(median change -780, -610 and -214 [5.25 mg /kg] and -534, -404 and
`-122 [3.5 mg /kg], respectively). Levels subsequently recovered slightly
`until redosing at Week 48, followed by a second (comparable) nadir.
`Lower CD4 /CD8 ratios were due to preferential reductions in CD4
`versus CD8 cells. Reductions were also observed in CD4 naïve and
`memory (CD45RA and CD45RO) T- helper cells, and to a lesser
`extent in CD8 naïve 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- cells.
`Conclusions: Treatment with cladribine
`tablets differentially
`affected CD4, CD8 and CD19 subpopulations. These findings may
`suggest a direct effect on T -cell function, humoral B 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, Darmstadt, Germany.
`
`P817
`
`Early onset of effect of treatment with cladribine tablets for
`relapsing -remitting multiple sclerosis in the 96 -week, phase
`III, double -blind, placebo -controlled CLARITY study
`P. Vermersch, G. Comi, S. Cook, G. Giovannoni, K. Rammohan,
`P. Rieckmann, P.S. Sorensen, P. Chang, A. Hamlett, 13. Musch,
`R. Verjee, S. Greenberg
`University of Lille (Lille, FR); University Vita -Salute (Milan, IT); University
`of Medicine and Dentistry (Newark, US); Barts and The London School of
`Medicine (London, UK); Ohio State University (Columbus, US); University of
`British Columbia (Vancouver, CA); Rigshospitalet (Copenhagen, DK);
`Merck Serono S.A. (Geneva, CH)
`Background: Cladribine is activated specifically in lymphocyte sub-
`types resulting in targeted and sustained immunomodulation, which
`provides the rationale for use of cladribine tablets as a short -course
`annual treatment in multiple sclerosis (MS). We investigated the time
`of onset of treatment effect with cladribine tablets relative to placebo,
`in the CLARITY (CLAdRIbine tablets Treating multiple sclerosis
`orally) study in patients with relapsing- remitting MS (RRMS).
`Methods: Patients with RRMS
`(McDonald criteria; Expanded
`Disability Status Scale [EDSS] score 0 -S.5) were randomised 1:1:1 to
`cladribine tablets (cumulative dose of 5.25 or 3.5 mg /kg), or matching
`placebo. Cladribine tablets were given in short courses (once daily for
`4 -5 days) in 4 or 2 consecutive months (28 -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 MRI parameters (T1 -Gd +, active T2, and combined unique [CU]
`lesions per patient per scan) were evaluated at 24, 48 and 96 weeks
`post -randomisation.
`Results: The ITT population comprised 456, 433 and 437 patients
`randomised to 5.25 mg /kg, 3.5 mg /kg 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 mg /kg vs. placebo: 0.27 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 mg /kg vs. placebo groups at Week
`24: 0.07 and 0.07 vs. 0.97 for T1 Gd+ lesions, 0.33 and 0.45 vs. 1.59
`for active T2 lesions, and 0.38 and 0.49 vs. 1.91 for CU lesions,
`respectively).
`Conclusions: Treatment with cladribine tablets resulted in early
`onset of effect in clinical and MRI outcomes. Taken together with
`the favourable tolerability 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 S.A. - Geneva, Switzerland, an affiliation of
`Merck KGaA, Darmstadt, Germany.
`
`msj.sagepub.com
`
`EXHIBIT JÇi (Q
`
`WIT:
`
`DATE:
`Marsha Yarberry7 CSR
`
`Posters II
`
`S249
`
`P818
`
`Cladribine tablets produce sustained improvements in
`relapsing- remitting multiple sclerosis in the 96 -week, phase
`III, double -blind, placebo- controlled CLARITY study
`K. Rammohan, P. Vermersch, G. Comi, S. Cook, G. Giovannoni,
`P. Rieckmann, P.S. Sorensen, P. Chang, A. Hamlett, B. Musch,
`R. Verjee, S. Greenberg
`Ohio State University (Columbus, US); University of Lille (Lille, FR);
`University Vita -Salute (Milan, IT); University of Medicine and Dentistry
`(Newark, US); Borts and The London School of Medicine (London, UK);
`University of British Columbia (Vancouver, CA); Rigshospitalet
`(Copenhagen, DK); Merck Serono S.A. (Geneva, CH)
`Background: Cladribine is activated specifically in lymphocyte sub-
`types resulting in targeted and sustained immunomodulation, which
`provides the rationale for use of cladribine tablets as a short -course
`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 (CLAdRIbine tablets Treating multiple sclerosis
`orally) study in patients with RRMS.
