{median change -230, -610 and -214 [5.25 mgikg} and -534, -404 and
`-122 [3.5 mgikili. respectively). Levels subsequently recovered slightly
`until redosing at Week 48, followed by a second (comparable) nadir.
`l.ower C‘.l)4iCD8 ratios were due to preferential reductions in CD4
`versus CD8 cells. Reductions were also observed in CD4 naive and
`memory (CD45liA and CD45ltO) T-helper cells, and to a lesser
`extent in CD8 naive and memory cytotoxic T cells. B-cell (CD19)
`marker also revealed rapid reductions to nadir values at Weeks 9
`and 16, followed by more marked recovery than observed with T—celis.
`Conclusions: Treatment with cladribine
`tablets differentially
`affected CD4, CD8 and CD19 subpopulatlons. These findings may
`suggest a direct effect on T-cell function, humorai ii cell activity and
`antigen-presenting cell activity, which may be involved in immune-
`mediated disease pathogenesis.
`
`Funded by Merck Serono S.A. — Geneva, Switzerland, an affiliation of
`Merck KGaA, Darmstadi. Germany.
`
`P8]?
`
`Iiarly onset of effect of treatment with clndrltilne tablets for
`relapsing-remitting multiple sclerosis in this 96-week, phase
`III, double-blind, placebo-controlled CLARITY study
`P. Vermersclt, G. Comi, 5. Cook, G. Giovannoni, K. Rammohan,
`P. Rieckrnann, P.S. Sorensen, I’. Chang, A. Hamlett, ii. Musch,
`R. tierjee, S. Greertberg
`
`iiniversity ofi.iiie (Liiie, Flt,],- University Vitrr-Snirrie (Miitrn, ii’); University
`o,"Meriicine nnri Dentistry (Neivnrit, U5); Boris nnd Tire Lomiorr School of
`Medicine (Lanrion, UK); Ohio State University (Columbus, US); University of
`Bririsir Coirrmbirr Wrnrcoitver, CA); itigsitospiinici (Caperrirngerr, DK);
`Merck Serono 5.A. (Geneva, CH)
`
`Ilaclrground: Ciadribirre is activated specifically in lymphocyte sub-
`types resulting in targeted and sustained immunomodulation, which
`provides the rationale for use of ciadribine tablets as a short-course
`annual treatment in multiple sclerosis (MS). We investigated the time
`of onset of treatment effect with cladrlbine tablets relative to placebo,
`in the CLARITY (CLAdRlbine tablets Treating multiple sclerosis
`ora|lY) study In patients with relapslngremitting MS (RRMS).
`Metlrorls: Patients with i'tliM5 (McDonald criteria; Expanded
`Disability Status Scale [EDSS] score 0-5.5} were randomised 1.-1:1 to
`cladribine tablets (cumulative dose of 5.25 or 3.5 mgikg), or matching
`placebo. Cladribine tablets were given in short courses (once daily for
`4-5 days) In 4 or 2 consecutive months (23-day periods) In the first 48
`weeks, then 2 short courses at Weeks 48 and 52 (for both groups).
`Qualifying relapses were evaluated serially throughout the study,
`and Mill parameters (T 1-Gd+, active T2, and combined unique [CU]
`lesions per patient per scan) were evaluated at 24, 48 and 96 weeks
`post-randomisation.
`Results: The l’i'i‘ population comprised 456, 433 and 43? patients
`randomised to 5.25 mgikg, 3.5 mgiltg or placebo groups, respectively.
`Differences in qualifying relapse rate between active treatment groups
`vs. placebo were apparent as early as 4 weeks post first treatment
`course (5.25 and 3.5 mgikg vs. placebo: 0.2? and 0.23 vs. 0.42, respec-
`tively}. Statistically significant differences for all three MRI parameters
`were also evident at the first assessment (mean number of lesions per
`patient per scan in the 5.25 and 3.5 mgikg vs. placebo groups at Week
`24: 0.0?‘ and 0.0? vs. 0.9? for Tl Gr1+ lesions, 0.33 and 0.45 vs. 1.59
`for active T2 lesions, and 0.38 and 0.49 VS. 1.9]
`for CU lesions,
`respectively).
`Conclusions: Treatment with cladrtbine tablets resulted in early
`onset of effect in clinical and MRI outcomes. Taken together with
`the favourable tolerabtlity and safety results observed in this study
`(reported elsewhere),
`these findings provide strong support
`for
`annual short-course treatment with cladribine tablets in patients
`with MS.
`
`Funded by Merck Serono 5.!-.. - Geneva, Switzerland, an affiliation of
`Merck l(GaA, Darmstadt, Germany.
