Tammy SamelliJCambridge!Biogen
`25-May-2007 08:55 PM
`Message Size: 13594.1 KB
`
`To
`
`Subject
`Fw: 73061
`
`Hello all:
`
`You will find below a request from FDA
`to convene a meeting on Tuesday to r1""'"""
`our EOP2 document to detem1ine
`
`Page 1 of331
`
`Biogen Exhibit 2281
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`-
`
`Page 2 of331
`
`

`

`Page 3 of331
`
`Page 3 of 331Page 3 of 331
`
`

`

`BG00012
`
`End-Of -Phase 2 Meeting Information Package
`Submitted ou July 28, 2006
`
`Page 4 of331
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`5 PRECLINICAL OVERVIEW ............................................................................................. 26
`
`5.2.3 Summary of Repeat-Dose Pharmacokinetic Studies ............................ ............. 30
`5.2.4 Summary of Tissue Distribution and Excretion Studies .................................... 33
`5.3 Toxicology .................................................................................................................. 33
`
`1
`
`Page 5 of331
`
`

`

`TABLE OF CONTENTS
`
`Page
`
`5.3.2 Repeat Dose Toxicology ..................................................................................... 35
`
`5.3.2.4 6-month study in rats ............... .................... ................... .................... ....... 37
`
`5.3.7 Overall Summary of Ongoing Toxicology Studies ................. .................... ....... 46
`5.3.7.1 Rat carcinogenicity study (Study POOOI2-04-Il) ..................................... 47
`5.3.7.2 Mouse Carcinogenicity Study (Study P00012-05-03) .............................. 48
`5.3.7.3 52-Week Toxicity Study In
`P00012-05-05) ........................ 48
`5.3.7.4 Cynomolgus monkey
`POOOJ2-05-08) ...................................................................................................... 49
`5.3.7.5 Rat (Study POOO 12-06-02) and rabbit (Study P0001 2-06-0 1)
`developmenta 1 studies ............................................................................................ 50
`5.4 References ................................................................................................................... 50
`
`7 CLINICAL PR()GR.A.J\1 ...................................................................................................... 59
`
`2
`
`Page 6 of331
`
`

`

`TABLE OF CONTENTS
`
`7. J Summary of MS program ........................................................................................... 59
`7.1.1 Study C-1900 Design .......................................................................................... 59
`
`Page
`
`7.3 Conclusion .................................................................................................................. 91
`
`8 CUNTCAL DEVELOPMENT PLAN FOR MUL TTPLE SCLEROSIS ............................. 94
`8.1 Overall Study Designs ................................................................................................ 94
`8.2 Subject Population (Major Inclusion and Exclusion Criteria) ..................................... 96
`8.3 Statistical Justification ................................................................................................ 97
`8.4 Dose Selection ......... ................ ...................................... ............................................. 98
`8.5 Length of Treatment ................................................................................................... 99
`
`3
`
`Page 7 of331
`
`

`

`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`
`
`Page 8 of331
`Page 8 of 331
`
`4
`
`

