CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204063Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`March 17, 2013
`
`Director
`Division of Neurology Products/HFD-120
`
`MEMORANDUM
`
`DATE:
`
`FROM:
`
`
`
`TO:
`
`SUBJECT: Recommendation for action on NDA 204063, for the use of
`Tecfidera (Dimethyl Fumarate) for the treatment of patients with Relapsing
`Remitting Multiple Sclerosis (RRMS)
`
`NDA 204063, for the use of Tecfidera (Dimethyl Fumarate) as an oral treatment
`for patients with Relapsing Remitting Multiple Sclerosis (RRMS), was submitted
`by Biogen Idec Inc., on 2/27/12. A major amendment, addressing Agency
`questions related to the carcinogenic potential of the drug, was submitted on
`10/5/12; as a result, the user fee goal date is 3/27/13.
`
`The application contains the results of two randomized controlled trials purporting
`to provide substantial evidence of the drug’s effect in the treatment of patients
`with RRMS. In addition, the application contains safety, non-clinical, clinical
`pharmacology, and chemistry and manufacturing control (CMC), data that the
`sponsor believes support the application’s approval.
`
`The application has been reviewed by Drs. David Claffey and Sarah Miksinski,
`Office of New Drug Quality Assessment (ONDQA); Michael Trehy and Anjanette
`Smith, Division of Pharmaceutical Analysis; Dr. Elsbeth Chikhale, ONDQA,
`Biopharmaceutics; Drs. Melissa Banks-Muckenfuss and Lois Freed,
`pharmacology/toxicology; Steve Thomson, Office of Translational Sciences,
`Office of Biostatistics; Dr. Jagan Parepally, Office of Clinical Pharmacology; Dr.
`Michael Skelly, Office of Scientific Investigations, Division of Bioequivalence and
`GLP Compliance; CDER QT Interdisciplinary Review Team; Dr. Heather Fitter,
`medical reviewer; Dr. Xiang Ling, Office of Biostatistics; Drs. Gerard Boehm and
`Sally Yasuda, safety team; Dr. Antoine El-Hage, Office of Scientific Investigations,
`Division of Good Clinical Practice Compliance; Drs. Carrie Ceresa and Nadia
`Hejazi, Pediatric and Maternal Health Staff; Dr. Alicja Lerner, Controlled
`Substance Staff; Dr. Andrew Fine, Office of Surveillance and Epidemiology
`(OSE), Division of Pharmacovigilance I; Drs. Kendra Worthy and Julie Neshiewat,
`OSE, Office of Medication Error Prevention and Risk Management; Shawna
`Hutchins, Office of Medical Policy Initiatives, Division of Medical Policy
`Programs; Dr. Quynh-Van Tran, Office of Prescription Drug Promotion (OPDP),
`Division of Professional Drug Promotion; Dr. Meeta Patel, OPDP, Division of
`Consumer Drug Promotion; Elizabeth Donohoe, Study Endpoints and Labeling
`Development (SEALD); and Dr. Billy Dunn, neurology team leader and Cross
`Discipline Team Leader (CDTL).
`
`
`
`File, NDA 204063
`
`
`
`Reference ID: 3283096
`
`1
`
`

`

`
`The review team recommends that the application be approved, albeit with
`recommendations for the imposition of Post-Marketing Requirements (PMRs).
`
`In this memo, I will briefly review the relevant data, and offer the rationale for the
`division’s recommendations for action on the application.
`
`Background
`
`Dimethyl fumarate (DMF) is rapidly and essentially fully metabolized to the active
`metabolite monomethyl fumarate (MMF); subsequent metabolism is through the
`tricarboxylic acid (TCA) cycle, and the active moiety is primarily eliminated as
`CO2. Although the precise mechanism of action is unknown, it is believed to
`activate the nuclear factor related factor 2 (Nrf2) antioxidant response pathway, a
`pathway believed to upregulate antioxidant response genes.
`
`DMF is not marketed anywhere, but a closely related product, Fumaderm, a
`combination of DMF and other salts of monoethyl fumarate, has been marketed
`in Germany since 1994 for the treatment of moderate to severe psoriasis.
`
`
`Effectiveness
`
`As noted above, the sponsor has submitted the results of two randomized
`controlled trials of relatively similar design to support a finding of substantial
`evidence of effectiveness (Studies 301 and 302). In addition, they have
`submitted the results of another controlled trial (Study C-1900) that served as the
`basis for the choice of doses studied in Studies 301 and 302. I will briefly review
`the results of these studies.
`
`C-1900
`
`This was a double-blind, multiple fixed dose study in which patients with RRMS
`were randomized to receive either placebo, or DMF 120 mg qd, 120 mg tid, or
`240 mg tid for 6 months. The primary outcome was the total number of new
`gadolinium-enhancing lesions measured at Weeks 12, 16, 20, and 24. New or
`newly enlarging T2 hyperintense lesions at Week 24 were also assessed, as
`were other MRI measures and annualized relapse rate. From 63-65 patients
`were randomized to each group.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`2
`
`

