CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204063Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Management Review
`
`February 6, 2013
`
`Kendra Worthy, Pharm. D., Team Leader, Division of Risk
`Management (DRISK)
`
`
`
`
`Mary Willy, Ph.D., Director (Acting), DRISK
`
`Tecfidera (dimethyl fumarate) delayed release capsules,
`120mg, 240mg
`
`Treatment of patients with relapsing multiple sclerosis
`
`
`Indication(s):
`
`Application Type/Number: NDA 204063
`
`Applicant:
`
`
`
`Biogen Idec.
`
`
`
`Date:
`
`Reviewer(s):
`
`
`Division Director
`
`Drug Name(s):
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3256682
`
`

`

`1 Introduction
`
`Th's review documents the Divis'nn ofM Mamgermnt’s (DRISK) evaluation of the
`need ibr a risk figment strategy for dirmthyl finmrate.
`
`Biogen Idec Slbmitted NDA 204063 ibr Tecfflera (dinethyl finmrate) with the proposed
`indication fin rehpsilg toms of mllt'pb scbrosis. The applicant did not propose a
`REMS or a r'sk Imnagermnt phn (RMP).
`
`2 Background
`Dinethyl finmrate ‘3 under corsideratbn fi)r the treatnnnt of patients with rehpshg
`torus of nult'ple sclerosis.
`It '3 dosed 120 mg orally twi:e daily for 7 days fi)llowed b
`aimintenance dose of 240
`cm tw'ne
`. The
`
`to osed hbel states
`
`Dimthyl finmrate (as a conbnntion product with monoefllyl finmrate salts) '3 approved
`as Furmderm in Germany ibr the treatnent of psoriasis (1994).
`
`3 Regulatory history
`
`3.1 ProductLabeIing
`
`The FDA-edited proposed hbeling includes the bllowing adverse reactions in the
`Warnings and Precautiom section of the hbeling,
`
`o Lynphopenia and Risk of Infection
`
`0 Fishing
`
`The hbel does not have a boxed waming.
`
`4 Materials reviewed
`
`4.1 Data Information Sources
`
`0 Midcyck review slides, Gerakl Boehm, M.D., M.P.H. (safety), Medical Oflbers,
`Div'sion ofNeurology Products (DNP), dated January 9, 2013
`
`0 Draft clinbal rev'Bw (eflicacy) by Heather Fitter, M.D., FACS, Medical Oflicers,
`DNP dated November 8, 2012.
`
`0 Clinical review (saiety) byGerakl Boehm, M.D., M.P.H., Medical Oflicers, DNP
`dated Jammy 9, 2013.
`
`0 Draft substantially conpbte label, Tecfidera (dinnthyl finmrate), Biogen Idec,
`dated February 4, 2013.
`
`Reference ID: 3256682
`
`

`

`5 Results of review
`5.1 Overview of Clinical Program
`Efficacy for the drug was established in two randomized, placebo-controlled trials with
`2,665 exposed patients. One trial evaluated safety and efficacy of dimethyl fumarate 240
`mg twice daily and 240 mg three times daily compared to placebo, and the second with
`an additional treatment arm of an “active comparator, Copaxone, in an open label rater
`blinded only fashion”1. Primary endpoints included the proportion of patients relapsing
`at 2 years (first trial) and the annualized relapse rate (ARR) (second trial). Both trials
`included secondary endpoints related to MRI findings. The medical officer summarized
`that “both trials reported very robust findings on the primary clinical measures of relapse
`and were associated with p values of <0.0001 for all comparisons of active study
`treatment to placebo”1, and that “all key secondary MRI endpoints for the active
`treatment vs. placebo comparisons in both trials were highly supportive (p<0.0001) of
`efficacy”. 1
`
`Safety data was compiled from integrated data from 5 controlled trials with an MS arm
`(3) and psoriasis arm (2); each arm had open-label extension pools. The applicant also
`submitted postmarketing safety data for Fumaderm. Eleven deaths occurred; 9 in the
`treatment arm. Of those 9, seven occurred in the MS trials and 2 in the psoriasis trials.
`The integrated MS trials mortality was 0.3%, 1.6/1000 PY.2
`
`5.2 Safety Concerns
`
`Lymphopenia
`In the MS placebo controlled trials, treated patients experienced a 30% mean decline
`from baseline in lymphocyte count, and the mean lymphocyte count remained reduced at
`26% below baseline four weeks after discontinuation. The clinical safety reviewer states
`that the magnitude of the observed lymphocyte count decline with dimethyl fumarate is
`within the range of declines described for fingolimod and teriflunomide, two recently
`approved oral MS treatments.
`
`Flushing
`Flushing occurred in over 40% of treated patients. Flushing symptoms generally begin
`soon after initiating dimethyl fumarate and usually improve or resolve over time. Three
`percent (3%) of patients discontinued dimethyl fumarate for flushing and <1% had
`flushing symptoms that were serious. The label states that administration of dimethyl
`fumarate with food may reduce the incidence of flushing.
`
`Renal toxicity
`Kidney changes (tubular and interstitial toxicity) were observed in the preclinical trials in
`multiple species; however there was no evidence of an increased risk to patients in the
`
`1 Draft clinical review (efficacy) by Heather Fitter, M.D., FACS, Medical Officers, DNP dated November 8, 2012.
`2 Midcycle review slides, Gerard Joehm, M.D., M P.H., Medical Officer, DNP, dated January 9, 2013.
`
`Reference ID: 3256682
`
` 2
`
`

