BG00012 IND (Modules 1-3)
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`TABLE OF CONTENTS
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`MODULE 1
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`1
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`Cover Letter
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`2-4
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`Nonclinical Overview
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`Biogen Exhibit 2330
`Coalition v. Biogen
`IPR2015-01993
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`‘biogen idec;
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`February 22, 2006
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`CDER Therapeutic Biological Products Document Room
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5901-8 Ammendale Rd
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`Beltsville, MD 20705-1266
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`Attn: Russell Katz, MD
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`RE:
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`Initial lnvestigational New Drug Application
`IND 73,061
`BGOOO12 (Dimethyl Fumarate): Multiple Sclerosis
`Serial No.: 000
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`Dear Dr. Katz:
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`Biogen ldec is submitting the lnvestigational New Drug (IND) Application for its product,
`BGOOO12, which is being developed as treatment of relapsing forms of multiple
`sclerosis. A pre-IND meeting was held on September 1, 2005 between representatives
`ot the FDA and Biogen ldec. The overall clinical development plan, pharmacology!
`toxicology information, previous human experience and the proposed clinical study were
`discussed at that meeting. A copy of the pre-IND meeting minutes is included in Module
`1.12.1.
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`The proposed clinical trial included in this application is a Phase 1 study entitled: “A
`Single—Center, Randomized, Blinded, Placebo- and Active-Controlled Study to Evaluate
`the QTc Interval Prolongation Potential of BGOOO12 When Administered to Healthy
`Volunteers“. A copy of this protocol is provided in Module 5.3.3.4.
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`This IND is being submitted in e—CTD format with hard copies of the cover letter and
`FDA Form 1571 following agreement with the agency at the pre-IND meeting.
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`Should you require any additional information, please contact Tammy Sarnelli, Associate
`Director, Regulator Affairs at 617-679-3513. The contact for technical aspects for this
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`submission ish, Senior Director, Regulatory Affairs Operations at 617-679-
`
`24116.
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`
`
`Senior Vice President, Regulatory Affairs
`Phone (817) 679-3783
`Fax (617l 679-3170
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`Biogen Idec '4 C<l1lLll -_'_;»; Ca,—ill»;r C-,t'i
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`1' NJ». \:1/‘« 091-4? Pl'n' 4* (317 (379 7030 \‘/\'/\'/.l2lII(;.I:1|x.'ll‘:CC3f"\
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`2.4
`Nonclinical Overview
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`TABLE OF CONTENTS
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`Page
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`4
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`4.1
`4.2
`4.3
`4.4
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`TOXICOLOGY ...................................................................................................15
`Single-Dose Toxicology ........................................................................................15
`Repeat Dose Toxicology........................................................................................16
`Genotoxicity...........................................................................................................23
`Carcinogenicity......................................................................................................25
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`1
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`2.4
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`Nonclinical Oven-'iew
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`LIST OF TABLES
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`Table 1-1: DMF
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`Batches Used in Non-Clinical Studies ...................................... .. 6
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`Table 4.2:
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`S11]_I].lJ.1a1‘y' of Animal Exposure Data for Calculation of Safety Margins for Select
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`Toxicities in Chronic. N011-clinical Safety Studies with DMF ............................ .. 31
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`2.4
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`Nonclinical O\'e1'vi£-W
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`OVERVIEW OF THE NON-CLINICAL TESTING STRATEGY
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`The purpose of this ovewiew is to present a critical evaiuation of the non-clinical prog1‘an1
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`for the develo ment of BG00012, the ri11:Ia1
`focus of which is to characterize the safety of
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`Non-clinicai safety studies with D1\/[F and FUMADERM were conducted in mice, rats, dogs,
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`and rabbits. the species cominonly used for toxicological tests and in which fumaric acid
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`occurs endogenously i11t11e bod 1. There is an oh oh] chronic toxicolo 7 stud in
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`The chronic toxicology study in NHP is being conducted at the
`e FDA ecause the NHP test svstem would be 3 more 3
`I0 riate s ecies the11
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`2.4
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`In addition, a 12-month repeat-dose chronic toxicity study in dogs is ongoing at doses of 5,
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`25, and 50 nigfkg adniinistered by daily oral gavage. Through 12 weeks of treatment: no
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`unusual fnidings have been noted in this study to date.
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`The studies conducted with FUMADERl\{ are being subtnitted as sup Ieinental to the pivotal
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`was initiated i11 October 2005.
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`Below s11:mn1a1'izes specific actions have been taken in response to input by the Agency at
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`our pre-IND meeting:
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`1. No FUTVIADERM study is being used to suppoit the clinical development or
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`registration of BGOOOI2. Studies reqtlired to support clinical development and
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`registration of BG00012 have been or wili be conducted entirel
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`A one ear chronic dos; stud with DMF is on oin
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`2.4
`Nonclinical Owrview
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`Table 1-1: DMF,‘ Batches Used in Non-Clinical Studies
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`Drug
`Pr:-clinical
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`Product
`Stud)’
`Pl edm,:ml.Smd“ Type
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`!\ umbel
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`~
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`7
`- X ear carcmogemclty afsessnlexlt
`(ongomg. rats)
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`Drug Substance Manufacturer
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`‘
`Dunethyl
`fiunarate
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`I
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`P0001:_04_1 1
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`TK
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`e eat-Dose 'l‘oxicity- Rats [6 months)*
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`*iudicatcs pivotal study; TK-Toxicokinctic analysis
`* indicates pivotal study: TK-Toxicokinetic analysis
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`4.2
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`Repeat Dose Toxicology
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`A 6-month repeat dose toxicolo
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`Carcinogenicity
`4.4
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`A 2-year carcinogenicity study with DMF in rats is c—u11‘ent1
`a finalized re 011 is antici ated in October 2007.