`
`Posters ii
`
`S249
`
`P818
`
`Cludribine tablets produce sustained improvements in
`relapsi.ng~I'emitllng multiple sclerosis in the 96-week. phase
`III, double-Islinrl, placebo-controlled CLARITY study
`K. ltammohan, P. Vermersch, G. Coml, S. Cook, G. Giovannoni,
`P. Rieclunann, P.S. Sotensen, I’. Chang, A. iiamlett, it. Musch,
`it. \r'er|ee, S. Greenbcrg
`Ohio State University (Cnirnnims, US); University o,Fi.iiie (Liiie, FR),-
`Univcrsity tiirn—5nirrre (Milan, ii); University ofiiiedicirae and Dentistry
`(Neivrrrir, US); Burrs and Tire Lonrian Scirooi ofiiieritci.-re (London, UK),-
`Universiiy afiiritisii Coinnibirr (lirnrronver, CA); ltigsirospitnier
`(Coperrirngeri, DK); Merck Scrtnro S.A. (Geneva, CH}
`
`Background: Cladrtl)tne is activated specifically in lymphocyte sub-
`types resulting in targeted and sustained immunomodulation, which
`provides the rationale for use of cladrlbine tablets as a shortcourse
`annual treatment in multiple sclerosis. Here we investigated multiple
`clinical and MRI efficacy parameters over time to assess the persis-
`tence of treatment effect with cladribine tablets relative to placebo,
`from the CLARITY (Cl.Adiiibine tablets Treating multiple sclerosis
`orallli) study in patients with RRMS.
`Methods: Patients with RRMS (McDonald criteria; Expanded
`Disability Status Scale [EDSS] score 0-5.5) were randomised l:i:l to
`cladriblne tablets (cumulative dose of 5.25 or 3.5 mgikg), or matching
`placebo. Cladrlbine tablets were given in short courses (once daily for
`4-5 days) in 4 or 2 consecutive months (23-day periods) in the first 43
`weeks, then 2 short courses at Weeks 48 and 52 (both groups). Efficacy
`endpoints included the annuallsed qualifying relapse rate (primary),
`the proportion of relapse—free patients, and Mill activity measures vs.
`placebo (1'1_~Gd+, active T2, and combined unique [CU]
`lesions.’
`parientiscan).
`Results: The i‘iT population comprised 456, 433 and 43'.-’ patients ran-
`domised to 5.25 mgikg. 3.5 mgikg or placebo groups. respectively. in
`the cladriblne 5.25 mgikg, 3.5 mgikg and placebo groups 95.6%, 93.8%
`and 66.6% patients, respectively, were T1-Gd+ lesion-free at Week 24;
`94.1%, 94.2% and 73.1% patients were T1-Gd+ lesion-free at Week 96;
`TB. 1%, ?6.2% and 49.?9t: patients were T2 lesion-free at Week 24; and
`32.2%, 82.2% and 61.6% patients were T2 lesion-free at Week 96. The
`proportions of patients that were relapse-free in the ciadribine 5.25 rrigi
`kg, 3.5 mgikg and placebo groups were, 91.2%, 92.1% and 82.8%,
`respectively, at Week 24; 86.0%, 85.9% and ?4.l'lii at Week 48; and
`28.9%, '.?9.?% and 60.9% at Week 96. Reductions in relapse rate and
`MRI lesion count were also observed at these time points.
`Conclusions:
`'l'reai:rnent with cladriblne tablets resulted in sus-
`talned, consistent benefits on clinical and Mitt outcomes. The early
`beneficial effects across several MRI parameters of disease activity were
`sustained at Week 96, 44 weeks after the last treatment dose. Taken
`together with the rapid improvement and favourable tolerabiiity and
`safety results observed in this study (reported elsewhere), these find-
`ings provide strong support for annual short-course treatment with
`cladribine tablets in patients with MS.
`
`Funded by Merck Serono S.A. ~ Geneva, Switzerland, an affiliation of
`Merck KGaA, Darmstadt, Germany.
`
`P319
`
`Glatiromer acetate 20mg subcutaneous twice-weekly versus
`daily injections: results of a pilot, prospective, randomised,
`and rater-blinded clinical and MRI 2-year study in relapsing-
`remittiug multiple sclerosis
`0. Khan, J. Perumal, C. Caon, A. Tselis, Z. Lstif, W. Ching, l-'. Bao,
`i. Zak
`
`Wayne State Urriversiiy School oflvieriiciire (Detroit, US)
`Objective: The optimal dose of giatiramer acetate (GA) In RRM5
`remains unknown. We have previously shown that GA administered
`on alternate days appears to be as effective as daily GA. There is con-
`siderable interest in studying a more patient friendly dosing regimen
`of GA that may be as efficacious and better tolerated than daily GA.