`

`
`
`
`
`Page 9 of 331Page 9 of 331
`
`Page 9 of 331
`
`

`

`
`
`
`
`Page 10 of331Page 10 of 331
`
`Page 10 of 331
`
`

`

`
`
`
`
`Page 11 of331Page 11 of 331
`
`Page 11 of 331
`
`

`

`
`
`
`
`Page 12 of 331Page 12 of 331
`
`Page 12 of 331
`
`

`

`
`
`
`
`Page 13 of 331Page 13 of 331
`
`Page 13 of 331
`
`

`

`
`
`
`
`Page 14 of331Page 14 of 331
`
`Page 14 of 331
`
`

`

`
`
`
`
`Page 15 of 331Page 15 of 331
`
`Page 15 of 331
`
`

`

`
`
`
`
`Page 16 of331Page 16 of 331
`
`Page 16 of 331
`
`

`

`
`
`
`
`Page 17 of 331Page 17 of 331
`
`Page 17 of 331
`
`

`

`
`
`
`
`Page 18 of331Page 18 of 331
`
`Page 18 of 331
`
`

`

`
`
`
`
`Page 19 of331Page 19 of 331
`
`Page 19 of 331
`
`

`

`
`
`
`
`Page 20 of 331Page 20 of 331
`
`Page 20 of 331
`
`

`

`
`
`
`
`Page 21 of331Page 21 of 331
`
`Page 21 of 331
`
`

`

`
`
`
`
`Page 22 of 331Page 22 of 331
`
`Page 22 of 331
`
`

`

`
`
`
`
`Page 23 of 331Page 23 of 331
`
`Page 23 of 331
`
`

`

`
`
`
`
`Page 24 of 331Page 24 of 331
`
`Page 24 of 331
`
`

`

`
`
`
`
`Page 25 of 331Page 25 of 331
`
`Page 25 of 331
`
`

`

`
`
`
`
`Page 26 of 331Page 26 of 331
`
`Page 26 of 331
`
`

`

`
`
`
`
`Page 27 of 331Page 27 of 331
`
`Page 27 of 331
`
`

`

`
`
`
`
`Page 28 of 331Page 28 of 331
`
`Page 28 of 331
`
`

`

`
`
`
`
`Page 29 of 331Page 29 of 331
`
`Page 29 of 331
`
`

`

`5
`
`PRECLINICAL OVERVIEW
`
`Page 30 of331
`
`26
`
`

`

`
`
`27
`
`Page 31 of 331
`
`Page 31 of 331Page 31 of 331
`
`

`

`
`
`28
`
`Page 32 of331
`
`Page 32 of 331Page 32 of 331
`
`

`

`
`
`29
`
`Page 33 of331
`
`Page 33 of 331Page 33 of 331
`
`

`

`Summary of Repeat-Dose Pharmacokinetic Studies
`5.2.3
`The PK ofDMF upon repeated dosing was evaluated in the mouse, rat, and dog in
`toxicology/toxicokinetic studies in the dose range of 50 to 500 mg./kg. The toxicology
`findings are presented in Section 5.3. The PK parameters are summarized Table 5-2.
`
`Page 34 of331
`
`30
`
`

`

`
`
`
`
`Page 35 of331
`
`Page 35 of 331Page 35 of 331
`
`31
`
`

`

`Table 5-2. Summary of Repeated-Dose Pharmacokinetics of MMF in Rodents and
`Dogs After Oral Daily DMF Administration
`
`DMF
`(POOO 12-04-06)
`
`Rat
`
`0.8%HPMC
`
`'Values represent tb.e average across multiple days.
`
`Page 36 of331
`
`32
`
`

`

`Toxicology
`5.3
`The nonclinical safety assessment ofBG00012 includes evaluation of
`and chronic administration in
`animal
`
`together, these data provide a comprehensive assessment of the toxicities and safety
`profile ofDMF in both rodent and nonrodent species. The completed, ongoing, and
`planned studies with DMF are proposed to be sufficient to suppo1t 8000012 registration
`(Table 5-2). A description of the completed studies, presented by study duration, is
`included in the sections below. Studies
`at the
`end of the toxicology section.
`
`Page 37 of331
`
`33
`
`

`

`Table 5-2: list of completed, ongoing and planned toxicology studies with DMF
`
`Biogen Idee Study
`No./
`
`Study Title
`
`GLP
`Compliance
`
`Status
`
`Support
`Phase
`
`Oral (Gavage) Carcinogenicity Study in
`with BGOOO 12
`-------------------------------------------------------------------------------
`
`Yes
`
`Ongoing
`
`Registration
`
`-------------------------------------------------------------------------------
`
`Page 38 of331
`
`34
`
`

`

`5.3.2
`
`Repeat Dose Toxicology
`""''·IS'-'-''IS from 4 weeks to 6 months were conducted in both mice and rats.
`
`Page 39 of331
`
`35
`
`

`

`
`
`36
`
`Page 40 of 331
`
`Page 40 of 331Page 40 of 331
`
`

`

`6-month study in rats
`5.3.2.4
`A 6-month repeat dose toxicology study was conducted with DMF in rats with a !-month
`recovery (P000 12-04-06). Doses ofO (0.8% HPMC), 25, 100, and 200 mglkg/day were
`administered by daily oral gavage to male and female rats. There were 15/sex/group for
`main study animals and 5 sex/group for recovery. A concunent toxicokinetic phase was
`
`37
`
`Page 41 of331
`
`

`

`conducted in a separate set of animals (8/sex/group) to evaluate systemic exposure to
`DMF.
`
`Page 42 of 331
`
`38
`
`

`

`
`
`39
`
`Page 43 of 331
`
`Page 43 of 331Page 43 of 331
`
`

`

`
`
`40
`
`Page 44 of 331
`
`Page 44 of 331Page 44 of 331
`
`

`

`
`
`41
`
`Page 45 of 331
`
`Page 45 of 331Page 45. of 331
`
`

`

`
`
`42
`
`Page 46 of 331
`
`Page 46 of 331Page 46 of 331
`
`

`

`
`
`43
`
`Page 47 of331
`
`Page 47 of 331Page 47 of 331
`
`

`

`
`
`44
`
`Page 48 of 331
`
`Page 48 of 331Page 48 of 331
`
`

`

`
`
`45
`
`Page 49 of331
`
`Page 49 of 331Page 49 of 331
`
`

`

`Overall Summary of Ongoing Toxicology Studies
`5.3.7
`Eight studies are currently ongoing with DMF, as indicated in the following table (Table
`5-3):
`
`Page 50 of 331
`
`46
`
`

`

`Table 5-3: List of Ongoing Studies
`
`A Two-Year Oral (Gavage)
`Carcinogenicity Study in Rats with
`BG00012
`Two-Year Oral (Gavage)
`Carcinogenicity Study in Mice with
`BG00012
`
`Yes
`
`Yes
`
`Yes
`
`P00012-05-03
`
`P00012-05-05
`
`P00012-05-08
`
`5.3.7.1
`Rat carcinogenicity study (Study P00012-04-11)
`A 2 year carcinogenicity study with DMF in rats is currently in the 21st month of dosing.
`des· were discussed a.nd
`the
`The doses used for this
`and the
`FDA
`
`Page 51 of 331
`
`47
`
`