`

`
`
`
`
`
`
`Pbo 120 qd
`
`120 tid
`
`240 tid
`
`6.7
`0.8
`
`4.1
`0.8
`
`1.5
`0.8
`
`0.78
`0.6
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.7
`0.002
`
`2.2
`0.0006
`
`0.8
`0.01
`
`0.44
`0.3
`
`The following chart displays the relevant results:
`
`
`
`
`Mean new Gd lesions
`Weeks 4-24
`
`P-value
`
`
`
`New enlarging T2
`Hyperintense lesions
`P-value
`
`
`
`New enlarging T1
`Hyperintense lesions
`P-value
`
`
`
`Annualized relapse rate
`P-value
`
`
`
`
`Study 301
`
`This was a double blind, multiple fixed dose, multi-center trial in which patients
`with RRMS were randomized to either placebo, DMF 240 mg BID, or DMF 240
`mg TID. The trial duration was two years, and the primary outcome was the
`proportion of patients relapsing. The study personnel consisted of Primary and
`Backup Treating Neurologists, Primary and Backup Treating Nurses, and
`Primary and Backup Examining Neurologists. All study personnel were blinded
`to treatment assignment. According to Dr. Fitter’s very clear explanation, the
`procedure for documenting that a relapse had occurred is described below:
`
`Patients who experienced new neurologic symptoms were to contact the treating
`neurologist or nurse within 48 hours. They completed a phone questionnaire,
`and a determination was made whether an unscheduled relapse assessment
`visit was necessary. If so, the patient had to have been seen by the treating
`neurologist within 72 hours of the onset of symptoms, and by the examining
`neurologist within 5 days of the onset of symptoms. The examining neurologist
`performed a relapse assessment and an expanded disability severity score
`(EDSS). Based on the examining neurologist’s examination, the treating
`neurologist determined if there were new objective findings.
`
`If the treating neurologist determined (based on the examining neurologist’s
`exam) that there were new objective findings, the treating neurologist referred the
`case to the Independent Neurologic Evaluation Committee (INEC), a body of
`three neurologists. The INEC reviewed the patients’ records independently (they
`
`
`6.6
`
`
`6.2
`0.9
`
`4.2
`
`
`3.8
`0.9
`
`1.7
`
`
`1.3
`0.7
`
`0.65 0.42
`
`0.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`3
`
`

`

`did not meet to discuss the cases). If a majority of the INEC determined that a
`relapse occurred, it was counted as a relapse. Only INEC-declared relapses
`were considered in the analyses of relapses.
`
`Subjects could be treated with intravenous methylprednisolone (IVMP) for an
`acute relapse only after they had been examined by the examining neurologist.
`If a patient had an INEC-confirmed relapse that occurred at or after Week 24,
`and had completed 48 weeks of study treatment, they had the following options:
`
`
`1) remain on blinded treatment
`2) switch to open-label alternative MS treatment and remain in the study
`3) discontinue study treatment, decline alternative treatment, and remain in
`the study
`
`
`Patients who experienced disability progression at any time during the study had
`the same options.
`
`Other outcome measures included:
`
`
`1) Disability Progression-defined as at least a 1 point increase in the EDSS
`from a baseline EDSS of at least 1.0 that was sustained for 12 weeks, or a
`1.5 point increase in EDSS from a baseline EDSS of 0, sustained for 12
`weeks.
`2) Annualized Relapse Rate (ARR)-including only INEC-confirmed relapses
`that occurred before a patient received alternative MS treatments
`3) MS Functional Composite (MSFC) Scale-a three part assessment
`consisting of a timed 25 foot walk, a 9-Hole Peg Test, and a paced
`auditory serial addition test 3 (PASAT 3, a cognitive test)
`4) Patient Reported Outcomes, including:
`1) Global impression of well-being: A visual analogue scale (VAS)
`from 0-100
`2) SF-36 Health Survey-a 36 item questionnaire with 8 quality of life
`domains
`3) EQ-5D-consisting of 2 domains; the descriptive system (5 health
`dimensions) and a VAS
`
`5) MRI assessments-
`
`MRI was assessed at only a subset of sites that had the appropriate
`facilities and expertise. All MRI scans were centrally read, and
`assessments were made at baseline and Weeks 24, 48, and 96. A partial
`list of measures included:
`
`
`1) New or enlarging T2 weighted lesion count
`2) T2 weighted lesion volume
`3) Gd-enhancing lesion count
`
`4
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`

