A Randomized, Placebo-Controlled Phase 2 Trial of a Novel Oral Fumarate, BG00012, in Patients With
`Relapsing-Remitting Multiple Sclerosis
`
`Ludwig Kappos,1 David Miller,2 Ralf Gold,3 Eva Havrdova,4 Chris Polman,5 Volker Limmroth,6 Gilmore O’Neill,7 Rebecca Conaghan7
`
`1University Hospital Basel, Basel, Switzerland; 2Institute of Neurology, Queen Square, London; 3Institute for Multiple Sclerosis Research, Goettingen, Germany; 4General Teaching Hospital, Prague, Czech Republic;
`5VU Medical Centre, Amsterdam, the Netherlands; 6University of Essen, Essen, Germany; 7Biogen Idec, Inc., Cambridge, MA, USA
`
`The 15th meeting of
`the European
`Neurological Society,
`Vienna, Austria,
`June 18-22, 2005
`
`INTRODUCTION
`• Currently available disease-modifying therapies (interferon beta
`[IFNβ] and glatiramer acetate) for multiple sclerosis (MS) reduce
`annualized relapse rate by about one-third;1-4 hence, there remains a
`significant unmet need for more effective MS therapies, especially
`an oral medication.
`
`• Fumaric acid esters have been used in Germany for the treatment of
`psoriasis; the efficacy of fumaric acid esters in psoriasis is thought to
`be mediated in part by their immunomodulatory activity, suggesting
`that these agents may also be effective in MS.
`
`• In an open-label pilot study of 10 patients with MS, oral fumaric
`acid ester therapy reduced the number and volume of gadolinium-
`enhancing (Gd+) lesions on T1-weighted magnetic resonance imag-
`ing (MRI) scans of the brain.5
`
`• A novel oral formulation of dimethylfumarate, BG00012, was devel-
`oped using improved formulation technology (Figure 1).
`
`Figure 1
`
`The active ingredient of BG00012:
`O
`
`Name:
`Formula:
`Molecular Weight:
`Appearance:
`Melting Point:
`Solubility:
`
`CH3 O
`
`O
`
`CH3
`
`O
`
`Dimethyl fumarate
`C6H8O4
`144.04 g/moL
`odorless, white, crystalline powder
`101 – 103°C
`very slightly soluble in Ethanol,
`slightly soluble in Water and Diethyl Ether,
`soluble in Acetone,
`highly soluble in Chloroform
`
`• Expanded Disability Status Scale (EDSS) score between 0.0 and
`5.0, inclusive
`
`• At least 1 relapse within the 12 months immediately prior to study
`entry with a prior cranial MRI scan demonstrating lesions consistent
`with MS OR evidence of Gd+ lesions of the brain on an MRI per-
`formed within the 6 weeks prior to study entry
`
`• Willingness to use appropriate contraceptive measures during the study
`Exclusion Criteria
`• A progressive form of MS
`• Treatment with IFNβ (3 months), glatiramer acetate (3 months), or
`intravenous immunoglobulin (6 months), or natalizumab (6 months)
`within the 6 months prior to randomization
`
`• Corticosteroid treatment within 30 days of randomization
`
`• An MS relapse within 50 days prior to randomization and/or not stabi-
`lized from a previous relapse
`
`• A history of malignancy, severe allergic or anaphylactic reaction, or
`known drug hypersensitivity
`
`• A history of abnormal laboratory results, HIV infection, drug or alco-
`hol abuse
`Study Design
`• Randomized, double-blind, placebo-controlled, parallel-group, dose-
`ranging study conducted at 42 clinical centers in Europe
`
`• The study consisted of a 24-week double-blind, placebo-controlled
`treatment phase followed by a 24-week, blinded, safety-extension
`phase (Figure 2).
`
`Figure 2. Study Design
`
`Blinded Placebo-Controlled
`Treatment Phase
`
`Blinded Safety-Extension
`Phase
`
`Screening
`
`• Study drug was administered according to the schedule shown in
`Table 1. Patients in the BG00012 720 mg/day dose group received
`120 mg tid for the first week to determine tolerability.
`
`Table 1. Schedule for Study Drug Administration
`
`Evening
`Midday
`Morning
`Treatment Group
`2P
`2P
`2P
`Placebo
`2P
`2P
`1A + 1P
`120 mg of BG00012 (1 capsule)
`1A + 1P
`1A + 1P
`1A + 1P
`360 mg of BG00012 (3 capsules)
`2A
`2A
`2A
`720 mg of BG00012 (6 capsules)
`P=placebo; A=active (BG00012, 120 mg of fumaric acid ester per capsule).
`
`• In the blinded safety-extension phase, the three BG00012 treatment
`groups continue at the dosage assigned in the placebo-controlled treat-
`ment phase, and the placebo group receives BG00012 720 mg/day
`(120 mg tid was given the first week).
`Study Endpoints
`• The primary endpoint is the total number of new Gd+ lesions on