`

`Table 5-4: Study P00012-04-11 -Number of surviving animals as of Week 91
`
`Group Dose Level Number of surviving rats(% survival)
`(mg/kg)
`Males
`Females
`38 (50.7%)
`47 (62.7%)
`0
`33 (44%)
`42 (56%)
`25
`24 (32%)
`34 (45.3%)
`50
`0 (0%)
`38 (50.7%)
`100
`0 (0%)
`41 (54.7%)
`150
`
`1
`2
`3
`4
`5
`
`5.3.7.2 Mouse Carcinogenicity Study {Study P00012-05-03)
`
`cunent number of surviving animals per group is given below (Table 5-5).
`
`Table 5-5: Study P00012-05-03 - Number of surviving animals as of Week 56
`
`Group Dose Level Number of surviving mice (%, survival)
`(mg/kg)
`Males
`Females
`65 (86.7%)
`69 (92%)
`0
`25
`65 (86.7%)
`64 (85.3%)
`64 (85 .3%)
`69 (92%)
`75
`68 (90.7%)
`71 (94.7%)
`200
`38 (50.7%)
`55 (73.3%)
`400
`
`1
`2
`3
`4
`5
`
`Both the rat and mouse studies will be used to support registration ofBG00012.
`
`5.3.7.3
`A 3-week pilot dog study with DMF capsules
`S
`er 2005 and is in the
`
`Page 52 of 331
`
`48
`
`

`

`A 52 week toxicity study with DMF capsules in dogs (SPOOO 12-05-05) initiated in
`October 2005 and is ongoing. Dose levels included 0 (placebo mi
`25 and 75
`administered as a divided dose twice dai
`oral
`
`5.3.7.4
`
`Cynomolgus monkey studies (Study P00012-05-07 and Study P00012-
`05-08)
`Based on discussions with FDA, it was recommended that the non-human primate (NHP)
`since the metabolism ofDMF
`be evaluated as the chronic non-rodent toxicology
`in NHPs more
`resembles that of humans.
`
`Page 53 of 331
`
`49
`
`

`

`
`
`
`
`50
`
`Page 54 of 331
`
`Page 54 of 331Page 54 of 331
`
`

`

`
`
`Page 55 of 331
`
`Page 55 of 331Page 55 of 331
`
`51
`
`5151
`
`

`

`
`
`
`
`Page 56 of 331Page 56 of 331
`
`Page 56 of 331
`
`

`

`
`
`
`
`Page 57 of 331Page 57 of 331
`
`Page 57 of 331
`
`

`

`
`
`
`
`Page 58 of 331Page 58 of 331
`
`Page 58 of 331
`
`

`

`
`
`
`
`Page 59 of 331Page 59 of 331
`
`Page 59 of 331
`
`

`

`
`
`
`
`Page 60 of 331Page 60 of 331
`
`Page 60 of 331
`
`

`

`
`
`
`
`Page 61 of331Page 61 of 331
`
`Page 61 of 331
`
`

`

`
`
`
`
`Page 62 of 331Page 62 of 331
`
`Page 62 of 331
`
`

`

`7
`
`CLINICAL PROGRAM
`
`As of December 2005, 10 studies have enrolled healthy subjects, psoriasis patients, or MS
`patients for the evaluation ofBG00012. These studies include 659 subjects exposed to
`BG00012 for as much as 20 months with doses up to 240 mg TID. The combined MS and
`psoriasis Phase 2 and Phase 3 studies have dosed 546 patients comprising 434 patient-years of
`exposure. This includes 250 MS patients followed for 204 patient-years and 296 psoriasis
`patients accounting for 230 patient-years.
`
`Summary of MS program
`7.1
`BG00012 has been evaluated in a single Phase 2 randomized, placebo-controlled safety and
`efficacy study of three dose levels ofBG00012 (C-1900) in subjects with relapsing-remitting
`multiple sclerosis
`This overview
`the overall
`and
`findings
`fi·om Study C-1
`
`Study C-1900 Design
`7.1.1
`Study C-1900 ofBG00012 for RRNIS bas recently been completed. This one year study was
`composed of two patts: a 24 week double-blind, placebo controlled safety and efficacy phase
`followed by a 24 week dose blinded safety extension phase (Figure 7-l). In Part I of this
`double-blind study, subjects were randomized in a I : I : I: I ratio to receive one of three doses of
`BG00012 (120 mg QD; 120 mg TID or 240 mg TID) or placebo for 24 weeks. In Part 2 of the
`·ects who received
`in Part l switched to BGOOOI2 240
`TID.
`
`Page 63 of 331
`
`59
`
`