`

`4) Gd-enhancing lesion volume
`5) T1 weighted lesion count
`6) New T1 weighted non-enhancing hypointense lesion count
`7) Percent brain volume change
`
`
`Results
`
` A
`
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`410
`408
`265
`
` 31
` 14
` 22
` 34
`317
` 53
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 BID
`
`240 TID
`
`411
`410
`284
`
` 4
` 7
` 61
` 18
`315
` 25
`
`
`
`
`
`
`
`
`
`
`
`
`416
`416
`289
`
` 10
` 7
` 56
` 18
`320
` 21
`
`
`
`
`
` total of 1237 patients were randomized at 198 sites in 28 countries. As noted
`by Dr. Ling, the highest enrolling countries, in descending order, were: US (203),
`Germany (172), Poland (132), and India (114). The following chart displays the
`patient disposition in the study:
`
`
`
`
`
`
`Randomized
`
`
`
`Pts dosed
`
`
`Number completing study drug
`Number discontinuing study drug:
`
`MS relapse
`
`
`
`
`MS progression
`
`
`
`Adverse event
`
`
`
`Consent withdrawn
`
`Number completing study
`
`Number receiving alternative MS tx
`
`
`The following chart displays the results of the primary analysis, Proportion of
`Patients Relapsing:
`
`
`
`
`
`Number relapsing
`Proportion relapsed at 2 yrs
`Hazard ratio
`
`
`Percentage reduction
`
`P-value
`
`
`
`
`Several worst-case analyses were performed by Agency reviewers, including
`counting all relapses, including those that occurred after the use of alternative
`MS treatments in the DMF-treated patients but including only those relapses that
`occurred prior to such alternative use in the placebo patients, and also including
`all patients who had an unknown relapse status at 2 years (16%, 21%, and 20%
`in the placebo, BID, and TID groups, respectively) as having had a relapse if they
`discontinued study medication for MS relapse, lack of efficacy, or alternative MS
`therapy having been started. These sensitivity analyses were consistent with the
`primary analysis, including the lack of dose effect.
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`240 TID
`
`171 (42%) 98 (24%)
`0.46
`
`0.27
`
`
`
`0.51
`
`
`
`48.5
`
`
`
`<0.0001
`
`95 (23%)
`0.26
`0.50
`49.5
`<0.0001
`
`
`
`Reference ID: 3283096
`
`5
`
`

`

`
`
`Annualized Relapse Rate (ARR)
`
`The following chart displays the results of the annualized relapse rates. The
`primary analysis of ARR excluded relapses that occurred after the institution of
`alternative MS treatments. The ARR for a treatment group was calculated as the
`total number of INEC-confirmed relapses divided by the total patient-time in study
`(subtracting time of alternative MS treatments).
`
`
`
`
`
`Adjusted ARR
`
`Rate Ratio
`
`Percentage Reduction
`P-value
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`0.364
`
`
`
`
`
`
`
`240 BID
`
`0.172
`0.473
`52.7%
`<0.0001
`
`
`
`
`
`
`
`
`240 TID
`
`0.189
`0.521
`47.9%
`<0.0001
`
` A
`
`
`
`
`
`
`
`Pbo
`
`89
`0.27
`
`
`
`
`
`
`
`
`
`
`
`
`240 BID
`
`
`57
`
`0.16
`
`0.62
`
`38.0
`0.005
`
`
`
`
`
`
`
`
`
`240 TID
`
`62
`0.177
`0.66
`33.8
`0.013
`
` worst case analysis in which relapses occurring after alternative MS treatments
`were started were included in the DMF groups, but not for the placebo group,
`yielded a similar outcome.
`
`Disability Progression
`
`The following chart displays the results of the analyses of disability progression:
`
`
`
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`Percent reduction
`
`P-value
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`6
`
`