`MRI scans performed at Weeks 12, 16, 20, and 24 (calculated as the
`sum of these 4 MRI scans).
`
`• Secondary MRI endpoints include:
`
`– Cumulative number of new Gd+ lesions from baseline to Week 24
`
`– Number of new or newly enlarging T2-hyperintense lesions at
`Week 24 compared to baseline
`
`• Other endpoints include:
`
`– Number of new T1-hypointense lesions at Week 24
`
`– Annualized relapse rate
`
`– Proportion of relapse-free patients
`
`– Disability progression as measured by EDSS
`
`Placebo
`
`BG00012 240 mg tid (720 mg/day)
`
`– Safety/tolerability
`
`• BG00012 has demonstrated substantial efficacy and good tolerability
`in patients with moderate-to-severe chronic plaque psoriasis.6
`
`Randomization
`
`BG00012 120 mg qd (120 mg/day)
`
`BG00012 120 mg tid (360 mg/day)
`
`BG00012 240 mg tid (720 mg/day)*
`
`• A randomized, double-blind, placebo-controlled, multicenter phase 2
`clinical trial is currently being conducted to explore the efficacy and
`safety of BG00012 in patients with MS. The design and baseline char-
`acteristics of patients enrolled in this phase 2 study are presented.
`
`METHODS
`
`Patients
`Inclusion Criteria
`• Men and women 18 to 55 years of age with a confirmed diagnosis
`of relapsing-remitting MS according to the McDonald criteria (#1-4)7
`
`24 weeks
`
`24 weeks
`
`*Patients received 120 mg tid during the first week to determine tolerability.
`
`• Patients were equally randomized to one of four treatment groups:
`
`– Placebo
`
`– BG00012 120 mg once daily (qd) (120 mg/day)
`
`– BG00012 120 mg three times daily (tid) (360 mg/day)
`
`– BG00012 240 mg tid (720 mg/day)
`
`RESULTS
`• A total of 257 patients were enrolled in the study.
`
`• The patient population was 63% females and the mean age of
`patients enrolled was 36 years (Table 2).
`
`• The mean (±SD) disease duration of patients was 4.6 (±4.9) years, the
`mean EDSS score was 2.6 (±1.2), and the mean number of relapses
`during the 3 years prior to enrollment was 2.5 (±1.3) (Table 2).
`
`Table 2. Patient Demographics and Clinical Characteristics
`All Patients
`(N=257)
`36.0 (±9.3)
`63
`98
`
`7.8 (±6.0)
`
`4.6 (±4.9)
`
`203 (79)
`54 (21)
`0 ( 0)
`2.63 (±1.2)
`2.5
`0.0, 5.0
`
`Age, mean years (±SD)
`Women, %
`Caucasian, %
`Time since onset of symptoms
`Mean years (±SD)
`Time since diagnosis
`Mean years (±SD)
`EDSS score, n (%)
`≤3.5
`4.0-5.0
`≥5.0
`Mean (±SD)
`Median
`Min, max
`Relapses,* n (%)
`1 (<1)
`0
`50 (19)
`1
`87 (34)
`2
`78 (30)
`3
`41 (16)
`≥4
`2.5 (±1.3)
`Mean (±SD)
`2.0
`Median
`0, 10
`Min, max
`SD=standard deviation; EDSS=Expanded Disability Status Scale.
`*During the 3 years prior to study enrollment.
`
`CONCLUSIONS
`
`• BG00012 represents a potentially important therapeutic option
`for patients with MS.
`
`• This study will provide the first double-blind, placebo-controlled
`data to evaluate the efficacy and safety of BG00012 in patients
`with MS.
`
`References
`1. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting
`multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled
`trial. Neurology1993;43:655-661.
`2. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progres-
`sion in relapsing multiple sclerosis. Ann Neurol1996;39:285-294.
`3. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disabil-
`ity in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind place-
`bo-controlled trial. Neurology1995;45:1268-1276.
`4. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple
`Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon ß-1a in
`relapsing/remitting multiple sclerosis. Lancet 1998;352:1498-1504.
`5. Schimrigk S, Brune N, Hellwig K, et al. An open-label, prospective study of oral fumaric acid ther-
`apy for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neurology2005;64(suppl
`1):A392. Abstract S46.003.
`6. Langner A, Spellman MC. Results of a phase 2 dose-ranging and safety extension study of a novel
`oral fumarate, BG-12, in patients with severe psoriasis. J Am Acad Dermatol 2005;52:P193.
`Abstract P2787.
`7. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis:
`guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol
`2001;50:121-127.
`
`Study sponsored by Biogen Idec, Inc. and Fumapharm AG
`
`Page 1 of 1
`
`Biogen Exhibit 2005
`Coalition v. Biogen
`IPR2015-01993
`
`Sawai (IPR2019-00789), Ex. 1034, p. 001
`
`

