Eflgmigifieu Material
`
`EfllTED a? JEFFREY A. COHEN
`
`nun RICHARD A. RUDICK
`
`M U LTIPLE SCLEROSIS
`
`TH ERAPEUTICS FOURTH EDITION
`
`
`
`
`
`CAHIHHIHL'IE
`
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`
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`Sawai (1PR2019-00789), EX. 1036, p. 001
`
`Sawai (IPR2019-00789), Ex. 1036, p. 001
`
`

`

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`Sawai (IPR2019WE)?7TD‘3E p. 002
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`Sawai (IPR2019-00789), Ex. 1036, p. 002
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`

`

`Section III
`
`Clinical trials of multiple sclerosis therapies
`
`Chapter31 Dimethyl fumarate to treat multiple sclerosis
`
`Robert J. Fox and Ralf Gold
`
`Unmet need for multiple sclerosis therapies
`For over 15 years, approved multiple sclerosis (MS) disease-
`modifying therapies were limited to parenteral routes of
`administration – subcutaneous, intramuscular, and intravenous
`modalities. These routes are not only unpleasant for patients
`because of needle-stick pain, but also lead to skin reactions
`such as rubor, pruritus, lipoatrophy, and rarely infection. Intra-
`venous administrations are inconvenient because they require
`routine visits to an infusion center or with a home care nurse.
`The US Food and Drug Administration approval of fin-
`golimod in 2010 marked the beginning of a new period of oral
`MS treatment. In addition to fingolimod, at least four addi-
`tional oral long-term MS disease-modifying therapies were in
`late Phase III trials in 2010. These oral therapies promise to lead
`to dramatic shifts in treatment patterns for relapsing forms of
`MS. As in any therapeutic area, a successful oral therapy will
`need to demonstrate convincing efficacy, reasonable safety, and
`convenience in administration. An emerging additional con-
`sideration for MS disease modifying therapies is their potential
`neuroprotective effects. MS is thought to be not only a neuroin-
`flammatory disease, but also a superimposed neurodegenera-
`tive disease. The detailed interplay between these two patho-
`physiologies is not well understood, but one potential model
`is that neuroinflammation in the early years sets up a cascade
`of accelerated neurodegeneration in later years. Whatever the
`cause, a gradually progressive clinical disorder becomes mani-
`fest in the later years of the MS course, and this stage of MS has
`been uniformly recalcitrant to currently available immunother-
`apies. If new anti-inflammatory therapies are also effective
`against the neurodegenerative component of MS, they would
`meet a hitherto unmet need in MS therapeutics. Dimethyl
`fumarate is an oral therapy in development for MS which may
`meet these needs.
`
`History of fumaric acid
`Fumaric acid is the common name of an unsaturated dicar-
`bonic acid (Fig. 31.1). In turn, the salts of this acid are named
`fumarate. In the Krebs cycle, succinate is converted via a
`specific dehydrogenase into fumarate, which subsequently is
`
`Fig. 31.1. Molecular structure of dimethyl fumarate.
`
`metabolized to maleate. To date, there is no known disease
`which arises from inborn errors of this pathway.
`In the late 1950s, the German chemist Walter Schweck-
`endiek postulated that the pathogenesis of psoriasis vulgaris
`was due, at least in part, to a disturbed Krebs cycle. Thus, he
`aimed at modulating this pathway by exogenous administration
`of fumaric acid. He first used fumaric acid on his own psoriatic
`skin and preferred application as an ointment of fumaric ester.
`He continued studies on himself by swallowing fumaric esters
`and published its success in 1959.1 Later, he used a combina-
`tion of monomethyl fumarate and dimethyl fumarate (DMF),
`and by changing the galenic pharmacological formulation and
`adding a tablet coating, he achieved delayed release in the duo-
`denum, leading to reduced side effects (Table 31.1). Further
`systematic studies demonstrated the efficacy of fumaric acids
`for the treatment of psoriasis.2,3 The Swiss company Fumaderm
`obtained German regulatory approval in 1994 for this fumaric
`acid formulation (called Fumaderm) for treatment of severe
`psoriasis. Since then, Fumaderm is the preferred systemic treat-
`ment of severe psoriasis in German-speaking countries.4 Thus,
`more than 100000 patient–years of experience have accumu-
`lated with minimal serious complications. The mixture of these
`fumarate esters has been found safe for long-term therapy.
`
`Table 31.1. Constituentsoffumaricacidpreparations
`
`Dimethyl fumarate
`Ethylhydrogen fumarate Ca-salt
`Ethylhydrogen fumarate Mg-salt
`Ethylhydrogen fumarate Zn-salt
`
`BG00012
`120 mg
`
`Fumaderm
`120 mg
`87 mg
`5 mg
`3 mg
`
`Multiple Sclerosis Therapeutics, Fourth Edition, ed. Jeffrey A. Cohen and Richard A. Rudick. Published by Cambridge University Press.
`C(cid:2) Cambridge University Press 2011.
`
`387
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`