`

`
`
`Dr. Ling performed two sensitivity analyses: one in which patients had to have
`had a 24 week sustained disability, and one in which patients who had met the
`protocol-definition of progression (sustained for 12 weeks) and in whom
`progression was sustained at the end of the study. The results are presented
`below:
`
`
`
`
`
`24 week sustained
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`Percent reduction
`
`P-value
`
`
`
`
`
`
`
`Sustained at study end
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`Percent reduction
`
`P-value
`
`
`
`The following results were obtained for the analyses of the main MRI
`assessments, taken from Dr. Ling’s Tables 8 and 9, page 19 of her review:
`
`
`Number of New or Newly enlarging T2 lesions at 2 years:
`
`
`
`
` N
`
`
`
`
`
`
`165
`17.0
`
`
`
`
`
`
`
`
`
`152
`
` 2.6
`
`-85
`<0.0001
`
`
`
`
`
`
`152
` 4.4
`-74
`<0.0001
`
`
`
`
`Adjusted Mean
`Percent reduction
`P-value
`
`
`The above results represent the protocol-specified analysis, which imputed
`missing data based on a constant-rate assumption. Dr. Ling performed various
`sensitivity analyses which used last observed data (the sponsor performed
`several sensitivity analyses that used only Week 96 data, but not earlier data if
`Week 96 data were missing). Dr. Ling performed analyses using the last
`
`
`
`Reference ID: 3283096
`
`7
`
`
`
`Pbo
`
`57
`0.17
`
`
`
`
`Pbo
`
`54
`0.18
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 BID
`
`44
`0.13
`0.77
`23.2
`0.19
`
`
`
`
`
`
`
`240 BID
`
`36
`0.10
`0.66
`34.6
`0.05
`
`
`
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 TID
`
`41
`0.12
`0.69
`30.5
`0.08
`
`240 TID
`
`35
`0.1
`0.62
`38.1
`0.03
`
`240 TID
`
`

`

`observed data only prior to institution of alternative MS treatments, and also
`using the last observed data including after switching to alternative therapies.
`These analyses were consistent with the primary analysis presented above.
`
`
`Number of Gd-Enhancing Lesions at 2 years:
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`
`
`240 TID
`
` N
`
`
`
`
`
`
`
`
`
`
`
`165
` 1.8
`
`
`
`
`
`
`
`
`
`152
`
` 0.1
`
`0.10
`<0.0001
`
`
`
`
`
`
`152
` 0.5
` 0.5
`<0.0001
`
`
`
`Mean
`Odds ratio
`P-value
`
`Study 302
`
`Study 302 was similar in design to Study 301, with one significant exception: This
`study also included an additional randomized arm, consisting of open-label
`glatiramer acetate, an approved injectable treatment for RRMS. Because this
`arm was open-label, I will not present the results for this arm. In addition,
`although similar outcomes were assessed and analyzed in both studies, in Study
`302, the primary outcome was ARR, not proportion of patients who relapsed.
`
` A
`
` further difference between the two studies was the rule for being eligible to
`receive alternative MS treatments. In Study 302, patients had the option to
`receive alternative MS treatments if they had completed 48 weeks of blinded
`treatment and had 2 INEC-confirmed relapses, or if they had significant disability
`progression at any time.
`
`Results
`
` A
`
` total of 1430 patients were enrolled at 200 sites in 28 countries. According to
`Dr. Ling, the highest enrolling countries, in descending order, were Poland (282),
`US (2670, India (107), and Ukraine (104).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`8
`
`

`

`The following chart displays patient disposition:
`
`
`
`
`
`
`Randomized
`
`
`
`Pts dosed
`
`
`Number completing study drug
`Number discontinuing study drug:
`
`MS relapse
`
`
`
`
`MS progression
`
`
`
`Adverse event
`
`
`
`Consent withdrawn
`
`Number completing study
`
`Number receiving alternative MS tx
`
`Annualized Relapse Rate (ARR)
`
`The following chart displays the results of the annualized relapse rates. The
`primary analysis of ARR excluded relapses that occurred after the institution of
`alternative MS treatments. The ARR for a treatment group was calculated as the
`total number of INEC-confirmed relapses divided by the total patient-time in study
`(subtracting time of alternative MS treatments).
`
`
`
`
`
`Adjusted ARR
`
`Rate Ratio
`
`Percentage Reduction
`P-value
`
`
`
` A
`
` worst case analysis in which relapses occurring after alternative MS treatments
`were started were included in the DMF groups, but not for the placebo group,
`yielded a similar outcome, including numerical superiority of the high dose
`compared to the low dose.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`9
`
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`363
`363
`234
`
` 28
` 10
` 22
` 12
`278
` 40
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 BID
`
`240 TID
`
`362
`359
`253
`
` 8
` 8
` 38
` 8
`284
` 25
`
`
`
`
`
`
`
`
`
`
`
`
`345
`345
`249
`
` 6
` 7
` 42
` 10
`273
` 28
`
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`0.401
`
`
`
`
`
`
`
`240 BID
`
`0.224
`0.560
`44.0%
`<0.0001
`
`
`
`
`
`
`
`
`240 TID
`
`0.198
`0.495
`50.5%
`<0.0001
`
`