`

`UNITED STATES PATENT AND TRADEMARKOFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGSV LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC — PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND,L.P.;
`HAYMAN CAPITAL MANAGEMENT,L.P.;
`HAYMAN OFFSHORE MANAGEMENT,INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS, and ERICH SPANGENBERG,
`Petitioner,
`
`Vv.
`
`BIOGEN MAINC.,
`Patent Owner.
`
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`
`DECLARATION OF GILMORE O’NEILL, M.D.
`
`Page 1 of 5
`
`Biogen Exhibit 2014
`Coalition v. Biogen
`IPR2015-01993
`
`Sawai (IPR2019-00789), Ex. 1034, p. 002
`
`

`

`
`
`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`
`I, Gilmore O’Neill, have personal knowledgeof the facts stated herein and
`
`provide the following testimony:
`
`Personal Background and Introduction
`
`l,
`
`Tam currently Senior Vice President, Drug Innovation Units at
`
`Biogen and haveheld this position since October2015. In this position, I am
`
`responsible for leading multi-disciplinary groups accountable for research and
`
`developmentin Pain, Immunology, Hemophilia and Rare Diseases, and Gene and
`
`Cell therapeutics.
`
`2,
`
`I received my medical degree from University College Dublin in 1988
`
`and completed residencies and fellowship training in internal medicine,
`
`pulmonology and neuropathology in 1993 at Beaumont Hospital, Dublin.
`
`I
`
`completed my residency in Neurology at Massachusetts General Hospital in 1997
`
`and was ChiefResident from 1996 to 1997 during that time. I also received a
`
`Master ofMedical Science degree from Harvard Medical School in 1999.
`
`I ama
`
`Clinical Instructor in Neurology at Harvard Medical School and a Neurologist at
`Massachusetts General Hospital and have held those positions since 1997, I joined
`Biogen in 2003 as Associate Director, Medical Research and, through my workat
`the company over approximately the past 12 years, am now Senior Vice President,
`
`Drug Innovation Units.
`
`Page 2 of 5
`
`Sawai (IPR2019-00789), Ex. 1034, p. 003
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`