`

`
`
`
`
`Page 64 of 331Page 64 of 331
`
`Page 64 of 331
`
`

`

`
`
`
`
`Page 65 of 331Page 65 of 331
`
`Page 65 of 331
`
`

`

`
`
`
`
`Page 66 of 331Page 66 of 331
`
`Page 66 of 331
`
`

`

`
`
`
`
`Page 67 of 331Page 67 of 331
`
`Page 67 of 331
`
`

`

`
`
`
`
`Page 68 of 331Page 68 of 331
`
`Page 68 of 331
`
`

`

`
`
`
`
`Page 69 of 331Page 69 of 331
`
`Page 69 of 331
`
`

`

`
`
`
`
`Page 70 of 331Page 70 of 331
`
`Page 70 of 331
`
`

`

`
`
`
`
`Page 71 of 331Page 71 of 331
`
`Page 71 of 331
`
`

`

`
`
`
`
`Page 72 of 331Page 72 of 331
`
`Page 72 of 331
`
`

`

`
`
`
`
`Page 73 of 331Page 73 of 331
`
`Page 73 of 331
`
`

`

`
`
`
`
`Page 74 of 331Page 74 of 331
`
`Page 74 of 331
`
`

`

`
`
`
`
`Page 75 of 331Page 75 of 331
`
`Page 75 of 331
`
`

`

`
`
`
`
`Page 76 of 331Page 76 of 331
`
`Page 76 of 331
`
`

`

`
`
`
`
`Page 77 of 331Page 77 of 331
`
`Page 77 of 331
`
`

`

`
`
`
`
`Page 78 of 331Page 78 of 331
`
`Page 78 of 331
`
`

`

`
`
`
`
`Page 79 of 331Page 79 of 331
`
`Page 79 of 331
`
`

`

`
`
`
`
`Page 80 of 331Page 80 of 331
`
`Page 80 of 331
`
`

`

`
`
`
`
`Page 81 of331Page 81 of 331
`
`Page 81 of 331
`
`

`

`
`
`
`
`Page 82 of 331Page 82 of 331
`
`Page 82 of 331
`
`

`

`
`
`
`
`Page 83 of 331Page 83 of 331
`
`Page 83 of 331
`
`

`

`
`
`
`
`Page 84 of 331Page 84 of 331
`
`Page 84 of 331
`
`

`

`
`
`
`
`Page 85 of 331Page 85 of 331
`
`Page 85 of 331
`
`

`

`
`
`
`
`Page 86 of 331Page 86 of 331
`
`Page 86 of 331
`
`

`

`
`
`
`
`Page 87 of 331Page 87 of 331
`
`Page 87 of 331
`
`

`

`
`
`
`
`Page 88 of 331Page 88 of 331
`
`Page 88 of 331
`
`

`

`
`
`
`
`Page 89 of 331Page 89 of 331
`
`Page 89 of 331
`
`

`

`
`
`
`
`Page 90 of 331Page 90 of 331
`
`Page 90 of 331
`
`

`

`
`
`
`
`Page 91 of331Page 91 of 331
`
`Page 91 of 331
`
`

`

`
`
`
`
`Page 92 of 331Page 92 of 331
`
`Page 92 of 331
`
`

`

`
`
`
`
`Page 93 of 331Page 93 of 331
`
`Page 93 of 331
`
`

`

`
`
`
`
`Page 94 of 331Page 94 of 331
`
`Page 94 of 331
`
`

`

`
`
`91
`
`Page 95 of 331
`
`Page 95 of 331Page 95. of 331
`
`

`

`
`
`92
`
`Page 96 of 331
`
`Page 96 of 331Page 96 of 331
`
`

`

`Conclusion
`7.3.3
`BG00012 holds promise as new treatment for RRMOS . Efficacy has been demonstrated short
`term on MRI endpoints with trends in clinical endpoints. Further, the safety profile to date
`does not preclude further investigation as an MS treatment. Therefore, Biogen Idee proposes
`initiation ofPhase 3 trials to investigate BG0012 as a treatment fonelapsing forms of MS.
`
`Page 97 of 331
`
`93
`
`

`

`8
`
`CLINICAL DEVELOPMENT PLAN FOR MULTIPLE SCLEROSIS
`
`Overall Study Designs
`8.1
`Biogen Idee's proposed clinical development plan of BG00012 will include two pivotal
`Phase 3 studies, as follows:
`
`Study I 09-MS-30 I : A double-blind, randomized, multicenter, placebo-controlled trial in
`900 subjects with RRMS; randomized 2:1 (BG00012: placebo) with the primary endpoint
`of2-year prop01tion of subjects relapsed (Figure 8-1) (Study I 09-MS-30 I full protocol,
`please refer to Appendix 1)
`
`Study l09-MS-302: A double-blind, randomized, multicenter, placebo-controlled trial
`with an open-label active control allowing comparison of the efficacy and safety of
`BGOOO 12 versus Copaxone® in 1173 subjects with RRMS randomized I : 1:1 with the
`primary endpoint of2-year propottion of subjects relapsed (Figure 8-2) (Study I 09-MS-
`302 full protocol, please refer to Appendix 2)
`
`Figure 8-1 : Design of Study 109-MS-301
`
`Year 1
`
`Year2
`
`Randomization
`2:1
`n = 900
`
`Open Label BG00012 240 mg tid
`Option for patients relapsing
`.. tt .. r w .... lc ?.41
`
`BG00012 240 mg tid
`*
`*
`*
`--1
`I
`
`52 weeks
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`52 weeks
`
`All relapses, in all patients, must be evaluated and confirmed by an independent, external, Neurology
`~v:.ln~tinn r.l"'mmi tt.:a.~ ~1"1\AIAV;::a.r th~ nrntnr./'\1 l.vill ::.llr'I\AI fnr ::lf'J 1f~ tro~imont nf rol:=-nc:.o l.vith r.nrtir.nc.tornirlc.
`
`Page 98 of 331
`
`94
`
`