`

`As in Study 301, analyses of the proportion of patients relapsing at 2 years was
`also performed:
`
`
`
`
`
`Number relapsing
`Proportion relapsed at 2 yrs
`Hazard ratio
`
`
`Percentage reduction
`
`P-value
`
`
`
`
`
`Disability Progression
`
`The following chart displays the results of the analyses of disability progression:
`
`
`
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`P-value
`
`
`
`As for Study 301, Dr. Ling performed two sensitivity analyses: one in which
`patients had to have had a 24 week sustained disability, and one in which
`patients met the protocol-definition of progression (sustained for 12 weeks) and
`in whom progression was sustained at the end of the study. The results are
`presented below:
`
`
`
`
`
`24 week sustained
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`P-value
`
`
`
`
`
`
`
`Sustained at study end
`
`Number progressed
`Proportion progressed
`Hazard ratio
`
`P-value
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 BID
`
`40
`0.13
`0.79
`0.25
`
`
`
`
`
`
`240 BID
`
`40
`0.08
`0.77
`0.06
`
`
`
`
`
`
`240 BID
`
`20
`0.06
`0.52
`0.02
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 TID
`
`38
`0.13
`0.76
`0.20
`
`240 TID
`
`38
`0.12
`0.09
`0.12
`
`240 TID
`
`26
`0.09
`0.73
`0.21
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`240 TID
`
`140 (39%) 93 (26%)
`0.41
`
`0.29
`
`
`0.66
`
`
`
`34.0
`
`
`
`0.002
`
`76 (22%)
`0.24
`0.55
`44.6
`<0.0001
`
`
`
`
`
`
`
`Pbo
`
`52
`0.17
`
`
`
`
`
`Pbo
`
`52
`0.13
`
`
`
`Pbo
`
`37
`0.13
`
`
`
`
`
`Reference ID: 3283096
`
`10
`
`

`

`
`The following results were obtained for the analyses of the main MRI
`assessments, taken from Dr. Ling’s Tables 14 and 15, page 23 of her review:
`
`
`Number of New or Newly enlarging T2 lesions at 2 years:
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`
`
`240 TID
`
`
`
`
`Adjusted Mean
`Percent reduction
`P-value
`
`
`The above results represent the protocol-specified analysis, which imputed
`missing data based on a constant-rate assumption. As for Study 301, Dr. Ling
`performed various sensitivity analyses which used last observed data (the
`sponsor performed several sensitivity analyses that used only Week 96 data, but
`not earlier data if Week 96 data were missing). Dr. Ling performed analyses
`using the last observed data only prior to institution of alternative MS treatments,
`and also using the last observed data including after switching to alternative
`therapies. These analyses were consistent with the primary analysis presented
`above.
`
`
`Number of New or Newly Enlarging T1 Lesions at 2 years:
`
`
`
`
`
`
`
`
`
`139
`17.4
`
`
`
`
`
`
`
`
`
`140
`
` 5.1
`
`-71
`<0.0001
`
`
`
`
`
`
`140
` 4.7
`-73
`<0.0001
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`
`
`240 TID
`
` N
`
` N
`
`
`
`
`
`
`139
` 7.0
`
`
`
`
`
`
`
`
`
`140
`
` 3.0
`
` 57
`<0.0001
`
`
`
`
`
`
`140
` 2.4
` 65
`<0.0001
`
`
`
`
`
`Mean
`Percent reduction
`P-value
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`11
`
`

