CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204063Orig1s000
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`

`

`Deputy Office Director Decisional Memo
`
`
`From
`Robert Temple. MD
`
`Subject
`Deputy Office Director Decisional Memo
`NDA/BLA #
`204063
`Su lement #
`
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established
`S ‘
`
`Name
`
`Dosage Forms / Strength
`Proposed Indication(s)
`Action:
`
`Bio {en Idec, Inc
`Feb
`.
`24. 2012
`March 27. 2013
`
`Tecfidera (dimethyl fumarate)
`
`delayed-release capsules/ 120 mg and 240 mg
`treatment of relapsing forms of multiple sclerosis
`A .roval
`
`
`
`Material Reviewed/Consulted
`0ND Action Packa - e. includin :
`
`Names of discipline reviewers
`
`Medical Officer Review
`
`Heather Fitter — efficacy: Gerard Boehm - safety
`
`-——
`
`-——
`
`De Dir for Safe Review
`
`OND=Office of New Drugs
`0PDP=0ffice of Prescription Drug Products
`DSI=Division of Scientific Investigations
`CDTL=Cross-Discipline Team Leader
`OSE= Office of Surveillance and Epidemiology
`DEPi= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`
`Reference ID: 3283838
`
`

`

`I. Introduction
`
`This memorandum explains the basis for approval of dimethyl fumarate (Tecfidera), an orally
`administered drug, for the treatment of patients with relapsing multiple sclerosis. What was studied was
`relapsing–remitting MS (RRMS) but we have concluded that effectiveness in RRMS supported the
`broader claim in relapsing MS. My conclusion is based on consideration of individual reviews of clinical,
`pharmacologic/toxicologic and chemistry data, supervisory reviews, including Dr. Katz’s Division
`Director Review and Dr. Dunn’s CDTL review, and Dr. Freed’s Pharm/Tox review. The reviewers are
`listed by subject area and organization (if outside DNP) in Dr. Dunn’s CDTL review and Dr. Katz’s
`Division Director review.
`
`Dimethyl fumarate (DMF) is a participant in the tricarboxylic acid (TCA) cycle and is rapidly
`metabolized to monomethyl fumarate (MMF) and excreted primarily as CO2. Its mechanism of action is
`not well-established and MMF has a very short half-life (about 1 hour); it is not present in circulation at
`24 hours in most patients. Its metabolism and excretion are not likely to be affected by hepatic or renal
`function or by metabolic enzymes. Food slowed absorption, roughly doubling Tmax from 2-2.5 hours
`(fasted state).
`
`The effectiveness of dimethyl fumarate in reducing relapse rates was clearly shown in two well-controlled
`studies (301, 302) of two years duration; these are extensively described by Drs. Katz and Dunn and I will
`note only highlights. Both studies showed highly significant and reasonably large reductions in
`annualized relapse rate (ARR) and in the proportion of patients relapsing (both endpoints were used as
`primary endpoints, proportion relapsing in study 301 and ARR in study 301), as well as effects on MRI
`endpoints. Effects on disability progression were also evaluated in both studies, with a significant
`reduction show in 301 and a favorable trend (but no significant effect) in 302. There appear to be no
`major differences in demographic subgroups (Fitter).
`
`Clinical studies showed tolerability problems (mainly flushing in about 40% of patients, rarely troubling
`enough to lead to hospitalization, and GI effects (abdominal pain, diarrhea, nausea, and vomiting), with
`more of these effects early in treatment than later. Some very modest elevations of aminotransferase were
`seen (4% vs 2% on placebo) but there was no excess of 3xULN elevations and no associated bilirubin
`elevations (“Hy’s Law” cases). Concerns raised by animal studies with respect to nephrotoxicity and
`carcinogenicity are discussed extensively by Drs. Dunn, Katz, and Freed and I concur in their
`conclusions, most importantly because the renal effects of DMF were intensely studied in the DMF
`database and no adverse effects were observed.
`
`II. Effectiveness
`
`Following a preliminary dose-finding 6-month study (C1900) in RRMS looking at placebo and doses of
`DMF of 120 mg od, 120 mg tid and 240 mg tid, focusing on decrease of gadolinium-enhancing lesions,
`which showed a significant effect only at the highest dose, two large trials in RRMS, 301 and 302, were
`carried out comparing placebo, DMF 240 mg bid and 240 mg tid. Great care was taken in being sure that
`the reported development of new neurologic symptoms in fact represented a relapse. Symptoms were
`reported to the treating neurologist or nurse within 48 hours and a phone questionnaire completed. If the
`treating neurologist thought it was reasonable, an unscheduled relapse assessment was scheduled within
`72 hours of symptoms onset and the examining neurologist had to see the patient within 5 days of onset;
`the examining neurologist performed a relapse assessment and did an expanded disability severity score
`(EDSS). If the treating neurologist based on the examining neurologist’s assessment, concluded that there
`were new objective findings, the case was referred to the Independent Neurologist Evaluation Committee
`(INEC), a body of 3 neurologists. If a majority of the INEC, after case review, concluded there was a
`relapse, it was counted. Only INEC-accepted cases were counted as relapses. This approach is very
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`Reference ID: 3283838
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`sensible (uncharacterized cases will dilute a drug effect) but such an intrepid search for true cases is
`unusual.
`
`
`Study 301 results
`
`
`
`
`Number treated
`Proportion relapsing at 2rs (primary)
`Percent reduction
`
`ARR
`Percent reduction
`
