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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 2
`
`

`

`2/26/2019
`
`  
`
`Archive History for NCT00168701
`
`demonstrating definite therapeutic efficacy in psoriasis (Carboni et al,
`
`2004; Altmeyer et al, 1994; Mrowietz et al, 1999) and possible
`
`therapeutic efficacy in MS (Schimrigk et al, 2001 ). However, the
`
`target site of action and the exact mechanism of action of DMF are
`unknown.
`
`Like psoriasis, MS has been postulated to be driven by a Th1
`
`cytokine reaction and to therapeutically respond to either
`
`immunosuppression or Th2 suppression (Weiner and Selkoe, 2002).
`
`Putative effects of BG00012 include suppression of circulating T cell
`
`population, down regulation of adhesion molecule expression,
`
`modulation of the Th1/Th2 cytokine expression profile, inhibition of
`
`neutrophil burst, and TNF-induced CD62E expression through
`
`suppression of NF-kB nuclear translocation.
`
`Methyl fumaric acid esters (FUMADERMO) have been shown to
`
`reduce peripherally in vivo circulating CD4+, CD8+ and CD52+
`
`mononuclear cells (Hoxtermann et al, 1998). This circulatory
`reduction has been associated with a decrease in intradermal
`
`mononuclear cell infiltration in psoriasis patients (another T cell-
`
`mediated disease) (Vandermeeren et al, 1997). DMF was recently
`
`shown to induce substantial plasma membrane alterations potentially
`
`linked to the deactivation via apoptosis of lymphocytes (Sebok et al,
`
`2000)
`
`Methylfumarates have been shown to modulate in vitro T cell cytokine
`
`profile from Th1 to Th2 (Ockenfels et al, 1998). DMF and MMF inhibit
`
`the proliferation of keratinocytes, possibly due to a temporary rise in
`
`the intracellular calcium concentration (Nibbering et al, 1993).
`
`Methylfumarates have been shown to prevent acute and chronic
`
`rejection in rat kidney transplantation models (Risch et al, 2001). It is
`
`difficult to assess the validity of some in vitro data that have been
`
`derived using doses that exceed serum levels found in human trials
`
`(Mrowietz et al, 1999).
`
`In summary, the putative immunomodulatory effects, the psoriasis
`
`efficacy of FUMADERM®, and the efficacy data in the pilot MS study
`
`of BG00012 support a proof of concept study in MS
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 3
`
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`
`
`Detailed Description:
`
`
`
`
`
`The study will be divided into two parts: Part 1 will be a 24 week,
`
`blinded, placebo-controlled treatment phase followed by Part 2, a 24-
`
`week blinded, safety extension phase in which all subjects will
`receive BG00012.
`
`All investigational drug (BG00012 or placebo) will be given orally.
`
`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
`
`3/12
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 3
`
`

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`
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 4
`
`

`

`2/26/2019
`
`Archive History for NCT00168701
`
`Study Phase:
`
`Phase 2
`
`lnterventional Study Model:
`
`Parallel Assignment
`
`Number of Arms:
`
`Masking:
`
`Double
`
`Allocation:
`
`Randomized
`
`Enrollment:
`
`260
`
`Arms and Interventions
`
`Intervention Details:
`
`Drug: BG00012
`
`Outcome Measures
`
`Primary Outcome Measures:
`
`1. The primary endpoint for the primary objective is the total number of Gd-enhancing lesions
`
`over four scans at Weeks 12, 16, 20, and 24 (calculated as the sum of these four MRI scans).
`
`Secondary Outcome Measures:
`
`2. Secondary MRI endpoints include:
`
`3.
`
`- the cumulative number of new Gd-enhancing lesions from baseline to Week 24, and
`
`4.
`
`- the number of new or
`
`newly-enlarging T2 hyperintense lesions at Week 24 compared to
`
`baseHne.
`
`5. Additional endpoints include:
`
`6.
`
`- the number of new T1 hypointense lesions at Week 24 compared to baseline
`
`7.
`
`- the incidence and severity of adverse events
`
`8.
`
`- EDSS scores and change from baseline in EDSS scores at Weeks 12, 24, 36, and 48, and
`
`9.
`
`- annualized relapse rate from Week 0 to Weeks 24 and 48, and the proportion of relapse-free
`
`subjects at Weeks 24 and 48.
`
`Eligibility
`
`Minimum Age
`
`: 18 Years
`
`Maximum Age
`
`: 55 Years
`
`Sex:
`
`All
`
`Gender Based:
`
`Accepts Healthy Volunteers:
`
`No
`
`Criteria
`
`:
`
`Inclusion Criteria:
`
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`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
`
`
`
`1. Must give written informed consent and authorize the release
`
`and use of protected health information (PHI), as required by
`local law.
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 5
`
`5/12
`
`& 
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 5
`
`