`

`clinical trials. The applicant states that they intend to monitor this potential risk in the
`post marketing setting with targeted follow-up of cases suggestive of renal toxicity3.
`
`Malignancy
`Dr. Boehm states in his review that the review team “became aware of publications that
`identified a metabolite of dimethyl fumarate, fumarate, as an ‘oncometabolite”, so the
`Agency extended the PDUFA goal date to examine additional data from the sponsor
`regarding this metabolite. He goes on to state:
`
`
`“The medical literature explains that mutations resulting in significant
`declines or loss of fumarate hydratase (FH) function result in increased
`intracellular levels of fumarate. Increased intracellular levels of fumarate
`are presumed to be responsible for the sequelae of leiomyomata and renal
`cell cancers seen in the Hereditary Leiomyoma and Renal Cell Cancer
`(HLRCC) syndrome.
`
`We lack information to determine if ingesting [dimethyl fumarate] results in
`increased intracellular levels of fumarate. Fumarate was not detected
`in plasma levels of patients administered DMF, but this does not
`necessarily preclude the possibility of increased intracellular
`fumarate levels.
`
`
`
`The available NDA data do not suggest that treatment with [dimethyl
`fumarate] results in the outcomes seen with reduced FH function. While
`this difference may be because treatment with [dimethyl fumarate] does
`not result in the increased intracellular fumarate levels seen with FH
`deficiency, as Biogen proposes, we do not currently have data to confirm
`this hypothesis.”3
`
`
`Dr. Boehm also recommended that the applicant monitor post marketing reports to
`identify cases of leiomyomata and or renal cell cancers in patients treated with dimethyl
`fumarate.
`
`Elevated Liver Enzymes
`Elevated hepatic transaminases were observed in the treatment (4%) and placebo (2%)
`groups in clinical trials, with the majority of the elevations being < 3 times the upper
`limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in
`patients treated with dimethyl fumarate relative to placebo was primarily seen during the
`first six months of treatment and occurred at levels < 3 times the ULN. Discontinuations
`due to elevations in hepatic transaminases were < 1% and were similar in both the
`treatment and placebo groups.4
`
`
`3 Clinical review (safety) by Gerald Boehm, M.D., M.P.H., Medical Officers, DNP dated January 9, 2013.
`4 Draft substantially complete label, Tecfidera (dimethyl fumarate), Biogen Idec.
`
`
`Reference ID: 3256682
`
` 3
`
`

