at 2 years- ITT
`(trial 302)........................................................................................................ 83
`Figure 11: ARR (INEC confirmed) at 2 years- rate ratio for the BG-12 240 mg bid vs.
`placebo comparison and 95% CI by demographic subgroup (trial 302)......... 86
`Figure 12: ARR (INEC confirmed) at 2 years- rate ratio for the BG-12 240 mg tid vs.
`placebo comparison and 95% CI by demographic subgroup (trial 302)......... 87
`Figure 13: Overview of Subject Disposition in Trial 303 ................................................ 88
`Figure 14: Time to discontinuation of study treatment (pooled data 301 and 302)........ 93
`Figure 15: Time to sustained progression of disability at 2 years as measured by EDSS
`(12 week confirmation)-ITT (trials 301 and 302 pooled)............................... 100
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`
`1 Recommendations/Risk Benefit Assessment
`
`I recommend approval of the BG-12 240 mg dose to be taken orally twice daily for the treatment
`4
`of patients with relapsing forms of multiple sclerosis
`I
`(b)(
`
`1.1 Recommendation on Regulatory Action
`
`The pivotal clinical efficacy trials demonstrated that BG-12 is effective for the treatment of
`41
`atients with rela sin a fonns of multiple sclerosis
`(b)(
`The two efficacy trials,
`1 09MS30 1 and 1 09MS302 were adequate and well controlled trials that compared two doses of
`BG-12 to placebo on clinically relevant endpoints in multiple sclerosis patients over the course
`of 2 years. Trial 1 09MS30 1 was a placebo contmlled randomized double blind trial in patients
`with relapsing remitting multiple sclerosis (RRMS) that evaluated the safety and efficacy of BG-
`12 240 mg twice daily (bid), BG-12 240 mg three times daily (tid) and placebo in patients with
`RRMS. The primruy endpoint was the propotiion of patients relapsing at 2 years, and the key
`secondary endpoints were the number of new and newly enlarging T2 hyperintense lesions, the
`number of Gd-enhancing lesions, the annualized relapse rate (ARR) and the delay of disability
`progression sustained for 12 weeks. The second trial109MS302 was of sitnilar design except it
`included au additional treatment rum of an active compru·ator, Copaxone (GA), in an open label
`rater blinded only fashion. This atm is not considered a well controlled atm and therefore data
`from this atm is not considered to contribute to substantial evidence of effectiveness to supp01t
`comparative claitns for BG-12 over Copaxone. Trial109MS302 evaluated the pritnruy endpoint
`of the ARR and included key secondaty endpoints of the number of new and newly enlarging T2
`hyperintense lesions, the number of new T 1 hypo intense lesions, the prop01iion of subjects
`relapsing at 2 years and the delay of disability progression sustained for 12 weeks. Both trials
`rep01ied vety robust findings on the primaty clinical measures of relapse and were associated
`with p values of <0.0001 for all comparisons of active study treatment to placebo. These robust
`findings were fiuiher supp01ted by multiple relevant sensitivity analyses such as the per protocol
`population, worst case scenario analyses on dropouts and on the ITT including data after patients
`switched to altemative medications. In addition, all key secondaty MRI endpoints for the active
`treatment vs. placebo comparisons in both trials were highly supportive (p<0.0001) of efficacy.
`
`The pre-specified analysis for trial109MS301 was supp01tive of efficacy on the delay of
`disability progression for both doses studied, yet the disability progression analysis for
`1 09MS302 was not. In trial 1 09MS30 1, the prop01tion of subjects that progressed by 2 years was
`0.271, 0.164 and 0.177 for the placebo, BG-12 bid and BG-12 tid groups, respectively. This
`represented a reduction in the risk of confnmed disability progression by 38% (p=0.005) and
`34% (p=0.0128) for the BG-1 2 bid and BG-12 tid compru·ison to placebo, respectively. The
`proportion of patients that progressed by 2 years in trial109MS302 was 0.169, 0.128 and 0.130
`in the placebo, BG-12 bid and BG-12 tid groups, respectively. These differences between the
`placebo group and the active treatment groups on this endpoint did not represent a statistically
`significant effect ofBG-12 over placebo. The sponsor proposes that au effect of disability
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`progression was not seen in 109MS302 because the placebo group had a low progression rate as
`compared to that of the placebo group in trial 109MS301. Although this may be the case, this
`fact isn’t sufficient to invalidate the disability progression analysis from trial 109MS302. The
`fact is that the placebo group in this second pivotal trial is relatively well balanced to the other
`treatment groups and as such, should be adequate to demonstrate a treatment effect on this
`endpoint if one exists. Therefore, in summary we have one pivotal trial that shows a positive
`treatment effect on disability progression for BG-12 over placebo and one pivotal trial that does
`not. Many products that have been studied for the treatment of MS have demonstrated an effect
`on relapse but were not able to show an effect on disability progression. In order to show an
`effect on disability progression either longer studies or studies with larger number of patients are
`often required. Pooling of the data in this case gives us the opportunity to assess the strength of
`the evidence through another analysis.