`

`Figure 8-2: Design of Study 109-MS-302
`
`Year1
`
`Year2
`
`BG00012 240 mg tid
`
`Open Label BG00012 240 mg
`tid Option for patients
`relapsing after Week 241
`
`Randomizatio
`n
`1:1:1
`n = 1173
`
`Copaxone SC 20 mg/day
`
`*
`.J
`I
`
`*
`
`*
`
`*
`
`52 weeks
`
`*
`.J
`I
`
`*
`
`*
`
`*
`
`*
`
`*
`
`52 weeks
`
`All relapses, in all patients, must be evaluated and confirmed by an independent, external,
`Neurology
`
`0 = EOSS and MSFC evaluations ouarterlv and unscheduled relapse visits
`.J = MRI at Baseline and week 48 in a subset of patients
`
`The studies have common features. Both are similar two-year, double-blind, trials of240
`mg TID BG00012 and placebo. Subjects will be evaluated for relapses as necessary,
`have EDSS and MSFC evaluations every three months, and a subset of subjects will have
`an MRI at baseline and Year 1. Subjects will be required to remain on assigned study
`treatment for 12 months following randomization, even if they experience a relapse. A
`blinded "examining neurologist" must examine all subjects with relapses, and all relapse
`assessments will be reviewed and confirmed by an independent neurology evaluation
`committee. Relapses are defined as new or recurrent neurological symptoms not
`associated with fever or infection, lasting at least 24 hours, and accompanied by new
`objective neurological findings upon examination by a blinded examining neurologist.
`The protocols allow for acute treatment of relapses with corticosteroids.
`
`After confirmed relapse, subjects in either trial will have the option of switcbjng to open(cid:173)
`label therapy if:
`
`The subject has completed 52 weeks (up to Visit 13) of blinded assigned study
`treatment following randomization and has had a confirmed relapse between
`Weeks 24 and 52 follm.ving randomization
`
`OR
`
`Page 99 of 331
`
`95
`
`

`

`The subject continued their blinded study treatment assignment through 52 weeks
`(Visit 13) and then suffered a confirmed relapse any time during the period from
`Week 52 to 96.
`
`Subjects who have had a confirmed relapse between baseline and Week 24 (Visit 6) must
`wait until a subsequent relapse occurring after Week 24 is confirmed in order to become
`eligible for open-label treatment. This 6-month delay ensures that the relapse has
`happened during a time when active treatments would be expected to be efficacious.
`
`Open Label
`All eligible subjects will be petmitted to switch to open-label BGOOOI2 after at least 52
`weeks of blinded treatment. Original treatment assignment will remain blinded.
`
`Subjects may choose to prematurely discontinue study treatment and remain in the study
`and complete all study visits per the protocol without receiving study treatment. Original
`treatment assignment will remain blinded. Subjects who do not suffer a protocol
`confirmed relapse will remain on their blinded study treatment assignment for the full 2
`years of the study. Allowing subjects to switch in this manner mitigates the risks to
`those subjects randomized to placebo without affecting the primary efficacy analysis of
`proportion relapsing, as once a relapse has occutTed, the subject has reached the primary
`endpoint.
`
`Subject Population (Major Inclusion and Exclusion Criteria)
`8.2
`Both studies will recruit subjects with RRMS defined by the following inclusion I
`exclusion criteria:
`
`Major Inclusion Criteria for Study 109-MS-301 and Study 109-MS-302:
`Must have a confirmed diagnosis ofRRMS according to McDonald criteria #1-4
`(McDonald et al, 2001 ).
`Must have a baseline EDSS between 0.0 and 5.0, inclusive.
`Must have experienced at least l relapse within the 12 months prior to
`randomization, with a prior cranial MRI demonstrating lesion(s) consistent with
`MS or show evidence of Gd-enhancing lesions of the brain on an MRI performed
`within the 6 weeks prior to randomization.
`Aged 18 to 55 years old, inclusive.
`
`Major Exclusion Criteria for Study 109-MS-301 and Study 109-MS-302:
`Diagnosis of primary progressive, secondary progressive, or progressive relapsing
`MS (as defined by Lublin and Reingold, 1996).
`MS relapse within 50 days prior to randomization AND/OR the subject has not
`stabilized from a previous relapse prior to randomization
`Any previous treatment with mitoxantrone or cyclophosphamide within 1 year
`prior to randomization; prior treatment with cyclosporine, azathioprine,
`methotrexate, natalizumab, intravenous immunoglobu.lin (IVIg), plasmapheresis,
`or cytapheresis within 6 months of randomization; prior treatment with
`interferon-alpha or interferon-beta within 3 months of randomization (subjects
`
`96
`
`Page 100 of 331
`
`