`Methods: We conducted a prospective, randomized, rater-blinded
`study to compare the clinical and MRI outcomes of GA 20 mg SC
`administered twice a week to GA administered daily. RRMS patients
`
`ms].sagepub.com
`
`Multiple Sclerosis 2009; 15: $151-$269
`
`MYLAN PHARMS. INC. EXHIBIT 1055 PAGE 1
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`

`
`5250
`
`Posters ii
`
`receiving Gail 2.0 mg SC daily for at least one year were randomized to
`either continue in the same fashion or switch to GA 20 mg SC twice
`weekly. Clinical assessments including EDS}; were performed every 6
`months and brain MRI scans were obtained at baseline and month 24.
`Results: 413 RRMS were randomized into two equal groups of either
`GA 20 mg SC daily or GA 20 mg SC bi-weekly. Both groups were well-
`matched for clinical demographics and MRI features at baseline. All
`patients remained in the study for the entire duration. After two years,
`the annualized relapse rate, mean EDS5, proportion of relapse-free
`patients, and the proportion of patients without disease progression
`were similar in the two groups. Brain MRI also did not demonstrate
`any significant differences in 't“2W or TIW lesion, or in the percentage
`brain volume change between the two groups. However, the inci-
`dence of lipoatrophy, local Injection site reactions, and Immediate-
`post ln}ection systemic reactions were significantly lower In the ‘alt
`twice-weekly group. Detailed analysts of the results will be presented.
`Conclusion: This study provides further evidence that Gil adminis-
`tered less frequently than daily may be as efficacious and better tol-
`erated than GA administered daily. This may have a significant
`impact on improving compliance and tolerability while maintaining
`the desired immunomodulating effect of GA. Furthermore, this may
`also have a favorable economic impact. l.arger, multi-center studies
`are warranted to confirm our findings and address a critical need of
`the MS patient community.
`
`P320
`
`Conversion of new inllantmotory lesions to persistent black
`holes In patients with relapsing multiple sclerosis
`participating in a phase 2 trial of DNA vaccine
`encoding myelin basic protein (IJIIT-3009)
`A. Papadopoulou, S. Traud, A. llaliman, J. Quan, R. King, 1-]. Garrett,
`L. Steinman, G. Cutter, L. Kappos, E.W. Radue
`University Hospital (Basel, CH); MIAC (Basel, CH); Brayiiiii Ttremperrtics
`(Stilt Mateo, US); Uiriversity ofzlloiurrrtn (Biriiririgltniri, US)
`Background: There is evidence that persistent T1-hypointense
`lesions, (persistent black holes, Pill-I] correlate better than T2 lesions
`with irreversible tissue damage, axonal loss and disability progression,
`in a Phase 2 Trial of a DNA Vaccine encoding Myelin Basic Protein
`(llHT-3009)
`in relapsing remitting multiple sclerosis (RIIMS)
`the
`median percentage change in T1-hypointense lesion volume was
`-3.76% in the low dose treatment group compared with 0% for pla-
`ceho (p=0.i}8) (Garren et al, Ann. Neurol. 2008).
`Objective: To determine the evolution of new inflammatory lesions
`to Pill-i and examine changes in lesion characteristics, such as size and
`degree of hypointensity, in Ill-lT-3009 treated patients compared with
`placebo.
`Methods: A post-hoc, rater-blinded evaluation of MRI scans collected
`during year it of the phase 2 trial was performed in RRMS patients,
`randomly assigned to receive placebo 0.5mg BHT-3009 or l.Smg iii-l‘i‘-
`3009. New and enlarging lesions (candidate lesions: Cl.) were selected
`at the first and second on—study MR1 (month 2 and 4) and were
`tracked on month 12 for T1-signal evolution. Lesions hypointense
`on 'l‘1-weighted pre contrast images of months 2 and 4 were consid-
`ereci acute black holes (Mil-i) and lesions not enhancing and hypoth-
`tense on month 12 were considered Pill-l. Size and degree of
`hypolntensity of ABH and PBH were also determined.
`Results: 650 (El. were found in 155 of 26? patients in the per protocol
`population, 180 CL in SDISF patients on placebo, 239 CL in SW96
`patients on 0.5 mg iii-i”i'-3009 and 231 (Ii. in diiiiié patients on 1.5 mg.
`4621650 Ci. were Gd enhancing. Average proportions of Cl. evolving
`into Plil-I were SDIISD (0.28) for placebo, 55f239 (0.23) for low dose
`and 49.’23l (0.21) for high dose treated patients. The mean proportion
`of CL per patient developing into Pill-1 was 0.25 in the two treatment
`groups (0.28 in the low dose and 0.21 in the high dose treatment
`group) and 0.29 in the placebo arm.