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`Section III: MS clinical trials
`
`The successful use of fumaric acid in dermatology eventu-
`ally led to its translational use in neurology. Since it was pos-
`tulated that fumarates induce a so-called Th2-shift,5 Peter Alt-
`meyer, dermatology chair at the Ruhr University of Bochum,
`inspired Horst Przuntek, his neurologist colleague, to test
`fumaric acids in active relapsing MS. From this study, the first
`small systematic observation on ten patients was published (see
`below), ultimately leading to a successful Phase 2 trial, the
`acquisition of Fumapharm by Biogen Idec, and finally the sub-
`sequent MS Phase 3 studies described below.6
`
`Mechanism of action of fumaric acid
`Immunomodulation
`In the past, dermatological investigators performed a wide array
`of studies focusing on the adaptive immune system. During
`clinical trials a reduction of peripheral blood leukocytes, mainly
`CD4+ T-cells (up to 90%) and CD8+ T-cells (up to 53%),
`was observed as a putative consequence of apoptosis.7 In addi-
`tion, a shift from Th1 to Th2 cytokine production was also
`detected.5 While levels of pro-inflammatory cytokines, tumor
`necrosis factor-alpha (TNF␣) and interferon-gamma (IFN␥),
`levels were reduced, the levels of anti-inflammatory Th2 type
`cytokines, namely interleukin (IL)-4, IL-5 and IL-10, were
`markedly increased.
`In vitro experiments showed that an increased secretion
`of Th2 cytokines up to ten-fold over normal was observed in
`CD45R0+ T-cells.5 In addition, other blood cells were mod-
`ulated. For example, dendritic cells, which play a central role
`in regulation of inflammatory processes, were down-regulated
`and secreted less IL-12. Apoptosis was also detected in den-
`dritic cells.5 Immunological effects of DMF were also observed
`in keratinocytes where major histocompatability complex class
`II gene products and the adhesion molecule, ICAM-1, were
`found to be down-regulated.8,9 The immunomodulatory effects
`of DMF were shown to be functionally relevant in a rat model of
`organ transplantation, where transplant rejection was success-
`fully modulated by fumarates.10 Fumaric esters were shown to
`inhibit acute and chronic rejection in rat kidney transplantation
`models, providing further evidence of its immunosuppressant
`properties.11
`Nonetheless, the molecular mechanisms of DMF have not
`been fully unraveled. In vitro studies in human endothelial
`cells have shown that DMF acts via transcriptional downreg-
`ulation of TNF-induced genes as well as inhibition of TNF-
`induced nuclear entry of nuclear factor kappa B (NF␬B).12 DMF
`inhibits NF␬B-dependent chemokines such as CXCL8, CXCL9
`and CXCL10. Most studies involving the molecular effects of
`fumaric esters have focused on T-cells, and there is very little
`information available on their effects on B-cells.
`
`Neuroprotection
`Recently, novel potentially neuroprotective effects of DMF were
`observed in rodent glial cells and neurons, both in vitro and
`
`in vivo.13 Since an oral formulation of DMF had demon-
`strated beneficial effects on MRI markers of axonal destruc-
`tion in a Phase 2 MS trial,14 one of us (RG)15 studied immune
`effects and potential axonal protection in experimental autoim-
`mune encephalomyelitis (EAE) induced by immunization with
`myelin oligodendrocyte glycoprotein peptide.16 In C57BL/6
`mice, preventive DMF treatment given twice a day by oral gav-
`age, afforded a significant beneficial effect on the EAE disease
`course and a strongly reduced macrophage inflammation in the
`spinal cord as revealed by histology.17 Multiparameter cytokine
`analysis from blood detected an increase of IL-10, an anti-
`inflammatory cytokine, in the treated animals. Thus, the under-
`lying biological activity of DMF in EAE appears to be complex.
`We then studied chronic EAE using the same C57BL/6
`mouse EAE model.13 Treatment with DMF improved preser-
`vation of myelin, axons, and neurons (Fig. 31.2). In vitro, the
`application of fumarates increased neuronal survival and pro-
`tected human astrocytes against oxidative stress. Additional
`studies evaluated the functional pathway of fumarates and
`found that application of fumarates led to direct modification
`of a protein called Kelch-like ECH-associated protein 1 (Keap-
`1) which is an inhibitor of nuclear-factor- E2-related factor-2
`(Nrf2). This modification of Keap-1 caused stabilization of Nrf2,
`activation of Nrf2-dependent transcription, and a concomi-
`tant accumulation of prototypical Nrf2 target proteins. In turn,
`there was induction of several substances which enhance cellu-
`lar resistance to free radicals such as glutathione and NAD(P)H
`dehydrogenate quinine 1 (NQO1). DMF treatment resulted in
`increased Nrf2 immunoreactivity in neuronal subpopulations,
`oligodendrocytes, and astrocytes. These DMF-mediated bene-
`ficial effects were completely abolished in Nrf2 deficient mice.
`Human autopsy studies have observed up-regulation of Nrf2 in
`MS lesions within the spinal cord lesions, suggesting that the
`Nrf2 pathway may be activated through the body’s endogenous
`protective mechanisms. Altogether, these observations suggest
`that DMF treatment may be effective in tissue preservation and
`protection in MS. The ability of DMF to activate Nrf2 may thus
`offer a novel cytoprotective modality that is not known to be
`targeted by other MS therapies. Fig. 31.3 illustrates the putative
`mechanism through which DMF may exert immunomodulat-
`ing and neuroprotective effects.
`
`Phase 1 clinical trial
`Fumaric acids were first studied in MS in a Phase 1, open-label,
`baseline-controlled trial using the combination fumaric acid
`ester preparation Fumaderm. Ten patients with relapsing remit-
`ting (RR) MS and at least one relapse within the prior year were
`enrolled in the study. A 6-week untreated baseline phase was
`followed by an 18-week treatment phase, then a 4-week wash-
`out phase, and finally a second 48-week treatment phase. With
`each treatment phase, fumaric acid esters were titrated over
`9 weeks. Primary efficacy outcome was the number and volume
`of triple-dose (0.3 mmol/kg body weight) gadolinium (Gd)-
`enhancing lesions.
`
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`