`

`5.3 Applicant’s Proposal for Risk Management
`The applicant did not propose a REMS or RMP for dimethyl fumarate.
`6 Discussion
`MS is a chronic demyelinating disorder of the central nervous system that can lead to
`progressive neurological disability. Treatment goals for MS are to shorten the duration
`and severity of symptoms associated with relapses, prevent the incidence of relapses, and
`delay the accumulation of disability.5 Dimethyl fumarate, an oral formulation, was found
`efficacious in reducing the frequency of clinical exacerbations as well as delaying the
`accumulation of physical disability with “no safety issues that preclude approval”.6 The
`other approved oral treatments for relapsing MS are Aubagio (Teriflunomide) and
`Gilenya (fingolimod).
`
`REMS Considerations
`Products used for the treatment of relapsing MS have a mixed safety profile; two
`products have safety risks that required REMS to ensure that the benefits outweigh the
`risks:
`
`
`
`
`• Gilenya (fingolimod) (oral) has a REMS consisting of a communication plan to
`inform healthcare providers about the serious risks associated with the drug,
`which includes bradyarrhythmia and atrioventricular block at treatment initiation,
`infections, macular edema, respiratory effects, hepatic effects, and fetal risk.
`
`• Tysabri (infusion) has a REMS consisting of elements to assure safe use
`(ETASU) to promote early diagnosis and timely discontinuation of Tysabri in
`the event of suspected progressive multifocal leukoencephalopathy (PML). The
`REMS also informs prescribers, infusion center healthcare providers, and
`patients about the risks associated with Tysabri, in addition to warning against
`concurrent use with antineoplastic, neosuppressant, or immunomodulating
`agents, and in patients who are immunocompromised.
`
`
`Products approved for the treatment of relapsing forms of MS that do not have an
`approved REMS include:
`
`
`
`
`
`
`
`
`
`
`• Avonex, Rebif, Betaseron (Recombinant interferon-b) (subcutaneous)
`
`• Copaxone (glatiramer acetate) (subcutaneous)
`
`• Mitoxantrone (infusion)
`
`
`5 Draft clinical review (efficacy) by Heather Fitter, M.D , FACS, Medical Officers, DNP dated November 8, 2012.
`6 Clinical review (safety) by Gerald Boehm, M.D , M.P.H., Medical Officers, DNP dated January 9, 2013.
`
`Reference ID: 3256682
`
` 4
`
`

`

`• Aubagio (Teriflunomide) (oral)
`
`
`Please see Table 1 appended to this review (completed by Dr. Fitter) for a comparison of
`these products.
`
`7 Conclusion
`After review of the safety data, DRISK concludes that a REMS for Tecfidera (dimethyl
`fumarate) is not necessary at this time. The risks identified at this time can be managed
`adequately through labeling and routine pharmacovigilance. Should DNP identify
`additional safety information that warrants risk mitigation measures, please send a
`consult to DRISK.
`
`
`Reference ID: 3256682
`
` 5
`
`

`

`Table 1: Table of currently available treatments for proposed indication
`Draft clinical review (efficacy) by Heather Fitter, M D., FACS, Medical Officers, DNP dated November 8, 2012.
`Indication
`Effect on exacerbation
`Effect on
`Safety issues (of
`(exac) rate
`disability
`concern)
`progression
`
`
`
`32% reduction (rn)
`
`37% rn
`
`30% reduction
`
`None
`described in
`label
`27% rn
`
`Decrease
`clinical exac,
`delay physical
`disability
`
`22 mcg
`29% rn
`
`44 mcg
`32 % rn vs.
`placebo and
`Avonex*
`
`decreased blood
`counts, hepatic
`injury, flu like
`symptoms
`
`injection site
`necrosis, flu like
`symptoms
`hepatic injury, flu
`like symptoms,
`injection site
`reaction
`
`Approved
`dose
`
`30 mcg IM q
`week
`
`0.25 mg sq
`qod
`
`22 mcg or 44
`mcg tiw
`
`20 mg sq q d
`
`Avonex¥
`(RMS)
`
`Betaseron¥
` (RMS)
`
`Rebif¥
` (RMS)
`
`Copaxone
`(glatiramer
`acetate)
`(RMS)
`
`Mitoxantrone
`(SPMS or
`worsening
`RRMS)
`
`Tysabri
`(natalizumb)
`(RMS)
`
`Gilenya
`(fingolimod)
`(RMS)
`
`Decrease
`clinical exac,
`slow physical
`disability
`
`Decrease
`clinical exac
`
`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
`
`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
`
`Post injection
`reaction, transient
`chest pain, skin
`necrosis
`
`64% rn
`
`
`Cumulative
`cardiotoxicity,
`AML1
`
`12mg/m2 IV
`q 3 months
`
`33% rn
`
`PML2,
`immunosuppression,
`hepatotoxicity
`
`300 mg IV q 4
`weeks
`
`54% rn
`
`30% rn
`
`Bradycardia,
`macular edema,
`infection
`
`0.5 mg po q
`day
`
`Teriflunamide
`
`32% rn
`
`Treatment of
`RMS
`1 acute myelogenous leukemia
`2 progressive multifocal leukoencephalopathy
`¥ Recombinant interferon-b
`*32% reduction in proportion of Rebif patients who experienced relapses compared to Avonex.
`
`26% rn for
`14 mg
`
`Hepatotoxic,
`Teratogenic
`
`7 mg or 14
`mg po q d
`
`Reference ID: 3256682
`
` 6
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KENDRA C WORTHY
`02/06/2013
`
`MARY E WILLY
`02/06/2013
`I concur
`
`Reference ID: 3256682
`
`