`

`who are positive for neutralizing antibodies to interferon-beta may receive
`interferon-beta treatment up to 2 weeks prior to randomization).
`Prior treatment with IV cotticosteroid treatment or oral cotticosteroid treatment
`within 30 days of randomization.
`
`Additional Exclusion Criteria for Study 109-MS-301 Only:
`Prior treatment with SC or oral glatiramer acetate within 3 months of
`randomization.
`
`Additional Exclusion Criteria for Study 109-MS-302 Only:
`Any previous treatment with SC or oral glatiramer acetate.
`
`8.3
`
`Statistical Justification
`
`Study 109-MS-301
`A sample size of900 subjects (600:300 BG00012:placebo) will have 91% power to
`detect a 25% reduction in the proportion of subjects relapsed by 2 years in the BGOOO 12
`group compared to the placebo group, based on log-rank test of the survival for the two
`groups. This calculation assumes that the estimates for propottion of subjects relapsed by
`2 years are 48% for the placebo group and 36% for BG00012. It also assumes a drop out
`rate of23% over the 2 years and an overallS% type 1 enor rate. This sample size
`calculation also takes into account one interim efficacy analysis.
`
`Study 109-MS-302
`The sample size determination is based on the comparison between BG00012 and
`placebo, and for GA vs. placebo separately. A sample size of391:391
`(BG00012:placebo) will have 90% power to detect a 25% reduction in the proportion of
`subjects relapsed by 2 years based on the log-rank test of the survival for the 2 groups.
`This calculation assumes that the estimate for proportion of subjects relapsed by 2 years
`are 48% for the placebo group and 36% for BG00012. It also assumes a drop out rate of
`23% over the 2 years is assumed and an overall 5% type l etTor rate. This sample size
`calculation also takes into account one interim efficacy analysis. Similar assumption for
`the comparison ofGA vs. placebo results in a total sample size of 1173.
`
`Interim Analysis
`An interim analysis for superiority of the primary efficacy endpoint based on the Gamma
`family alpha spending function with nominal alpha level of0.0096 will be perfonned. In
`each trial, the interim analysis will occur when the average follow-up time in the study
`for all subjects is 18 months and all subjects have completed at least one year. It is
`estimated that at the time of the interim analysis, approximately 85% of the fina l events
`(first relapses) for the primary efficacy analysis will have occulTed. In order to control
`the type I euor, a Gamma alpha-spending function (Hwang, Shih, DeCani, 1990) 'vvith
`parameter gamma = - 11 will be used to decide on the nominal alpha levels at which
`statistical tests will be petfonned both at the interim and final analyses for the primary
`
`97
`
`Page 101 of 331
`
`

`

`efficacy endpoint. This approach guarantees that the final overall type I enor will be
`preserved at the 0.05 level. The Gamma family alpha-spending function is a more
`conservative spending function compared to the Lan-Demets O'Brien-Fleming spending
`function in this setting. The Gamma family alpha-spending function has the functional
`form:
`
`'Y i 0 J
`
`')' = 0 .
`
`if
`tf
`
`f •
`
`•
`
`•
`
`With gamma=-11 , it can be seen that the interim analysis should be canied out at a
`nominal alpha level of 0.0096 at 85% of total events, while the final analysis should be
`performed at nominal alpha level 0.0495. For any deviations fi·om this plan (interim look
`at 85% of total events and final analysis at I 00% ), the Gamma (-11) spending function
`will be used to adjust the nominal alpha levels of the statistical tests performed
`appropriately. When the actual analysis occurs at the interim, the number of events will
`be monitored, and the nominal alpha level for the superiority analysis will be re(cid:173)
`computed based on the actual percentage of the final events that have occurred and the
`corresponding erTor available for spending at that percentage (e.g., if less than 85% of the
`events have occurred, then the alpha level may be less than 0.0096, and if more than 85%
`of the events have occuned, then the alpha level may be more than 0.0096), but the
`overall Type I enor rate will remain unchanged at 0.05.
`
`If evaluation of the primary endpoints with this conservative statistical approach at 18
`months reveals BG00012 is superior to placebo, then this effect should be maintained at
`two years.
`
`Dose Selection
`8.4
`After single-dose Phase 1 studies demonstrated that the severity of flushing associated
`with doses of360 mg were not tolerated, 240 mg ofBG00012 was determined to be the
`maximum tolerated dose (MTD).
`
`Efficacy analysis of the Phase 2 RRMS study (Study C-1900) of three doses of BGOOO 12
`indicate that only the highest dose of240 mg TID demonstrated a statistically significant
`effect compared to placebo on the primary efficacy parameter of Gd-enhancing lesions on
`four monthly brain MRis from weeks 12-24. This dose also showed a statistically
`significant effect on several other MRI endpoints. Although there appeared to be a dose
`related trend for BG00012 effect on the primary MRI efficacy parameter, there was a
`marked difference in efficacy between the top two doses, which was more marked when
`data analyses adjusted for the number of Gd+ lesions on baseline MRI. The effect of the
`lower doses (120 mg daily and 120 mg TID) did not reach statistical significance on any
`MRl parameter.
`
`Safety analysis of the data revealed that the 240 mg TID dose was not associated with
`any consistent increases in adverse events compared to the two lower doses. Although,
`
`98
`
`Page 102 of 331
`
`