`

`Chapter 31: Dimethyl fumarate to treat MS
`
`Fig. 31.2. Quantification of axonal density in EAE
`lesions of carrier-fed mice (“placebo”), or recipients
`of MHF or DMF. As illustrated in the Bielschowsky
`stain (right side) there are more black axonal
`profiles preserved under DMF treatment (see also
`color plate section).
`
`Fig. 31.3. Illustration of how dimethyl fumarate
`may exert both immunomodulatory and
`neuroprotective effects.
`
`Of the ten patients enrolled, six completed the study. One
`patient each stopped because of unplanned pregnancy, gas-
`trointestinal side effects, lack of compliance, and loss to follow-
`up. The most common adverse events were flushing and gas-
`trointestinal symptoms (diarrhea, nausea, cramps), which were
`reported by almost all patients during the initial phase of the
`study. In general, symptoms improved over 6 weeks.
`After 18 weeks of treatment, a significant reduction in
`Gd-enhancing lesions was observed. There were a mean of
`11.3 Gd-enhancing lesions per patient at baseline, which
`decreased to 1.5 per patient at 18 weeks. Gd-enhancing
`lesions reduced further during the second treatment period,
`decreasing to a mean of 0.28 per scan per subject. The
`volume of Gd-enhancing lesions also decreased from 245
`mm3 at baseline, to 26.1 mm3 at 18 weeks, to 2.1 mm3 at
`70 weeks. Clinical scores showed modest, non-significant
`improvements over
`the course of
`the study,
`including
`Expanded Disability Status Scale (EDSS), Ambulation Index,
`and nind-hole peg test. Two relapses were observed –
`one at week 18 and one at week 46. Immunologic studies on
`peripheral blood of these patients during the first 28 weeks
`showed similar findings to that from dermatology: an increase
`
`in IL-10 from CD4+ T-cells during treatment, as well as a
`transient increase in apoptosis of CD4+ T-cells. No change in
`IFN␥ was observed over the course of treatment.
`
`Phase 2 clinical trial
`Based upon the encouraging Phase 1 results, Fumapharm part-
`nered with Biogen Idec to conduct a Phase 2 trial of DMF
`in RRMS. To improve gastrointestinal tolerability, they used
`only dimethyl fumaric acid (rather than the multiple fumaric
`acid esters which constitute Fumaderm) and employed enteric-
`coated microtablets. This preparation of DMF is currently des-
`ignated BG00012.
`The Phase 2, multicentered, placebo-controlled clinical trial
`was performed to provide proof-of-concept evidence of DMF’s
`efficacy in relapsing MS.14 In this trial, 257 RRMS patients were
`enrolled and randomized to one of four treatment groups: 120
`mg BG00012 once daily (and matching placebo twice daily),
`120 mg BG00012 thrice daily (360 mg daily dose), 240 mg
`BG00012 thrice daily (720 mg daily dose), and placebo thrice
`daily. One patient did not receive treatment, so all results were
`based upon 256 patients. The high-dose group was titrated to
`
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`