`

`Number of Gd-Enhancing Lesions at 2 years:
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`
`
`240 BID
`
`
`
`240 TID
`
`
`169
`
` 0.5
`
`0.26
`
` 74
`<0.0001
`
`
`
`
`
`
`
`170
` 0.4
`0.35
` 65
`<0.0001
`
`
`
`
`
`Mean
`
`Odds ratio
`Percent reduction
`P-value
`
`
`
`Safety
`
`The sponsor has submitted safety data for the total of 3,424 subjects/patients
`who received at least one dose of DMF. A total of 2,210 patients with MS
`received at least 6 months of treatment, 1,787 received at least 12 months of
`treatment, and 712 patients received at least 3 years of treatment. A total of
`2,665 patients with MS were treated with DMF and 2,537 patients with MS
`received doses of at least 240 mg BID.
`
`The sponsor also performed studies in patients with Psoriasis (N=320), in
`patients with Rheumatoid Arthritis (RA; N=101), and inn healthy subjects (N=338).
`
`The sponsor submitted the safety data in various pools of patients:
`
`Pool A-controlled MS trial data (Studies C-1900, 301, and 302; N=1,720)
`Pool B-controlled and open-label MS studies (N=2,513)
`Pool C-controlled trials in Psoriasis (Study 12/01, 3 months, same doses as C-
`1900, N=144; Study 01/02, 4 months, 240 mg TID, N=213)
`Pool D-controlled and open-label Psoriasis studies (N=296)
`
`The sponsor also submitted data from several other studies in MS patients,
`healthy subjects, and patients with RA.
`
`The primary safety analyses were performed on Pool A, though, of course, Dr.
`Boehm has reviewed all safety data.
`
`Deaths
`
`There were a total of 11 deaths in the development program; 9 occurred in DMF-
`exposed patients (N=7 MS, N=2 Psoriasis). A total of 3 deaths occurred in MS
`controlled trials; 1 in the 240 mg BID group (though the death occurred during
`titration, while the patient received 120 mg BID) and 2 occurred in the 240 mg
`TID group. Dr. Boehm has reviewed the deaths in detail (pages 21-24 of his
`review). None of the deaths has any obvious or suspected relation to treatment.
`
`
`
`
`
`
`
`167
` 2.0
`
`
`
`
`
`
`
`
`
`
` N
`
`
`
`Reference ID: 3283096
`
`12
`
`

`

`
`Serious Adverse Events (SAEs)
`
`In controlled MS trials, the incidence of SAEs was greater in the placebo group
`(21%) than in the combined DMF groups (16%) or in any DMF dose group
`(greatest incidence 18% in the 240 mg BID group). No individual AE occurred in
`at least 1% of DMF-treated patients and at a greater incidence than in the
`placebo group.
`
` total of 17% of DMF-treated MS patients experienced at least one SAE. Only
`MS Relapse occurred at an incidence of more than 1% (9%). Only
`Gastroenteritis (N=10), gastritis (N=8), Urinary Tract Infection (N=8), Falls (N=5),
`and Road Accident (N=5) occurred in at least 5 patients.
`
`Dr. Boehm has identified several SAEs that he has characterized as being of
`potential concern. He includes in this list: hypersensitivity (N=2), anaphylactic
`and anaphylactoid reaction (N=1 each), Stevens Johnson Syndrome (SJS; N=1),
`allergic dermatitis (N=1), chronic hepatitis, hepatic failure, cholestatic hepatitis
`(N=1 each), rhabdomyolysis (N=1), increased Beta-2 microglobulin (N=1),
`proteinuria (N=1), and myopericarditis (N=1). Several of these will be discussed
`later in subsequent sections.
`
`Regarding these events, there were plausible alternative explanations for the
`anaphylactic reaction (patient with nut allergy ate a nut); and SJS (patient was
`treated with carbamazepine, which was discontinued, and remained on DMF).
`The patient with hepatic failure took a fatal overdose of acetaminophen. The
`patient with rhabdomyolysis began a weight training program after having not
`done so in years.
`
`The patient with myopericarditis was a 64 year old man with pain in the upper
`thorax and neck on Day 174 of treatment. EKG showed ST elevations in
`numerous leads, and angiography showed 60% stenosis of 2 vessels. He
`discontinued treatment on Day 178.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` A
`
`
`
`Reference ID: 3283096
`
`13
`
`

`

`Discontinuations
`
`The following table, based on Dr. Boehm’s Table on pages 31-2 of his review,
`displays the incidence of adverse events that led to study discontinuation at a
`rate greater than placebo in any DMF dose group in the MS controlled studies:
`
`
`Event
`
`
`
`
`
`Pbo
`
`
`
`240 mg BID
`
`240 mg TID
`
` N
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`836
`
`<1%
`<1%
`0%
`0%
`<1%
`<1%
`
`
`
`
`
`
`
`
`
`
`769
`
`3%
`<1%
`<1%
`1%
`1%
`2%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`823
`
`2%
`2%
`2%
`1%
`2%
`2%
`
`
`
`Flushing
`
`Diarrhea
`
`Nausea
`
`Vomiting
`Abdominal pain
`Skin disorders
`
` A
`
` total of 11 patients discontinued treatment for events called Hypersensitivity.
`According to Dr. Boehm, they were not well described, but some included the
`terms: itching, edema of the lips/face, flushing, pruritis, shortness of breath,
`burning face; some patients were treated with steroids and antihistamines. Four
`of these occurred on the first day of dosing, 5 occurred within the first month, 2
`occurred from about 3 and 4 months on treatment, and one occurred after about
`one year on treatment.
`
`Common Adverse Events
`
`The following table, adapted from Dr. Boehm’s table on pages 75-6 of his review,
`displays the common adverse events that occurred in the MS controlled trials,
`and that occurred in any dose group at a rate of 1.5 times more frequent than in
`the placebo group.
`
`
`Event
`
`
`Flushing
`
`Diarrhea
`
`Nausea
`Abdominal pain
`Pruritis
`
`Vomiting
`
`Rash
`
`Hot flush
`
`Erythema
`
`Urinary albumen
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Pbo
`
`5%
`10%
`9%
`4%
`4%
`5%
`3%
`2%
`1%
`3%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`240 mg BID
`
`240 mg TID
`
`34%
`14%
`12%
`9%
`8%
`8%
`8%
`7%
`5%
`6%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`29%
`17%
`14%
`8%
`8%
`7%
`7%
`7%
`7%
`4%
`
`
`
`Reference ID: 3283096
`
`14
`
`