`

`adverse events were rep01ted sljghtly more often for BG00012 240 mg TID compared to
`120 mg TID, adverse-event-related dmg discontinuations were similar for the two doses.
`Thus from these data, there was no consistent dose effect on overall safety.
`
`Therefore, Biogen Idee believes that the 240 mg TID BG00012 is the dosage with the
`most favorable benefit/risk profile, and subjects in the Phase 3 studies, when randomized
`to BG00012 active treatment, will receive 240 mg TrD.
`
`Length of Treatment
`8.5
`Study subjects who emoll in either of the proposed Phase 3 trials will be followed on
`their assigned therapy for a minimum of 1 year and for up to 2 years. Biogen Idee
`proposes a 2-year placebo-controlled study in which subjects who have a confirmed
`relapse fi·om Week 24 through Week 52 will be permitted to switch to open-label
`BG00012 after the first year of the study. Subjects who have a confirmed relapse in the
`second year will be permitted to switch to open-label BGOOO 12.
`
`Page 103 of 331
`
`99
`
`

`

`
`
`
`
`Page 104 of 331Page 104 of 331
`
`Page 104 of 331
`
`

`

`
`
`
`
`Page 105 of 331Page 105 of 331
`
`Page 105 of 331
`
`

`

`
`
`
`
`Page 106 of 331Page 106 of 331
`
`Page 106 of 331
`
`

`

`
`
`
`
`Page 107 of 331Page 107 of 331
`
`Page 107 of 331
`
`

`

`
`
`
`
`Page 108 of 331Page 108 of 331
`
`Page 108 of 331
`
`

`

`
`
`
`
`Page 109 of 331Page 109 of 331
`
`Page 109 of 331
`
`

`

`Table 8-2: Estimate of the BG00012 Safety Database at the Time of the NDA Filing
`
`Study
`
`Single
`Exposure:::: l
`Exposure;;:: 6
`year
`Months
`Exposure
`(1500)J
`(100):..1
`(300-600)L..,
`M\ltf;iut.e_ :Scle'rQsis S.'tudles: tlt',;q;,:~ii~~¥;~}~;0f%:~-·;l>:::qi;fJ\tt'k:J%'ff~).%"}~}}'$J'~;*~f>i~'l'i~%2K\~%~~~}}'~""?i~~%:~~~~iw,,~,~2&.~l~;:tJ~w.~~~
`Phase 2b (C-1900) (n=257)
`120 mg BG00012
`360 mg BG00012
`720 mg BG000 12
`Phase 3 (Study 109-MS-301) (2: 1)
`Phase 3 (St11dy I 09-MS-302) (l: I: I)
`Phase 3 Open-Label Safety
`Combination Safety (Avonex"") (n=60)
`Combination Safety (Copaxone·") (n=60)
`Subjects at or above the proposed conunercial dose
`Total Multiple Sclerosis Subjects
`
`(n= 900)
`(n = 1173)
`
`64
`64
`122
`600
`391
`200
`30
`30
`1373
`1501
`
`103
`600
`391
`0
`0
`0
`1094
`1094
`
`52
`600
`391
`0
`0
`0
`1043
`1043
`
`, ;~1;.~:-_ :·f:.<<.'!,>,\•t''~·,y -<<.-'l"'c'?.~_,.-.?Z!H:<ii,,\i'·@,iff%5.
`0
`
`8
`
`32
`24
`36
`
`12
`
`i·CfullcatR'b al:iilacolo2V, S'tu.dies,+~~;f~~l4~ii
`QTc Interval single dose of360 mg BGOOOI2 (n =52; 52
`Healthy volunteers)
`ADME 240 mg dose of BG-12 (n - 8 Healthy
`volunteers)
`Phase 1 Impaired Renal Function (n = 64)
`Phase 1 Impaired Hepatic Function (n - 48)
`Food Effect (C-1903) 240 mg dose ofBG00012;
`(n = 36: Healthy volunteers)
`Bioavailability 240 mg dose ofBGOOOI2
`(n = 12; Healthy volunteers)
`IKP/ID33 (n = 15; Healthy voltmteers)
`15
`12
`FAG-201-FG-PK-02/02 (n = 12; Healthy volunteers)
`IKP/JD32 (n = 8; Healthy volunteers)
`8
`18
`FAG-20 1-FG-PK-03/04 (n = 18; Healthy volunteers)
`217
`Total Subjects
`l1£s()ria~''Stu&Je~~;~~~~~ff,~*'~~$f0
`';lf;;~;:.:: '1~"'7t~ ~"" '"'
`FAG-201-WP-12/0 1 (double-blind portion; n- 144)
`120 mg BG00012
`36
`360 mg BG00012
`36
`720 mg BGOOOI2
`36
`FAG-201-\VP-12/01 (open-label portion; n - 108)
`360 and/or 720 mg BGOOOI2
`FAG-201-KG-01/02 720 mg (n= 175)
`FAG-201-KG-03/03 720 mg (n = 143)
`Subjects dosed at or above the commercial dose (c)
`Total Psoriasis Subjects
`
`44 (a)
`105
`6 (b)
`146
`246
`
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`0
`0
`
`... , ..
`.. ,
`
`64
`0
`137
`137
`201
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`0
`0
`
`0
`0
`87
`87
`87
`
`1964
`
`1295
`
`GRAND TOTAL:
`UTCH gu1dance
`(a) Of the 44 patients, 28 received placebo and 16 rec.eived 6000012 in the double-blind portion of the
`study. The 16 patients are also included in the double-blind portion of FAG-201-WP-12/01.
`(b) Of tbe 6 patients, 5 received placebo and 1 received BG00012 in study FAG-201-KG-O l/02. Ibis one
`patient is also included in FAG-201-KG-01/02.
`(c) Patients who received 360 mg BGOOOI2 and increased dose to 720 mg BGOOOI2 in the open-label
`portion ofFAG-201-\VP-12/01 are not included.
`
`1130
`
`Page 110 of 331
`
`106
`
`