`

`Section III: MS clinical trials
`
`full dose by taking 120 mg thrice daily for one week. Dosage
`reduction was allowed for one month for patients unable to tol-
`erate the standard dose or for abnormal liver, renal, and hema-
`tology tests. Separate study personnel were assigned to perform
`neurologic assessments (blinded examining neurologist) and
`treat patients (treating neurologist and nurse). To help prevent
`potential unblinding of study personnel, patients were asked to
`not take their study medication within four hours of their study
`visit. MRI was performed monthly from baseline through week
`24. Each MRI study included a dual echo fast (turbo) spin echo
`sequence for proton density and T2-weighted images and a con-
`ventional spin echo before and after standard-dose Gd contrast.
`Images were read centrally.
`The primary outcome of the Phase 2 trial was the total
`number of new Gd-enhancing lesions on monthly scans from
`weeks 12–24. Secondary imaging outcomes included cumula-
`tive number of new Gd-enhancing lesions from weeks 4 to
`24, the number of new or enlarging T2 lesions, and new T1-
`hypointense lesions (T1 holes) at week 24. The effect on relapse
`rate, disability progression, safety, and tolerability were also
`assessed.
`Over the 24 weeks of the study, 21 (8.2%) of 256 patients
`who received study drug withdrew from the study. Another 30
`patients (11.7%) discontinued treatment but completed follow-
`up. More patients receiving the higher two doses discontinued
`treatment than the other two groups.
`The study met its primary outcome: patients receiving
`720 mg/d of BG00012 had a 69% reduction in the number
`of new Gd-enhancing lesions compared to placebo patients
`(1.4 vs. 4.5, P ⬍ 0.0001; Fig. 31.4). A sensitivity analysis of
`the intention-to-treat population showed similar results (P ⬍
`0.0001). In contrast, the primary outcome was not met with
`either of the lower two dose groups. However, the middle (240
`mg/d) dose group had a 76% higher mean number of Gd-
`enhancing lesions at baseline, which may have obscured a treat-
`ment effect. If the primary outcome is re-displayed as % reduc-
`tion from each group’s baseline enhancing lesion activity, a
`dose–response becomes more apparent (Fig. 31.4).
`Secondary imaging outcomes were also met in the 720 mg/d
`group. Compared with placebo, there was a 44% reduction in
`Gd-enhancing lesions from week 4 to 24 (P = 0.002), a 48%
`reduction in number of new or enlarging T2 lesions over 24
`weeks (P = 0.0006), and a 53% reduction in the number of T1
`holes (P = 0.014). No significant difference was observed in
`either of the lower dose groups compared to placebo. The annu-
`alized relapse rate in the 720 mg/d group was 32% lower than
`the placebo group, although this was not statistically significant.
`As with many Phase 2 trials in relapsing MS, this study was not
`powered to detect a significant effect of treatment on relapses.
`Additional analyses evaluated conversion of Gd-enhancing
`lesions to T1 holes. A subset of Gd-enhancing lesions will later
`become T1 hypointense lesions (T1 holes), and this type of
`lesion is thought to represent more significant tissue injury than
`lesions that do not develop into T1 holes. Imaging data from
`several clinical trials have evaluated the effect of different ther-
`
`390
`
`(a)
`
`(b)
`
`Fig. 31.4. Gadolinium-enhancing lesion outcome from the Phase 2 clinical
`trial in relapsing MS:14 (a) mean enhancing lesions per subject per scan at
`baseline and averaged over weeks 12, 16, 20, and 24; (b) percent reduction in
`enhancing lesions at weeks 12–24, compared with baseline.
`
`apies on the evolution of enhancing lesions into T1 holes.18,19
`T1 hole conversion is an imaging measure that is thought to
`reflect the potential neuroprotective effect of a therapy, beyond
`anti-inflammatory effects measured by new enhancing lesions
`and T2 lesions. A post hoc analysis of the BG00012 Phase 2 trial
`was performed to evaluate the evolution of new Gd-enhancing
`lesions into T1 holes.20 New lesions that developed between
`weeks 4 and 12 were evaluated at week 24 to identify the pro-
`portion that evolved into T1 holes. The odds ratio (OR) for the
`evolution of new Gd-enhancing lesions into T1 holes in the 720
`mg/d BG00012 group compared to placebo group was 0.51 (P
`⬍ 0.0001). After adjusting for baseline Gd-enhancing lesions,
`years since disease onset, and relapses in the previous 3 years,
`the OR decreased to 0.40. The treatment effect was greater for
`smaller lesions (OR 0.30) than large lesions (OR 0.62). Analysis
`of the lower dose BG00012 groups was not reported, since they
`did not show a significant reduction in Gd-enhancing lesions.
`The most common adverse events reported in the BG00012
`treatment groups were flushing, headache, and gastrointestinal
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`