`

`
`
`
`
`
`Pbo
`
`2%
`1%
`
`
`
`
`
`
`240 mg BID
`
`240 mg TID
`
`4%
`2%
`
`
`
`
`
`
`
`4%
`3%
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
`-0.05
`-0.63
`-0.66
`
`
`
`
`
`-0.10
`-0.54
`-0.58
`
`Pbo
`
`3%
`<1%
`
`
`
`
`
`
`240 BID
`
`240 TID
`
`28%
` 6%
`
`
`
`
`21%
` 3%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.04
`0.02
`0.02
`
`
`
`
`
`
`
`
`
`
`
`
`
`Event
`
`AST increased
`Hyperhidrosis
`
`
`Laboratory Findings
`
`DMF causes lymphopenia. In MS controlled trials, mean decreases in
`lymphocyte counts are seen at Week 4, at the first determination. Mean counts
`continue to decrease until Week 48, after which the counts stabilize. Specifically,
`the following values were seen:
`
`
`Lymphocyte count (change from baseline; x109/L)
`
`
`
`Week 4
`Week 48
`Week 96
`
`These mean changes were accompanied by an increase in the number of
`patients who met outlier criteria for low lymphocyte counts:
`
`Lymphocytes (x109/L)
`
`
`<0.8
`<0.5
`
`The data are suggestive that, at 4 weeks post discontinuation of dosing, the
`lymphocyte count continues to approach baseline, though does not return to
`baseline.
`
`Similar, though smaller, changes were seen for total WBC, neutrophils,
`hemoglobin, hematocrit, and platelets (see Dr. Boehm’s table, page 79-80).
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3283096
`
`15
`
`

`

`There was a slight increase in Eosinophil count at Week 4 that resolved at later
`time points:
`
`Eosinophil count (change from baseline; x109/L)
`
`
`
`Week 4
`Week 8
`
`Dr. Boehm has examined the incidence of patients who had eosinophil counts at
`least 2 x ULN at Weeks 4, 8, and 12:
`
`
`Week
`
`
`
`
`
`
`
`
`
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
`0.00
`0.00
`
`
`
`
`0.19
`0.02
`
`
`
`
`
`
`
`0.15
`0.01
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
` 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`<1%
`<1%
`0
`
`
`
`
`
`
`
`
`
`5.5%
`<1%
`
`<1%
`
`
`
`
`
`
`3.9%
`<1%
`0
`
`Chloride
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
`
`0.13
`-0.03
`
`-0.33
`-0.29
`
`
`
`
`
`Bicarbonate
`
`
`0.17
`
`0.03
`-1.48
`-0.29
`
`
`
`0.02
`0.05
`
`
`
`
`
`
`
`0.53
`
`0.55
`-1.27
`-0.01
`
`Trigylcerides
`
`-0.16
`-0.15
`
`
`
`
`
`
`
`
`
`
`
`
`-0.23
`-0.25
`
`0.48
`0.63
`-1.08
`-0.06
`
`-0.14
`-0.14
`
`
`8
`12
`
`Other chemistries
`
`DMF caused small mean decreases in serum chloride and triglycerides, and
`small mean increases in serum bicarbonate compared to baseline, as shown
`below:
`
`
`
`Week
`
`Week 12
`Week 96
`
`
`
`Week 4
`Week 24
`Week 52
`Week 96
`
`
`
`
`Week 4
`Week 96
`
`
`
`
`Reference ID: 3283096
`
`16
`
`

