`
`Fumapharm-BII MC meeting,
`
`Page 1 of 17
`
`Biogen Exhibit 2091
`Mylan v. Biogen
`IPR 2018-01403
`
`Luzern.
`
`February 16th 2006.
`
`Gilmore N. O’Neill, MB, MMedSc, MRCPI
`
`Director, Clinical Development
`
`Biogenidec.
`
`Biogen Exhibit 2091
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 17
`
`
`
`- The patients.
`- The Advisory Committee:
`— R. Gold
`
`
`
`E. Havrdova
`
`L. Kappos (Chairman)
`V. Limmroth
`
`D. Miller
`
`C. Polman
`
`- The Safety Monitoring Committee:
`— C. Confavreux
`
`— O. Lyon-Caen
`
`— J. Ware
`
`Page 2 of 17
`
`Page 2 of 17
`
`
`
`Z. Ambler, Pizen, Czech Rep.
`
`C. Hawkins, Stoke-on-Trent, UK
`
`S. Schimrigk, Bochum, Germany
`
`A. Belova, Novogorod, Russia
`
`J. Hillert, Huddinge, Sweden
`
`K. Selmaj, Lodzi, Poland
`
`A. Boiko, Moscow, Russia
`
`R. Hintzen, Rotterdam, Netherlands
`
`M. Sharief, London, UK
`
`A. Csanyi, Gyor, Hungary
`
`G. Jakab, Budapest, Hungary
`
`B. Sharrack, Sheffield, UK
`
`L. Csiba, Debrecen, Hungary
`
`L. Kappos, Basel, Switzerland
`
`S. Shvarkov, Moscow, Russia
`
`W. Drozdowski, Bialystok, Poland
`
`R. Karabudak, Ankara, Turkey
`
`A. Siva, Istanbul, Turkey
`
`E. Ehler, Pardubice, Czech Rep.
`
`J. Kochanowicz, Bialystock, Poland
`
`l. Zavalishin, Moscow, Russia
`
`A. Skoromets, St. Petersburg, Russia
`
`A. Elchaninov, St. Petersburg, Russia
`
`H. Kwiecinski, Warsaw, Poland
`
`|. Stolyarov, St. Petersburg, Russia
`
`M. Eraksoy, Istanbul, Turkey
`
`J. Lycke, Goteborg, Sweden
`
`A. Szczudlik, Krakow, Poland
`
`W. Fryze, Gdansk, Poland
`
`Z. Maciejek, Bydgoszcz, Poland
`
`R. Talab, Hradec Kralove, Czech Rep.
`
`G. Giavannoni, London, UK
`
`E. Meluzinova, Prague, Czech Rep.
`
`0. Vorobieva, Moscow, Russia
`
`R. Gold, Gottingen, Germany
`
`T. Olsson, Stockholm, Sweden
`
`V. Vozlov, Novosibirsk, Russia
`
`H-P. Hartung, Dusseldorf, Germany
`
`M. Odinak, St. Petersburg, Russia
`
`A. Wajgt, Katowice-Ligota, Poland
`
`E. Havrdova, Prague, Czech Rep.
`
`C. Polman, Amsterdam, Netherlands
`
`I. Rektor, Brno, Czech Rep.
`
`Page 3 of 17
`
`Page 3 of 17
`
`
`
`° Rationale:
`
`— In Vitro:
`
`° Thl—)Th2 cytokine profile shift. Ockenfels et al. 1998. Asadulah et al.
`1997. De Jong et a]. 1996.
`
`MHF and DMF inhibited monocyte differentiation into dendritic cells.
`Zhu and Mrowz'etz, 2001.
`
`Decrease TNF 0L induced endothelial adhesion molecule (e-selectin,
`VCAMl, ICAMl) expression. Vandermeeren et a]. 1997.
`
`Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E
`expression in an NF-kb-dependent manner Loewe et al 2001.
`
`Decreases TNF-induced nuclear entry of NF-kappa b/p65 in human
`endothelial cells. Loewe eta12002.
`
`— In Vivo:
`
`
`
`Jr Acute and chronic rejection. Risch et a]. 2001. Lehmann 2002,
`-
`— In man (oral DMF/MHF):
`
`° Decrease Gd enhancing lesions in MS. Schimrz’gk et al. #846003, AAN
`2005.
`
`° Decrease Circulating T cells. Treumer et a]. 2003. Hoxtermann et al. I 998.
`
`Page 4 of 17
`
`Page 4 of 17
`
`
`
`° 24 weeks therapy; 4 arms:
`
`— Placebo; 120 qd; 120 TID; 240 TID.
`
`- Primary efficacy endpoint:
`
`
`
`— Cumulative # of Gd-enhancing lesions over six scans at
`weeks 4, 8, 12, 16, 2O & 24 vs. Placebo (EEP).
`
`— Total # of Gd-enhancing lesions over four scans at
`weeks l2, 16, 20 & 24 vs. Placebo (EEP).
`
`- Additional MRI efficacy endpoints:
`
`— # Of new or newly enlarging T2 hyper-intense lesions
`at week 24 compared to baseline (EEP).