`

`symptoms (nausea, diarrhea, abdominal pain). Flushing typ-
`ically started within 30 minutes of dosing and resolved by
`90 minutes. The frequency of flushing and gastrointestinal
`adverse events decreased markedly after 1 month. Flushing was
`reported in 66% of patients during month 1, but only 5% during
`month 6. Gastrointestinal adverse events were reported in 52%
`of patients during month 1, but only 4% during month 6.14
`The frequency of infections was generally similar between
`treatment groups. One case of pelvic inflammatory dis-
`ease was the only serious infection reported in the study.
`Adverse events that led to drug discontinuation included
`flushing (two patients), nausea (two patients), vomiting (two
`patients), diarrhea (two patients), and increased alanine amino-
`transferase (one patient). No clinically meaningful trends
`in laboratory tests were observed over the course of the
`study. A mild, dose-related increase in transaminase levels
`were observed, with most less than twice the upper limit
`of normal. None were associated with increase in biliru-
`bin or other evidence of
`impaired hepatic function and
`no patients reported symptoms of hepatitis. In all cases,
`laboratory abnormalities resolved upon discontinuation of
`BG00012 and some patients tolerated later re-treatment with-
`out recurrent increase in transaminases. There were no clin-
`ically significant shifts in hematology profiles, anemia, or
`neutropenia.
`Subjects who successfully completed the 24-week placebo-
`controlled study were offered enrollment into an open-label,
`dose-blinded, 24-week extension study.14 Those on BG00012
`in the first half of the study remained on the same dose of
`BG00012, while those on placebo were transitioned to 240 mg
`thrice daily (720 mg/d) of BG00012. 225 patients enrolled in
`open-label extension study. The profile of adverse events in
`the open-label study was similar to that seen in the placebo-
`controlled phase, with no new safety issues.
`
`Phase 3 clinical trials
`Following the successful Phase 2 clinical trial, BG0012 was fur-
`ther evaluated in two large, placebo-controlled Phase 3 clini-
`cal trials in relapsing remitting MS – the DEFINE and CON-
`FIRM trials. Both trials were two years in duration and com-
`pared two doses of BG00012 with placebo. In addition to the 240
`mg thrice daily (720 mg/d) dose found beneficial in the Phase 2
`trial, 240 mg twice daily (480 mg/d, plus placebo capsules once
`a day) was also evaluated. This 480 mg/d dose is between the
`high (720 mg/d) and middle (360 mg/d) doses evaluated in the
`Phase 2 trial. The 480 mg/d dosing regimen also utilized twice
`daily dosing, which is more desired by patients than the thrice
`daily dosing of the 720mg/d dosing regimen. In addition, the
`CONFIRM trial has glatiramer acetate as an additional, fourth
`arm. This “tracking” arm is a requirement of some regulatory
`agencies, providing a comparator to an established, available
`relapsing MS therapy. The glatiramer acetate arm is open-label
`to the patients and treating neurologist (i.e. there are no placebo
`capsules for this group and no placebo injections for the oral
`
`Chapter 31: Dimethyl fumarate to treat MS
`
`BG00012 and placebo groups), but blinded for the examining
`neurologists and image analysis team. Randomization was
`equal among each treatment arm.
`Clinical assessments included clinical relapses and EDSS
`progression, as well as Multiple Sclerosis Functional Composite