`Methods: Patients with RRMS (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 mg /kg), or matching
`placebo. Cladribine tablets were given in short courses (once daily for
`4 -5 days) in 4 or 2 consecutive months (28 -day periods) in the first 48
`weeks, then 2 short courses at Weeks 48 and 52 (both groups). Efficacy
`endpoints included the annualised qualifying relapse rate (primary),
`the proportion of relapse -free patients, and MRI activity measures vs.
`placebo (T1 -Gd +, active T2, and combined unique [CU] lesions/
`patient /scan).
`Results: The ITT population comprised 456, 433 and 437 patients ran-
`domised to 5.25 mg /kg, 3.5 mg/kg or placebo groups, respectively. In
`the cladribine 5.25 mg /kg, 3.5 mg /kg and placebo groups 95.6 %, 93.8%
`and 66.6% patients, respectively, were Tl -Gd+ lesion -free at Week 24;
`94.1 %, 94.2% and 77.1% patients were Tl -Gd+ lesion -free at Week 96;
`78.1 %, 76.2% and 49.7% patients were T2 lesion -free at Week 24; and
`82.2 %, 82.2% and 61.6% patients were T2 lesion -free at Week 96. The
`proportions of patients that were relapse -free in the cladribine 5.25 mg/
`kg, 3.5 mg /kg and placebo groups were, 91.2 %, 92.1% and 82.8 %,
`respectively, at Week 24; 86.0%, 85.9% and 74.1% at Week 48; and
`78.9 %, 79.7% and 60.9% at Week 96. Reductions in relapse rate and
`MRI lesion count were also observed at these time points.
`Conclusions: Treatment with cladribine tablets resulted in sus-
`tained, consistent benefits on clinical and MRI 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 tolerability 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.
`
`P819
`
`Glatiramer 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 -
`remitting multiple sclerosis
`O. Khan, J. Perumal, C. Caon, A. Tselis, Z. Latif, W. Ching, F. Bao,
`I. Zak
`Wayne State University School of Medicine (Detroit, US)
`Objective: The optimal dose of glatiramer acetate (GA) in RRMS
`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
`
`Multiple Sclerosis 2009; 15: 5151 -S269
`
`MYLAN PHARMS. INC. EXHIBIT 1068 PAGE 1
`
`

`
`5250
`
`Posters II
`
`receiving GA 20 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 EDSS were performed every 6
`months and brain MRI scans were obtained at baseline and month 24.
`Results: 48 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 EDSS, 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 T2W or T1W 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 injection systemic reactions were significantly lower in the GA
`twice -weekly group. Detailed analysis of the results will be presented.
`Conclusion: This study provides further evidence that GA 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. Larger, multi- center studies
`are warranted to confirm our findings and address a critical need of
`the MS patient community.
`
`P820
`
`Conversion of new inflammatory lesions to persistent black
`holes in patients with relapsing multiple sclerosis
`participating in a phase 2 trial of DNA vaccine
`encoding myelin basic protein (BHT -3009)
`A. Papadopoulou, S. Traud, A. Rahman, J. Quan, R. King, H. Garren,
`L. Steinman, G. Cutter, L. Kappos, E.W. Radue
`
`University Hospital (Basel, CH); MIAC (Base!, CH); Bayhill Therapeutics
`(San Mateo, US); University of Alabama (Birmingham, US)
`Background: There
`is evidence that persistent Tl- hypointense
`lesions, (persistent black holes, PBH) 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
`(BHT -3009) in relapsing remitting multiple sclerosis (RRMS) the
`median percentage change in Tl- hypointense lesion volume was
`-3.76% in the low dose treatment group compared with 0% for pla-
`cebo (p =0.08) (Garren et al, Ann. Neurol. 2008).
`Objective: To determine the evolution of new inflammatory lesions
`to PBH and examine changes in lesion characteristics, such as size and
`degree of hypointensity, in BHT -3009 treated patients compared with
`placebo.