`
`Page 5 of 17
`
`Page 5 of 17
`
`
`
`0 Patients 18 to 55 years of age (inclusive) With:
`
`— Confirmed diagnosis of relapsing-remitting MS per
`McDonald criteria1
`
`
`
`— 21 relapse Within the 12 months prior to randomization
`OR
`
`— Baseline expanded disability status scale (EDSS) score
`
`between 0 and 5.0 (inclusive)
`
`evidence of Gd+CEL Within 6 weeks of randomization
`
`Page 6 of 17
`
`Page 6 of 17
`
`
`
`screened
`
`randomized
`
`120 mg TID
`
`
`
`240 mg TID
`
`Completed
`
`Completed
`
`Completed
`
`Completed
`
`Dose blinded
`
`extension
`
`Page 7 of 17
`
`Page 7 of 17
`
`
`
`Placebo
`
`120 qd
`
`120 tid
`
`240 tid
`
`65
`
`64
`
`64
`
`63
`
`34.8
`
`(10.18)
`
`36.3
`
`(9.45)
`
`
`
`3 year relapse
`Median
`
`Mean (SD)
`
`1 year relapse
`
`Median
`
`EDSS
`Mean (SD)
`
`Gd+CEL
`Mean (SD)
`
`Page 8 of 17
`
`2.67 (1.229)
`
`2.52 (1.105)
`
`2.51 (1.018)
`
`2.87 (1.333)
`
`0.8 (1.37)
`
`1.2 (1.83)
`
`2.5 (4.22)
`
`1.2 (3.52)
`
`Page 8 of 17
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 9 of 17
`
`Page 9 of 17
`
`
`
`Preferred
`
`Placebo
`
`120 qd
`
`120 tid
`
`240 tid
`
`
`
`------
`Upper
`-——-—-
`------
`-——-—-
`
`Term
`
`Page 10 of 17
`
`Page 10 of 17
`
`
`
`—————
`—————
`
`”II—.-
`“II-.—
`
`
`
`“II-II-
`”II—'-
`
`Page 11 of 17
`
`Page 11 of 17
`
`
`
`Placebo
`
`120 mg
`
`120 mg
`
`240 mg
`
`QD
`
`TID
`
`TID
`
`due to AE
`
`Total study drug
`discontinuations
`
`N(%)
`
`N(%) N(%) N(%)
`
`6 (9)
`
`6 (9)
`
`8 (13)
`
`10 (16)
`
`Discontinuations
`
`O (O)
`
`4 (6)
`
`6 (9)
`
`6 (9)
`
`Page 12 of 17
`
`Page 12 of 17
`
`
`
`- BG00012 was generally safe and well tolerated.
`
`- Common AEs associated with BG00012 include
`
`headache, GI symptoms and flushing.
`
`
`
`0 Similar proportion of patients with SAEs in
`placebo and BG00012 groups.
`
`0 Similar incidence of infections between groups.
`
`0 Reversible 23X ULN transaminases seen in 8
`
`BG00012 treated patients.
`
`Page 13 of 17
`
`Page 13 of 17
`
`
`
`0 MRI efficacy:
`
`— BG00012 240 mg TID associated with decreased
`
`numbers of active lesions compared with placebo
`
`- Gd+ at 12, 16, 20 & 24 weeks:
`
`69% i
`
`0 New and enlarging T2-hyperintense:
`
`48% i
`
`
`
`ARR compared to placebo
`° Unadjusted ARR at 24 weeks
`
`0 Clinical efficacy:
`
`— BG00012 240 mg TID associated with trend to reduce
`
`32% i
`
`Page 14 of 17
`
`Page 14 of 17
`
`
`
`- All patients were allowed to enroll in a 6 month
`dose-blinded extension study.
`
`— Cost drivers:
`
`' Two CROs required to cover Europe AND Russia.
`
`0 Despite rigorous study simplification exercise,
`costs were too high (~5 % of Phase 3 pivotal
`costs):
`
`
`
`0 Little negative feedback from investigators:
`
`— Retention of patients in study NOT affected by
`announcement.
`
`Page 15 of 17
`
`Page 15 of 17
`
`
`
`0 Efficacy of a novel oral single-agent fumarate, BGOOOlZ,
`in patients with relapsing-remitting multiple sclerosis:
`results of a phase 2 study (Ab. Nr. 631)
`
`
`
`— L. Kappos, D.H. Miller, D.G. MacManus, R. Gold, E. Havrdova,
`V. Limmroth, C. Polman, K. Schmierer, T. Yousry, M. Yang, M.
`Eraksoy, E. Meluzinova, l. Rektor, G.N. O'Neill
`
`Safety of a novel oral single-agent furnarate, BGOOOlZ, in
`patients with relapsing-remitting multiple sclerosis: results
`of a phase 2 study (Ab. Nr. 638)
`
`— R. Gold, E. Havrdova, L. Kappos, V. Limmroth, D. Miller, C.
`Polrnan, M. Yang, M. Eraksoy, E. Meluzinova, I. Rektor, G.N.
`O'Neill
`
`Page 16 of 17
`
`Page 16 of 17
`
`
`
`clinical exacerbations in Relapsing
`
`Remitting Multiple Sclerosis.
`
`- Phase 3 Development Plan:
`
`- Target indication: Reduce the frequency of
`
`& Pivotal 3-arm active comparator study X l
`
`— Pivotal Placebo Controlled Phase 3 study X 2
`
`& MRI driven active comparator study
`
`OR
`
`— Pivotal Placebo Controlled Phase 3 study X l
`
`Page 17 of 17
`
`Page 17 of 17
`
`
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