`

`
`
`
`
`Page 111 of331Page 111 of331
`
`Page 111 of 331
`
`

`

`
`
`
`
`Page 112 of 331Page 112 of 331
`
`Page 112 of 331
`
`

`

`
`
`
`
`Page 113 of 331Page 113 of 331
`
`Page 113 of 331
`
`

`

`
`
`
`
`Page 114 of 331Page 114 of 331
`
`Page 114 of 331
`
`

`

`
`
`
`
`Page 115 of 331Page 115 of 331
`
`Page 115 of 331
`
`

`

`
`
`
`
`Page 116 of 331Page 116 of 331
`
`Page 116 of 331
`
`

`

`
`
`
`
`Page 117 of 331Page 117 of 331
`
`Page 117 of 331
`
`

`

`
`
`
`
`Page 118 of 331Page 118 of 331
`
`Page 118 of 331
`
`

`

`
`
`
`
`Page 119 of 331Page 119 of 331
`
`Page 119 of 331
`
`

`

`
`
`
`
`Page 120 of 331Page 120 of 331
`
`Page 120 of 331
`
`

`

`
`
`
`
`Page 121 of 331Page 121 of 331
`
`Page 121 of 331
`
`

`

`
`
`
`
`Page 122 of 331Page 122 of 331
`
`Page 122 of 331
`
`

`

`
`
`
`
`Page 123 of 331Page 123 of 331
`
`Page 123 of 331
`
`

`

`
`
`
`
`Page 124 of 331Page 124 of 331
`
`Page 124 of 331
`
`

`

`
`
`
`
`Page 125 of 331Page 125 of 331
`
`Page 125 of 331
`
`

`

`
`
`
`
`Page 126 of 331Page 126 of 331
`
`Page 126 of 331
`
`

`

`
`
`
`
`Page 127 of 331Page 127 of 331
`
`Page 127 of 331
`
`

`

`
`
`
`
`Page 128 of 331Page 128 of 331
`
`Page 128 of 331
`
`

`

`
`
`
`
`Page 129 of 331Page 129 of 331
`
`Page 129 of 331
`
`

`

`
`
`
`
`Page 130 of 331Page 130 of 331
`
`Page 130 of 331
`
`

`

`
`
`
`
`Page 131 of 331Page 131 of 331
`
`Page 131 of 331
`
`

`

`
`
`
`
`Page 132 of 331Page 132 of 331
`
`Page 132 of 331
`
`

`

`
`
`
`
`Page 133 of 331Page 133 of 331
`
`Page 133 of 331
`
`

`

`
`
`
`
`Page 134 of 331Page 134 of 331
`
`Page 134 of 331
`
`

`

`
`
`
`
`Page 135 of 331Page 135 of 331
`
`Page 135 of 331
`
`

`

`
`
`
`
`Page 136 of 331Page 136 of 331
`
`Page 136 of 331
`
`

`

`
`
`
`
`Page 137 of 331Page 137 of 331
`
`Page 137 of 331
`
`

`

`
`
`
`
`Page 138 of 331Page 138 of 331
`
`Page 138 of 331
`
`

`

`
`
`
`
`Page 139 of 331Page 139 of 331
`
`Page 139 of 331
`
`

`

`
`
`
`
`Page 140 of 331Page 140 of 331
`
`Page 140 of 331
`
`

`

`
`
`
`
`Page 141 of 331Page 141 of 331
`
`Page 141 of 331
`
`

`

`
`
`
`
`Page 142 of 331Page 142 of 331
`
`Page 142 of 331
`
`

`

`
`
`
`
`Page 143 of 331Page 143 of 331
`
`Page 143 of 331
`
`

`

`
`
`
`
`Page 144 of 331Page 144 of 331
`
`Page 144 of 331
`
`

`

`
`
`
`
`Page 145 of 331Page 145 of 331
`
`Page 145 of 331
`
`

`

`
`
`
`
`Page 146 of 331Page 146 of 331
`
`Page 146 of 331
`
`

`

`
`
`
`
`Page 147