`(MSFC) and visual contrast sensitivity test. A subset of patients
`were offered enrollment in an optional MRI sub-study. Analysis
`for the MRI sub-study included new Gd-enhancing lesions, new
`or enlarging T2 lesions, and atrophy. In addition, magnetiza-
`tion transfer ratio (MTR) imaging is included as an exploratory
`neuroprotection outcome. Safety assessments included labora-
`tory studies and electrocardiographs. Rescue therapy is allowed
`for patients with clinical disease activity (relapses or progressive
`disability on EDSS).
`The primary outcomes of the two trials were slightly differ-
`ent. The primary outcome of the DEFINE trial was the pro-
`portion of patients relapsing, while the primary outcome of
`the CONFIRM trial was the annualized relapse rate. Secondary
`outcomes were slightly different between the two studies, but
`included rate of disability progression at two years, reduction in
`new or newly enlarging T2 lesions, Gd-enhancing lesions, and
`T1 holes.
`Both studies completed enrollment in 2009, with DEFINE
`enrolling 1239 subjects and CONFIRM enrolling 1431 subjects.
`Both are expected to complete two years of follow-up and report
`results in 2011. Preliminary, top-line results from the CON-
`FIRM trial are very encouraging. Compared with placebo, MS
`patients treated with 240 mg twice daily (480 mg/d) had a 49%
`reduction in the proportion with relapses (the primary out-
`come), 53% reduction in annualized relapse rate, 85% reduction
`in new or enlarging T2 lesions, 90% reduction in Gd-enhancing
`lesions at 2 years, and 38% reduction in sustained progression
`of disability. No new significant safety issues were found.
`
`Summary
`The use of DMF in autoimmune diseases arose from a personal
`view of the immune system, whereby autoimmunity is caused
`by disruption in the Krebs’s cycle. Despite the incorrect rea-
`son, it appears that DMF does indeed have immunomodulatory
`properties in both animals and humans. Perhaps equally impor-
`tant, laboratory evidence and preliminary imaging evidence
`from human clinical trials suggests that DMF may have neuro-
`protective properties via antioxidative mechanisms. A Phase 2
`trial found that 720 mg/d of BG00012 both reduced active
`inflammation (Gd-enhancing lesions and T2 lesions) as well
`as conversion of Gd-enhancing lesions to T1 holes. BG00012
`showed a favorable safety profile, with the main side effects
`being flushing and gastrointestinal symptoms. Phase 3 trials
`will provide pivotal and definitive evidence regarding the safety
`and efficacy of BG00012 in MS. Ongoing laboratory studies and
`advanced imaging studies in the Phase 3 trials are evaluating
`the potential neuroprotective effects of BG00012. Fumaric acids
`such as BG00012 are an exciting new class of potential MS treat-
`ment.
`
`391
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`

`

`Section III: MS clinical trials
`
`References
`1. Schweckendiek W. [Treatment of
`psoriasis vulgaris]. Med Monatsschr.
`1959;13:103–4.
`2. Balasubramaniam P, Stevenson O,
`Berth-Jones J. Fumaric acid esters in
`severe psoriasis, including experience
`of use in combination with other
`systemic modalities. Br J Dermatol
`2004;150:741–746.
`3. Ormerod AD, Mrowietz U. Fumaric
`acid esters, their place in the treatment
`of psoriasis. Br J Dermatol
`2004;150:630–2.
`4. Altmeyer PJ, Matthes U, Pawlak F, et al.
`Antipsoriatic effect of fumaric acid
`derivatives. Results of a multicenter
`double-blind study in 100 patients. J
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