`Methods: A post -hoc, rater -blinded evaluation of MRI scans collected
`during year 1 of the phase 2 trial was performed in RRMS patients,
`randomly assigned to receive placebo 0.5mg BHT -3009 or 1.5mg BHT -
`3009. New and enlarging lesions (candidate lesions: CL) were selected
`at the first and second on -study MRI (month 2 and 4) and were
`tracked on month 12 for Tl- signal evolution. Lesions hypointense
`on Tl- weighted pre contrast images of months 2 and 4 were consid-
`ered acute black holes (ABH) and lesions not enhancing and hypoin-
`tense on month 12 were considered PBH. Size and degree of
`hypointensity of ABH and PBH were also determined.
`Results: 650 CL were found in 155 of 267 patients in the per protocol
`population, 180 CL in 50/87 patients on placebo, 239 CL in 57/96
`patients on 0.5 mg BHT -3009 and 231 CL in 48/84 patients on 1.5 mg.
`462/650 CL were Gd enhancing. Average proportions of CL evolving
`into PBH were 50/180 (0.28) for placebo, 55/239 (0.23) for low dose
`and 49/231 (0.21) for high dose treated patients. The mean proportion
`of CL per patient developing into PBH 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 PBH in treated patients
`compared with placebo was detected.
`
`Supported by: Bayhill Therapeutics.
`
`Immunosuppression
`
`P821
`
`Cancer risk in a MS population treated with
`immunosuppressants
`Y. Handouk, S. De Riso, E. Perticaroli, M. Danni, V. Angeleri,
`L. Provinciali
`
`Neurological Clinic (Ancona, IT)
`Background: Use of the immunosuppressant drugs (mitoxantrone,
`methotrexate, azatioprine, etc..) are linked to cancer risk.
`Objective: we evaluated the presence of cancer in our multiple
`sclerosis (MS) cohort.
`Methods: In a population of 616 MS patients, we followed up 73
`patients, previously treated (43) or actually in treatment (30) with
`immunosuppressants: 10 with mitoxantrone (MTX) until the maxi-
`mum cumulative dose, 49 with azatioprine (AZA), 2 with methotrex-
`ate (MTH), 2 with ciclofosfamide (CTX). 10 patients received more
`than 1 immunosupressant. The mean follow up period since first
`drug administration was 104.9±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 CTX 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, AZA
`and MTH.
`Conclusion: The prevalence rate of uterine cancer in our MS cohort
`(1.3 %) was higher than in the general population (0.01 %).
`
`P822
`
`ASPIRE (Azathioprine Secondary Progressive Interferon
`treated patients Randomised Evaluation) study: 2 -year
`double -blind and 1 -year open, randomised, multicentre,
`pilot study. Multiple Sclerosis Functional Composite (MSFC)
`and magnetic resonance data
`E. Montanari, L. Manneschi, I. Pesci, L. Motti, E. Merelli, M.R. Tola,
`D. Caputo, L. Provinciali, E. Scarpini, M.G. Marrosu, A. Ghezzi,
`P. Cavalla, L. Durelli
`Osp. Civile (Fidenza, IT); Osp. Civile (Reggio Emilia, IT); University of
`Modena (Modena, IT); Cl. Neurologica (Ferrara, IT); Cl. Neurologica
`(Milan, IT); Cl. Neurologica (Ancona, IT); Cl. Neurologica (Cagliari, IT);
`Cl. Neurologica (Gallarate, IT); Cl. Neurologica (Turin, IT); Cl. Neurologica
`(Orbassano, 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 tolerability of azathioprine
`(AZA) when added to IFN f3-lb in patients with secondary progressive
`MS who had an incomplete response to IFN fi-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 Expanded Disability Status Scale (EDSS) variability,
`quality of life (QOL) effects according to the MSQOL -54 Instrument,
`magnetic resonance (MRI) data, neutralizing antibodies and cyto-
`chine evaluations.
`85 patients completed randomization, 42 with azathioprine and IFN
`13-lb and 43 with placebo and IFN f3-lb treatment. At the end of
`36 months 45 patients completed the study (23 and 21 respectively),
`resulting in an high number of drop -outs. MSQOL -54 and safety data
`analyzed showed a slight worsening in AZA group.
`MSFC data were compared to basal data and showed a slight worsen-
`ing at 36 months in azathioprine group in comparison to placebo.
`MRI data showed a reduction in enhancing lesions only at 12 months
`of treatment in AZA group, while there was not consistent variation in
`the two groups at 24 and 36 months.
`
`Multiple Sclerosis 2009; 15: S151 -S269
`
`msj.sagepub.com
`
`MYLAN PHARMS. INC. EXHIBIT 1068 PAGE 2