`

`2/26/2019
`
`  
`
`Archive History for NCT00168701
`
`2. Must be 18 to 55 years old, inclusive, at the time of informed
`consent
`
`3. Must have a confirmed diagnosis of relapsing-remitting MS
`
`according to McDonald criteria #1-4 (McDonald et al, 2001;
`
`Appendix 2).
`
`4. Must have a baseline EDSS between 0.0 and 5.0, inclusive.
`
`5. Must meet one of the following two criteria:
`
`1. have experienced at least one relapse within the 12
`
`months prior to randomization, with a prior cranial MRI
`
`demonstrating lesion(s) consistent with MS (it is not
`
`necessary to obtain a current scan if a scan performed
`
`previously is available from the subject’s history; if a scan
`
`is not available from the subject’s history, then the
`
`baseline scan may be used). For inclusion purposes, a
`
`relapse is defined as neurologic signs and/or symptoms
`
`documented by a neurologist in the medical record and of
`
`at least 24-hours duration to be determined by the
`
`investigator or the treating neurologist. Time since
`
`relapse should be measured from the time of relapse
`
`onseL
`
`OR
`
`2. show evidence of Gd-enhancing lesions of the brain on
`
`an MRI performed within the 6 weeks prior to
`
`randomization (if a scan is not available from the
`
`subject’s history, then the baseline scan may be used).
`
`6. Male and female subjects must be willing to take appropriate
`
`measures to prevent pregnancy while participating in this study.
`
`Male subjects and female subjects of child-bearing potential
`
`must use adequate contraception as appropriate (either intra-
`
`uterine device, oral or depot contraceptive, or barrier plus
`
`spermicide) and be willing and able to continue contraception
`
`for 30 days after their last dose of investigational drug. The
`
`rhythm method is not to be used as the sole method of
`
`contraception. Females who have not been stable on oral or
`
`depot contraceptives for 3 months prior to the first dose of
`
`investigational drug must also agree to use a barrier method
`
`throughout the study. Female subjects are exempt from
`
`contraceptive use if they are post-menopausal for at least 1
`
`year prior to the start of the study or are surgically sterile
`
`(females need to have either no uterus or no ovaries to be
`
`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
`
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 6
`
`6/12
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 6
`
`

`

`2/26/2019
`
`  
`
`Archive History for NCT00168701
`
`considered surgically sterile; males or females who have tubes
`
`tied or cut are not considered surgically sterile).
`
`All female subjects who are not post-menopausal or surgically sterile
`
`must have a negative pregnancy test at screening and at various time
`
`points throughout the study to receive investigational drug.
`
`Exclusion Criteria:
`
`1.
`
`Primary progressive, secondary progressive, or progressive
`
`relapsing MS (as defined by Lublin and Reingold, 1996
`
`[Appendix 3]). These conditions require the presence of
`
`continuous clinical disease worsening over a period of at least
`
`3 months. Patients with these conditions may also have
`
`superimposed relapses, but are distinguished from relapsing-
`
`remitting patients by the lack of clinically stable periods or
`
`clinical improvement.
`
`. History of malignancy unless an exception is granted by the
`
`Biogen ldec Medical Director.
`
`. History of severe allergic or anaphylactic reactions or known
`
`drug hypersensitivity.
`
`. History of abnormal laboratory results indicative of any
`
`significant cardiac, endocrinologic, hematologic, hepatic,
`
`immunologic, metabolic, urologic, pulmonary, gastrointestinal,
`
`dermatologic, psychiatric, renal, neurologic (other than MS),
`
`and/or other major disease that would preclude administration
`of BG00012.
`
`. History of human immunodeficiency virus (HIV).
`
`. History of drug or alcohol abuse (as defined by the Investigator)
`
`within the 2 years prior to randomization.
`
`. An MS relapse that has occurred within the 50 days prior to
`
`randomization AND/OR the subject has not stabilized from a
`
`previous relapse prior to randomization.
`
`. Body weight >100 kg.
`
`. Positive for hepatitis C antibody and/or positive for hepatitis B
`
`surface antigen (HBsAg) at screening.
`
`10.
`
`Any of the following abnormal blood tests at screening:
`
`0 alanine transaminate/serum glutamate-pyruvate
`
`transaminase (ALT/SGPT), or aspartate
`
`transaminase/serum glutamic—oxaloacetic transaminase
`
`(AST/SGOT), or gamma-glutamyl-transferase (GGT) >2
`
`times the upper limit of normal (ULN)
`
`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
`
`
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 7
`
`7/12
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 7
`
`