`

`There was a slight increase in the percent of patients on DMF who had
`bicarbonate levels > ULN-32 mmol/L (7%, 11%, and 11% for placebo, 240 BID
`and TID, respectively). There was also a higher percent of DMF-treated patients
`who had a shift in bicarbonate levels from normal at baseline to high (9%, 16%,
`and 15% for placebo, BID, and TID, respectively).
`
`Parathyroid hormone (PTH) and Vitamin D
`
`PTH was increased and Vitamin D levels were decreased in DMF treated
`patients compared to placebo. These differences were reflected in mean
`changes, as well as shifts compared to baseline and patients with values greater
`than baseline, as displayed below:
`
`
`PTH
`
`Week
`
`
`Week 48
`
`Week 96
`
`Shift High
`
`>ULN
`>1.5 X ULN
`
`
`Vitamin D
`
`Week 48
`Week 96
`Shift Low
`
`Dr. Boehm has calculated the percent of patients who had both elevated PTH
`(>ULN) and decreased Vitamin D (<LLN) at both Weeks 48 and 96:
`
`
`
`Week 48
`Week 96
`
`There were no changes in measures of serum Calcium (mean changes from
`baseline, shifts from baseline, or percent meeting outlier criteria).
`
`Vital signs
`
`There were no appreciable changes in vital signs in either of the treatment
`groups compared to placebo.
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
`
`
`
`10%
`6.7%
`
`9.1%
`11.1%
`
`
`
`
`7.9%
`13.0%
`
`
`
`Reference ID: 3283096
`
`17
`
`Placebo
`
`240 mg BID
`
`240 mg TID
`
`-0.96
`3.07
`
`8%
`
`8.6%
`0.9%
`
`
`7.97
`12.02
`19%
`
`19.8%
`3.5%
`
`
`0.58
`-20.97
`5%
`
`
`-18.31
`-31.92
`8%
`
`
`
`
`
`
`
`
`
`
`
`
`10.4
`15.4
`22%
`22.8%
`4.6%
`
`-24.69
`-36.17
`10%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`EKG
`
` A
`
` thorough QT study was performed comparing the effects of single doses of
`DMF of 240 and 360 mg and 400 mg moxifloxacin and placebo. The study had
`adequate assay sensitivity (increase in the QT in the moxifloxacin group of 11
`ms) and showed no effect on QT in either of the DMF groups.
`
`Adverse Events of Special Interest
`
`Flushing
`
`DMF causes flushing in about 30% of DMF treated patients, compared to 5% in
`placebo patients; it appears not to be dose-related. Typically, flushing occurs
`early, occurring on the first day in about 45% of the patients who develop flushing,
`and in about 60% of patients within the first week. The incidence appears to
`drop considerably by the second month of treatment, though in some patients it
`does not resolve. In controlled trials, almost 70% of the episodes were
`considered mild, with about 4% considered severe.
`
`The sponsor reported 4 events of flushing as being serious, but one was a
`hypersensitivity reaction, and one was an anaphylactoid reaction. None were
`life-threatening, though several of these events were treated with steroids and/or
`antihistamines.
`
`The sponsor investigated pre-treatment with aspirin as a prophylaxis against
`flushing, but the number of patients treated was small, and the differences in
`incidence of flushing between the ASA-treated and non-ASA-treated patients
`was minimal. The sponsor performed a cross-over study comparing the rates of
`flushing when the drug was taken with or without food. A total of 96% of patients
`(34/36) experienced flushing when DMF was taken without food, compared to
`68% (23/34) who experienced flushing when DMF was taken with food.
`
`Liver injury
`
`DMF caused a slight increase in the percent of patients who experienced at least
`one elevated transaminase compared to placebo (ALT: 35%, 48%, and 53%;
`AST 21%, 26%, and 31% for placebo, 240 mg BID, and 240 mg TID,
`respectively), but no appreciable differences in the percent of patients
`experiencing elevations equal to or greater than 3 X ULN. There were no
`differences between DMF- and placebo-treated patients in the percentages with
`elevated bilirubin, and no patient experienced an LFT elevation of at least 3 X
`ULN and bilirubin at least 2 X ULN.
`
`
` total of 3 events related to possible liver injury were reported as serious.
`
` A
`
`
`
`Reference ID: 3283096
`
`18
`
`

`

`
`One was a patient who committed suicide by acetaminophen overdose.
`
`One was a 29 year old woman with fluctuating transaminase levels during
`treatment with 240 mg BID in Study 301. Her levels were normal at the end of
`that study. She was off drug for the next 6 months, after which she entered an
`open-label extension; her LFTs were elevated at baseline for that phase