`
`
`When the data from the two pivotal trials are pooled, the proportion of patients that progressed at
`2 years was 0.222, 0.146 and 0.125 in placebo, BG-12 bid and BG-12 tid, respectively. These
`differences represented statistically significant treatment effects for both the placebo vs. BG-12
`bid comparison (p=0.0034) and for the placebo vs. BG-12 tid comparison (p =0.0059). Further
`substantiation of this endpoint is provided by the robust effect on relapse and MRI lesion load
`reduction which are related clinical endpoints. I conclude that the data provided in this
`submission on the effect of BG-12 over placebo on disability progression sustained over 12
`weeks represent substantial evidence of effectiveness when the data is considered from trial
`109MS301 and the pooled analysis from trials 109MS301 and 109MS302.
`
`Both doses studied in these efficacy trials, BG-12 240 mg bid and 240 mg tid, had very
`comparable efficacy on the primary endpoints and all key secondary endpoints. Since the 240
`mg tid dose offered no additional efficacy to the 240 mg bid dose, I recommend approval of the
`240 mg bid dose only. The higher dose would offer no clear additional benefit and would be
`associated with poorer tolerability and safety.
`
`1.2 Risk Benefit Assessment
`
`The BG-12 development program for RRMS has demonstrated efficacy in both decreasing the
`rate of relapses and the proportion of subjects relapsing in both pivotal efficacy trials, as well as,
`in delaying disability progression in one pivotal placebo controlled trial and in the pooled
`analysis of both pivotal efficacy trials. In addition, this product showed robust effects on the
`reduction of MRI lesion burden through the reduction of new and newly enlarging T2
`hyperintense lesions, new Gd-enhancing lesions and new T1 hypointense lesions in patients
`enrolled in these trials. Therefore, benefit of this product has clearly been demonstrated for
`patients with RRMS. With adequate safety monitoring recommended in the product’s label this
`product should have an acceptable risk/benefit ratio. Please refer to Dr. Gerard Boehm’s safety
`review for a more detailed discussion of the risk assessment of this product.
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`Heather Fitter, M.D.
`NDA 204063
`BG-12
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`None recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`I recommend the requirement of a postmarketing trial for pediatric patients age 10 -17 conducted
`as a randomized, controlled parallel group superiority trial to evaluate the single and multiple
`dose pharmacokinetics of BG-12 and the safety and efficacy of BG-12 compared to
`control/placebo for the treatment of relapsing remitting multiple sclerosis followed by a long
`term extension study. I do not recommend a requirement to study patients under age 10 due to
`the small numbers of patients with MS in this age range, making the study of this these younger
`patients highly impractical.
`
`2 Introduction and Regulatory Background
`Multiple Sclerosis (MS) is a progressive neurologic illness with a distinctly variable phenotype
`and course in different individuals. The etiology remains unknown, although several factors,
`such as genetic susceptibility, autoimmune mechanisms, viral infection and sun exposure up to
`adolescence are thought to contribute to the development of MS in an individual. This illness is
`thought to trigger an autoimmune response that leads ultimately to demyelination in the central
`nervous system (CNS). More recently, data is accumulating to suggest that there also is a
`significant degree of gray matter involvement. Treatment for MS is generally directed in three
`areas 1) reduction of relapses, 2) delay of disability progression and/or 3) symptomatic relief.
`The development program for BG-12 has explored this medication’s utility to reduce relapses
`and delay disability progression. Currently there are several other first or second line therapies
`with this target. Most are injectable products yet two newer products are administered orally.
`One product, Gilenya, received marketing authorization in December 2010, is associated with
`multi-organ safety signals and requires six hours of monitoring in a clinic after administration of
`the first dose. The other oral product, Teriflunamide, has two safety signals described in a black
`box warning namely, hepatotoxicity and the risk of teratogenicity. BG-12 , if marketed, will
`provide another oral alternative to patients with MS.
`
`2.1 Product Information
`
`BG -12 is a fumarate ester drug product formulation that contains the active ingredient dimethyl
`fumarate (DMF). DMF is rapidly metabolized to its primary active metabolite, monomethyl
`fumarate (MMF). BG-12 is a new molecular entity (NME), and as such, has not been marketed
`in any region including the United States (US). A product that includes DMF in combination
`with other salts of monoethyl fumarate, Fumaderm, has received marketing authorization in 1994
`for the treatment of moderate to severe psoriasis in Germany.