`

`
`
`USS. Patent No. 8,399,514
`Case: IPR2015-01993
`
`3
`
`I understand that the U.S. Patent and Trademark Office has instituted
`
`an Inter Partes Review (“IPR”) proceeding involving Biogen’s U.S. Patent No.
`
`8,399,514 (“the ’514 patent”). Iam a named co-inventor on the 514 patent based
`
`on my contribution to the claimed subject matter.
`
`‘h.
`
`I understand that Biogen submitted Ex. 2005, a poster entitled “A
`
`Randomized, Placebo-Controlled Phase 2 Trial of a Novel Oral Fumarate,
`
`BG00012, in Patients With Relapsing-Remitting Multiple Sclerosis” presented at
`
`the 15" Meeting of the European Neurological Society on June 18-22, 2005, in
`
`support of its Patent Owner Preliminary Response. I am a co-author on that poster
`
`(Ex. 2005), which I have reviewed.
`
`5;
`
`I provide this declaration based on my personal knowledge of Ex.
`
`2005.
`
`I am not being compensated to provide this declaration, nor will I receive
`
`_ any compensation based on a favorable outcomefor Biogen in this proceeding.
`
`Ex. 2005 is a True Copyof the Poster Presentation Madein June 2005
`
`6.
`
`I attended the 15" Meeting of the European Neurological Society held
`
`in Vienna, Austria from June 18-22, 2005. I believe that Ex. 2005 is a true and
`
`accurate copy of the poster that was presented at that meeting.
`Ds
`At Biogen,I led the MS Clinical Development Team’s (“CDT”)
`
`efforts to design a Clinical Development Plan for the MS indication and to design a
`
`Phase 2 proof-of-conceptclinical trial using BG-00012, an orally administered
`
`Page 3 of 5
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`Sawai (IPR2019-00789), Ex. 1034, p. 004
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`

`

`U.S. Patent No, 8,399,514
`Case: IPR2015-01993
`
`pharmaceutical composition containing dimethyl fumarate (“DME”) as the sole
`
`active agent and one or more pharmaceutically acceptable excipients, to treat MS
`
`patients,
`
`8.
`
`I wasthe principal lead on Biogen’s Phase 2 study, the clinical design
`
`of whichis summarized in Ex. 2005. I confirm, based on my personal knowledge,
`
`that the active dosage units of DMFusedin that study contained 120 mg of DMF
`
`per capsule. The study did not use capsules containing 240 mg of DMF. Thus, for
`
`example, patients in the 720 mg/day group took two 120 mg DMEcapsulesthree
`
`times a day as shown in Table 1 of Ex. 2005.
`
`Il. Conclusion
`
`9,
`
`I declare that all statements made herein of my own knowledge are
`
`true and thatall statements made on information and belief are believed to be true,
`
`and, further, that these statements are made with knowledgethat willful false
`
`statements and thelike are punishable by fine or imprisonment, or both, under
`
`Section 1001 of Title 18 of the United States Code and may jeopardize the
`
`patentability of Biogen’s U.S. Patent No. 8,399,514.
`
`10.
`
`In signing this declaration, I understandthat the declaration may be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office. I acknowledge that I may be
`
`subject to cross-examination in the case and that cross-examinationwill take place
`
`Page 4 of 5
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`Sawai (IPR2019-00789), Ex. 1034, p. 005
`
`

`

`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`
`within the United States. If cross-examination is required of me, I will appear for
`
`cross-examination within the United States during the time allotted for cross-
`
`examination.
`
`Dated: April 14, 2016
`
`(, u bs AA AX
`BOL
`
`
`
`Gilmore O’Neill, M.D.
`
`Page 5 of 5
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`Sawai (IPR2019-00789), Ex. 1034, p. 006
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