`Proportion with progressing
`Recent disability reduction
`
`Placebo
`408
`0.46
`____
`
`0.364
`____
`
`0.27
`____
`
`240 bid
`410
`0.27
`49%
`p < 0.0001
`0.172
`52.7%
`p < 0.0001
`0.16
`38%
`p = 0.005
`
`240 tid
`416
`0.26
`49%
`p < 0.0001
`0.189
`47.9%
`p , 0.0001
`0.18
`34%
`p = 0.013
`
`
`There were also marked reductions (from 17% to 2-4%) in newly enlarging T2 MRI lesions at 2 years.
`
`The study was globally enrolled, with about 1/6 from US.
`
`
`
`Study 302 Results
`
`
`
`Number treated
`ARR (primary)
`
`Placebo
`363
`0.401
`____
`
`Proportion progressive disability
`Percent reduction
`
`0.17
`____
`
`240 bid
`359
`0.224
`44.0%
`p < 0.0001
`0.13
`21%
`p = 0.25
`
`240 tid
`345
`0.198
`50.5%
`p < 0.0001
`0.13
`24%
`p = 0.20
`
`
`Study 302 did not show significant reduction in disability, although there was a favorable trend.
`
`MRI findings were favorable, as in Study 301.
`
`Overall, the two large controlled studies provide strong evidence of a substantial reduction of relapses in
`these RRMS patients and some evidence of an effect on progression. Neither study showed a greater
`effect of tid dosing, so the bid dose will be recommended. Study 302 did include an unblinded (because
`given by injection) comparator arm, but we do not consider these results adequate to form a conclusion.
`There are also no data as yet that provide information on whether use of DMF provides additive effects
`when used with other MS treatments, certainly a matter of future interest.
`
`III. Safety
`
`Dr. Boehm’s review, and the reviews by Drs. Katz and Dunn consider safety issues. As noted by Dr.
`Dunn, Dr. Banks-Muckenfuss (non-clinical) was very concerned about the nephrotoxicity seen in
`animals, leading her to urge non-approval at this time. Dr. Freed acknowledged the nephrotoxicity, but
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`Reference ID: 3283838
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`noted the lack of similar findings to date in humans, including the substantial experience with Fumaderm
`(MMF plus DMF) in Germany since 1994, the valuable effect in MS, and the planned further post-
`marketing study. She , therefore did not believe the animal data were a basis for not approving the drug. I
`concur with that conclusion, as do Drs. Dunn and Katz.
`
` I
`
` agree with Dr. Katz’s conclusion that the 9 deaths in the DMF program (7 MS, 2 psoriasis) are not
`plausibly related to the test drug and that the single cases of SAEs of concern (anaphylaxis, hepatic
`failure, SJS, rhabdomyolysis, and myopericarditis) had satisfactory alternative explanations.
`
`Flushing (3%) and GI symptoms (about 3%) were the most prominent causes of discontinuation and there
`were about 9 early cases of flushing, itching, facial edema, some of which were treated with steroids
`and/or antihistamines. The adverse events in controlled trials were primarily flushing and related AE’s
`(hot flash, erythema, etc), as shown in labeling.
`
`
`
`
`DMF clearly causes lymphopenia, as discussed by Dr. Katz, but so far this has had no infectious
`consequences. As noted, minor elevations of aminotransferase (to above ULN) were seen but no
`difference in frequency of 3x ULN. Dr. Katz discusses 3 cases of more severe injury, including one death
`from an acetaminophen overdose and two patients with underlying liver disease who did not clearly
`worsen on treatment. Renal toxicity was prominent in several animal species, but no toxicity was seen in
`controlled trials; indeed, serum creatinine was slightly reduced on DMF in controlled trials.
`
`In animal carcinogenicity studies (mice and rats), renal tubular adenomas and carcinomas were seen. The
`controlled clinical data showed no excess of malignancies but would have little power to have done so. As
`noted, trials also did not show renal toxicity.
`
`Fumaderm, DMF plus MMF, which has been marketed in Germany since 1994 for psoriasis, has had 3
`reports of progressive multifocal encephalopathy (PML), a well-recognized consequence of natalizumab,
`a treatment for MS. This will clearly bear watching.
`
`Post-marketing requirements include a long-term observational study of adult MS patients (at least 5000
`followed for a minimum of 5 years. It will look for serious infections, malignancies including renal cell
`cancer, other serious AE’s (hepatic, renal).
`
`IV. Conclusion
`
`Data clearly support a claim for DMF in RRMS and, as Dr. Katz explains, we have broadened such
`findings to include all relapsing forms of MS, and that is the labeled claim here. The Indications do not
`specifically refer to the benefits attained, but section 14 of labeling includes both results on relapse rates
`and progression, although the latter effect is fully supported in only Study 301 (and pooled data for 301
`
`
`
`flushing
`abdominal pain
`diarrhea
`nausea
`vomiting
`pruritus
`rash
`erythema
`
`Placebo
`90
` 6
`10
`11
` 9
` 5
` 4
` 3
` 1
`
`240 bid
`90
` 4
`18
`14
`12
` 9
` 8
` 8
` 5
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`Reference ID: 3283838
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`and 302). DMF also appears safe for its intended use. Concerns about nephrotoxicity raised by animal
`studies did not lead to human renal disease as far as could be determined (serum creatinine actually fell)
`from an extensive (n – 2210 for MS treatment > 6-months with 1787 > 12 months and 712 > 3 years. As
`noted, a post-marketing study will follow at least 5000 patients for 5 years.
`
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`Reference ID: 3283838
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT TEMPLE
`03/27/2013
`
`Reference ID: 3283838
`
`