`

`2/26/2019
`
`  
`
`Archive History for NCT00168701
`
`o leukocytes <3500/mm3
`
`o eosinophils >0.7 x 103/mL or >0.7 Gl/L, and
`
`0 serum creatinine >ULN.
`
`11. Any previous treatment with FUMADERM®, FAG-201, or
`BG00012.
`
`12. Prior treatment with the any of the following:
`
`0 total lymphoid irradiation
`
`o cladribine
`
`o T-cell or T-cell receptor vaccination
`
`0 any therapeutic monoclonal antibody, with the exception
`
`of ANTEGREN® (natalizumab) (see exclusion #14)
`
`13. Prior treatment with any of the following within 1 year prior to
`randomization:
`
`o mitoxantrone
`
`o cyclophosphamide
`
`14. Prior treatment with any of the following medications or
`
`procedures within the 6 months prior to randomization:
`
`o cyclosporine
`
`o azathioprine
`
`o methotrexate
`
`o natalizumab
`
`o intravenous immunoglobulin (Mg)
`
`0 plasmapheresis or cytapheresis.
`
`15. Prior treatment with any of the following within the 3 months
`
`prior to randomization:
`
`o subcutaneous or oral glatiramer acetate
`
`0 interferon-alpha
`
`o interferon-beta (subjects who are positive for neutralizing
`
`antibodies to interferon-beta may receive interferon-beta
`
`treatment up to 2 weeks prior to randomization).
`
`16. Treatment with any of the following medications within the 30
`
`days prior to randomization:
`0 IV corticosteroid treatment
`
`0 oral corticosteroid treatment
`
`0 4-aminopyridine or related products.
`
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`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 8
`
`8/12
`
` 
`
`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 11
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`

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`2/26/2019
`
`Archive History for NCT00168701
`
`Plan to Share IPD:
`
`References
`
`Citations:
`
`Fox RJ, Kita M, Cohan SL, Henson LJ, Zambrano J, Scannevin RH,
`
`O'Gorman J, Novas M, Dawson KT, Phillips JT. BG-12 (dimethyl
`
`fumarate): a review of mechanism of action, efficacy, and safety. Curr
`
`Med Res Opin. 2014 Feb;30(2):251-62. doi:
`
`10.1185/03007995.2013.849236. Epub 2013 Oct 22. Review.
`PubMed 24131282
`
`Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth
`
`V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M,
`
`Meluzinova E, Rektor l, Dawson KT, Sandrock AW, O'Neill GN; BG-
`
`12 Phase llb Study Investigators. Efficacy and safety of oral fumarate
`
`in patients with relapsing-remitting multiple sclerosis: a multicentre,
`
`randomised, double-blind, placebo-controlled phase llb study. Lancet.
`
`2008 Oct 25;372(9648):1463-72. doi: 10.1016/80140-
`
`6736(08)61619-0. Erratum in: Lancet. 2009 Apr 18;373(9672):1340.
`PubMed 18970976
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`Links:
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`Available lPD/lnformation:
`
`Scroll up to access the controls
`
`Scroll to the Studyfip
`
`U.S. National Library of Medicine | U.S. National Institutes of Health | U.S. Department of Health & Human Services
`
`https://c|inicaltrials.gov/ct2/history/NCT00168701?A=1&B=1&C=merged
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 12
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`12/12
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`MYLAN PHARMS. INC. EXHIBIT 1057 PAGE 12
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`