`Conclusions: in this exploratory analysis a trend to lower propor-
`tions of CL and CL per patient evolving into Pill-I In treated patients
`compared with placebo was detected.
`
`Supported by: Bayhill Therapeutics.
`
`lmmunosuppression
`
`P821
`
`Cancer risk in a MS populations treated with
`irnmunosuppressants
`Y. Handouk, S. De illso, l:'.. Perticaroli, M. Danni, V. Angeleri,
`L. Provlncialt
`
`Neurologlcrrl Clinic (Ailmtlfl, IT)
`Background: Use of the immunosuppressant drugs tmitoxantrone,
`methotrexate, azatloprine, etc..) are linked to cancer risk.
`Obit.-ctivc: we evaluated the presence of cancer in our multiple
`sclerosis (MS) cohort.
`Methods: in a population of 616 MS patients, we followed up F3
`patients, previously treated (43) or actually in treatment (30) with
`immunosuppressants: 10 with mitoxantrone (MTX) until the maxi-
`mum cumulative dose, 49 with azatloprlne (AREA), 2 with methotrex-
`ate (M'i'l-t), 2 with ciclofosfamide (CT)(}. 10 patients received more
`than 1 lmmunosupressant. The mean follow up period since first
`drug administration was 104.9.-l:62 months (min: 32 months, max:
`348 months). Mean treatment period was 65:51 months (min: 12
`months, max: 312 months).
`Results: One patient treated with CT): developed an uterine cancer
`two years after CTX withdrawal. The age at cancer diagnosis was 26
`years. No cancer was developed in patients treated with MTX, i'\'£..i\
`and M't‘i-i.
`Conclusion: '|‘he prevalence rate of uterine cancer in our MS cohort
`(1.3%) was higher than in the general population (0.01%).
`
`P822
`
`ASPIRE (Azatlnioprlne Secondary Progressive Interferon
`treated patients Randomised Evaluation} study: 2-year
`double-blind and 1-year open, randomised, multlcentre,
`pilot study. Multiple Sclerosis Functional Composite (MSFC)
`and magnetic resonance data
`E. Montanart, L. Manneschi, i. Pesci, L lviottl, E. lvierelll, M.lt. Tola,
`D. Caputo, L. Provinciall, E. Scarpini, M.G. Marrosu, A. Ghezrj,
`P. Cavalla, L. Durelli
`
`Osp. Clvile (Firleuzrr, ii); Osp. Civlle (Reggie Emilie, IT); University of
`Mariam: (Modem-', ll); Ci. Neirraloxlcrr (Ferraro, ll); Ci. Neuroiogiro
`(lvtilmr, H); Ci. Neuroiogice mucoira, ii"); Ci. Neuroioglcrr (Crrgiim-i, ff);
`Cl. Neuralogicrr (Grrllrirrrtc, i'l),- Ci. Nenroiogim (Turin. IT); Ci. Neuroiogtcrr
`(Drfmssnrro, IT)
`
`Combination therapy has been routinely used in autoimmune disease
`and, in the last years, even for multiple sclerosis (MS). The aim of the
`study was to assess the efficacy, safety and tolerahility of azathjoprine
`(AKA) when added to ll-‘N fl-lb In patients with secondary progressive
`MS who had an incomplete response to il~‘N ii-lb. The study provides
`an overall evaluation of illness stabilization, with the primary end-
`point being the variation in MS functional composite (MSFC) over the
`2-year double-blind and 1-year open treatment period. Secondary
`endpoints were léxpanded Disability Status Scale (ILDSS) variability,
`quality of life ((101,) effects according to the MSQUL-54 instrument,
`magnetic resonance (MRI) data, neutralizing antibodies and cyto-
`chine evaluations.
`35 patients completed randomization, 42 with azathloprine and IFN
`[l-lb and 43 with placebo and IFN ii-lb treatment. At the end of
`36 months 45 patients completed the study (2.3 and 21 respectively),
`resulting in an high number of drop-outs. MSQOL—.S4 and safety data
`analyzed showed a slight worsening in MA group.
`MSFC data were compared to basal data and showed a slight worsen-
`ing at 36 months in aaathioprine group in comparison to placebo.
`‘MRI data showed a reduction in enhancing lesions only at 12 months
`of treatment in Am group, while there was not consistent variation in
`the two groups at 24 and 36 months.
`
`Multiple Sclerosis 2009; 15: $151-$269
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`msj.sagepub.com
`
`MYLAN PHARMS. INC. EXHIBIT 1055 PAGE 2