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`in the 15th month of dosin _ and
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`011 re istmtion of BG00012.
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`Table 4.2: Summary of Animal Exposure Data for Calculation of Safety Margins for Select Toxicities in Chronic Non-clinical
`Safety Studies with DMF
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`Species (Study #)
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`Duration
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`Dose (mg/kg)
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`Mean AUC (0-24 hr) (ug*hr/mL) Mean Cmax (ug/mL)
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`Rat (P00012-04-06)
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` x 1-year dog study is ongoing (doses
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`are daily oral gavage administration at 0, 5, 25, and 50 mgfkg) and a 1-year NHP st11dy is
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`ongoing (doses are daily o1'al gavage administration at 0, S, 25, and 75 mgfkg). Overall,
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`there are sufficient data to support Phase 1 studies.
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`5
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`INTEGRATED OVERVIEW AND CONCLUSIONS
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`The main target organs of toxicity identified in the toxicology studies with DMF were the
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`stomach, kidneys, liver, and to a lesser degree. the testes. The for'estomach tumors identified
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`in the rat are not considered to be relevant to human risk for a number of reasons. including
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`differences between the anatomy of the rat versus humans and differences in the formulation
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`administered to rats versus humans. The rodent forestomach constitutes the proximal two-
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`thirds of the stomach and is continuous with the esophagus. There is no counterpart to the
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`rodent forestomach in humans. The rodent forestomach is lined by the same cell type as is
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`the esophagus and is sharply demarcated by the limiting ridge from the glandular stomach.
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`Although there is no direct counterpart in humans, the cells lining the esophagus and parts of
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`the oral cavity in humans are similar to those in the forestomach of the rat. Thus, if
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`administered as an oral gavage solution to humans as in the rat study, this finding could
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`reflect a potential increased risk of human tumors of the esophagus or oral cavity. However,
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`the product is administered to patients as enteric coated microtablets in capsules, most likely
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`rninimizing exposure to the oral cavity and esophagus.
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`The forestomach is a storage organ colonized by microflora and subjected to changes in pH.
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`Substances in solution or suspension given orally come into direct contact with the
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`forestomach epithelium and can do so for prolonged periods of time. Forestomach tumors in
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`rats have a very low spontaneous incidence (approximately 0.1% based on National
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`Toxicology Program control database (Haseman et al, 1998). In a summary report from the
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`International Agency for Research on Cancer (IARC, 1999) a range of chemicals are
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`discussed that are known to induce either forestomach tumors alone, or these tumors in
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`addition to other sites of tumorigenesis. The summary concludes that agents that a1'e DNA
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`reactive and cause tumors at multiple sites are of greater concern than non-DNA reactive
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`agents and./or those that are restricted to the forestomach as the site of tumorigenesis. DMF
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`and FUMADERM have been shown to be non—genotoxic in a complete battery of in vtrro and
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`in vivo genotoxicity assays. Although the administration of Dl\/[F by oral gavage was
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`Nonclinica] Ove-1'view
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`The increase in renal cell volume observed in dogs treated with FUlViADERM® after 52
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`weeks was also not consistent with CPN. While test-article related, this effect was not
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`considered to be significant and did not have a histological correlate in the rat. Renal
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`findings not classically associated with CPN were also noted in the inale rat fertility and 6-
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`month rat studies conducted with DIWF. These findings included cortical tubular changes
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`(diffuse dilation, hyaline droplet accurnulation, nuclear/cellulai‘ hypertrophy of epithelial
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`cells, segmental epithelial regeneration) and hypertrophy of the parietal epithelium of
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`Bowman‘s capsule. The relevance to the human situation is not clear since these other
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`changes may still be unique to the rodent and safety data for renal changes in BG00012
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`human trials is very limited.
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`The changes in the liver caused by chronic dosing with D1\/[F consisted of ininirnal rnultifocal
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`hepatic necrosis and minimal bile duct hyperplasia, predominantly in females in the 100 and
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`200 ingfkgfday groups in the 6-month chronic rat study. At the end of the recovery period.
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`rninirnal hepatic necrosis was still present in female recovery animals, although the incidence
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`was slightly lower than at tl1e main study timepoint. The lesio11 of nlininial bile duct
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`hyperplasia had recovered. While the histological changes were clearly present, the changes
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`were of lnjnimal severity and not associated with liver enzyme elevations or evidence of
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`filnctional abnormalities. It is not clear why these changes were not seen in the 52-week
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`1:Ul\/[ADERM study in rats. The mechanism of pathogenesis of the liver lesions was 11ot
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`clear, although bile d11ct hypeiplasia is comnionly a secondary, nonspecific response to
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`There were no in viva carcinogenicity assessments performed with FUEIADERM. In
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`support of BG000I2 re _ist1‘ation, there are on oin 2- ear carcino enici
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`In totality, there has been adequate exposure to DMF in rats and dogs to define its safety
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`profile to a degree that suppoits safe use in humans for Phase 1 studies up to 4 weeks in
`dtlration.
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`2.4
`Nonclinical Overview
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`35
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`2.4
`Nonclinical Overview
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