`
` a size 0 hard
`The BG-12 product is formulated as
`gelatin capsule and will be available in two dosage strengths, 120 mg and 240 mg capsules if
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`(b) (4)
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`marketed. The recommended dose will be 240 mg bid, yet patients will be instructed to use 120
`mg bid for the first week and then increase the dose up to 240 mg bid to prevent common
`adverse events (AEs) with initiation of this product including gastrointestinal discomfort and
`flushing.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`
`Please refer to Table 1 below.
`
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`Table 1: Table of currently available treatments for proposed indications
`Indication
`Effect on
`Effect on
`Safety issues
`(of concern)
`exacerbation (exac)
`disability
`rate
`progression
`32% reduction (rn)
`37% rn
`
`
`Approved
`dose
`
`30 mcg IM
`q week
`
`0.25 mg sq
`qod
`
`22 mcg or
`44 mcg tiw
`
`20 mg sq q
`d
`
`12mg/m2
`IV q 3
`months
`
`300 mg IV
`q 4 weeks
`
`0.5 mg po q
`day
`
`decreased
`blood counts,
`hepatic injury,
`flu like
`symptoms
`injection site
`necrosis, flu
`like symptoms
`hepatic injury,
`flu like
`symptoms,
`injection site
`reaction
`
`Post injection
`reaction,
`transient
`chest pain,
`skin necrosis
`Cumulative
`cardiotoxicity,
`AML1
`
`PML2,
`immunosuppr
`ession,
`hepatotoxicity
`
`Bradycardia,
`macular
`edema,
`infection
`
`32% rn
`
`26% rn for
`14 mg
`
`Hepatotoxic,
`Teratogenic
`
`7 mg or 14
`mg po q d
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`
`
`Avonex
`(RMS)
`
`
`Betaseron
`(RMS)
`
`Rebif
`(RMS)
`
`Decrease
`clinical
`exac, slow
`physical
`disability
`Decrease
`clinical exac
`
`Decrease
`clinical
`exac, delay
`physical
`disability
`
`Copaxone
`(glatiramer
`acetate)
`(RMS)
`
`Mitoxantrone
`(SPMS or
`worsening
`RRMS)
`
`Tysabri
`(natalizumb)
`(RMS)
`
`Gilenya
`(fingolimod)
`(RMS)
`
`30% reduction
`
`22
`mcg
`29%
`rn
`
`44 mcg
`32 % rn
`vs.
`placebo
`and
`Avonex*
`75% rn in first trial
`(n=48)
`29% rn in second
`trial (n=251)
`
`60% rn
`exacerbations;
`Primary outcome:
`86% rn in new
`enhancing lesions
`61% rn
`
`None
`described in
`label
`27% rn
`
`None
`described in
`label
`
`64% rn
`
`
`33% rn
`
`54% rn
`
`30% rn
`
`Reduce
`relapses
`including
`patients with
`CIS
`Reduce
`neurologic
`disability
`and/or
`relapses
`To delay
`physical
`disability
`and reduce
`exac
`Decrease
`ARR and
`reduce
`disability
`progression
`Teriflunamide Treatment
`of RMS
`1 acute myelogenous leukemia
`2 progressive multifocal leukoencephalopathy
`*32% reduction in proportion of Rebif patients who experienced relapses compared to Avonex.
`
`Four classes of agents are approved as first line treatment for the prevention of clinical relapses
`in relapsing forms of MS. The first class is recombinant interferon-b (IFN-b), which includes
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`Clinical Review
`Heather Fitter, M.D.
`NDA 204063
`BG-12
`three formulations, specifically Avonex, Betaseron and Rebif. IFN-b is hypothesized to exert
`many effects at critical points in MS pathogenesis. It induces the expression of a number of
`genes and effects major histocompatability complex (MHC) gene expression, antiviral and
`antiproliferative actions and monocyte activation in vitro. The exact mechanism that leads to
`improvement in MS patients is not well understood1. Another first line compound is glatiramer
`acetate (GA), which is a random polypeptide made up of four amino acids in a specific molar
`ratio that resembles myelin basic protein. This compound is thought to exert its
`immunomodulatory effect due to altered T cell activation and differentiation2. Fingolimod
`(gilenya) is a third class of agent approved as first line treatment for MS. This product was the
`first oral agent approved for this indication and has a proposed mechanism related to its ability to
`sequester lymphocytes in lymph nodes, thereby reducing the number of circulating lymphocytes.
`This product is a sphingosine 1 phosphate receptor modulator and requires that the first dose be
`administered under medical supervision due to the associated risk of bradycardia. In addition,
`multiple safety concerns including the development of macular edema, case reports of sudden
`death, AV blocks, lymphopenia, infection, reduced pulmonary function tests and PML (generally
`following Tysabri use) have led to a cautious approach concerning the use of this product by the
`community. Teriflunomide was approved recently, September, 2012, and is another oral agent
`that reduces the frequency of relapses and delays the accumulation of physical disability (at the
`14 mg dose) in patients with