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`Message
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`From:
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`Sent:
`To:
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`cc:
`
`isabelle.emer
`
`
`12/17/2003 11:23:17 AM
`
`Gordon FrancisI ; Maria Lopez-Bresnahan PF
`21002| Ain
`Micaleftis ; S2rnir Shh ia
`| 82210 A 0UrySS | Amer
`Jaber(its ; Germano Oberto as
`NS ; (520e!!2 Ce! Martin
`S00 £7:I; Pac's Ricci
`a VOC©5120I, Stephen_rmarcuga
`Mario Maioee | Stuart McMillan
`a ; 5520S205 Hic
`
`ee Francois Maillardee
`
`
`david.browr
`; kate. bentle
`; Dodie Frank
`
`| 0! ke2
`LanNeuer
`Cladribine - draft for iii
`Subject:
`Attachments: Clabribine Briefing Document 17 Dec 2003.doc;
`
`a D
`
`ear All,
`
`
`Please find hereunderthefirst draft of the Briefing document[nn .
`In the table below, the names of the reviewersis indicated with section(s) to be reviewed.
`
`
`
`
`
`
`
`Lee
`
`ReviewBrief
`
`
`Briefing docuneniii
`Document:
`
`
`IPR2023-00049
`
`
`Merck 2078
`
`TWi v Merck
`
`
`
`Message
`
`
`From:
`
`Sent:
`To:
`
`cc:
`
`isabelle.emer
`
`
`12/17/2003 11:23:17 AM
`
`Gordon FrancisI ; Maria Lopez-Bresnahan PF
`21002| Ain
`Micaleftis ; S2rnir Shh ia
`| 82210 A 0UrySS | Amer
`Jaber(its ; Germano Oberto as
`NS ; (520e!!2 Ce! Martin
`S00 £7:I; Pac's Ricci
`a VOC©5120I, Stephen_rmarcuga
`Mario Maioee | Stuart McMillan
`a ; 5520S205 Hic
`
`ee Francois Maillardee
`
`
`david.browr
`; kate. bentle
`; Dodie Frank
`
`| 0! ke2
`LanNeuer
`Cladribine - draft for iii
`Subject:
`Attachments: Clabribine Briefing Document 17 Dec 2003.doc;
`
`a D
`
`ear All,
`
`
`Please find hereunderthefirst draft of the Briefing document[nn .
`In the table below, the names of the reviewersis indicated with section(s) to be reviewed.
`
`
`
`
`
`
`
`Lee
`
`ReviewBrief
`
`
`Briefing docuneniii
`Document:
`
`
`IPR2023-00049
`
`
`Merck 2078
`
`TWi v Merck
`
`
`
`
`
`a S
`
`a ClabribineBriefingDocument17Dec2003.doe
`
`ections
`reviewed:
`
`CMC section (Section 2)
`
`
`
`Germano Oberto, Steve Marcus
`
`Sections
`reviewed:
`
`to
`
`Nonclinical section (Section 3)
`
`Alain Munafo, Steve Marcus
`
`Sections to be
`reviewed:
`
`PK and PD human info (Section 4.2)
`
`Maria Lopez-Bresnahan, Gordon Francis, Alain Micaleff, Samir Shah, Nazih Ammoury,
`Isabella Cei Martini, Alison Ernst, Paola Ricci, Steve Marcus
`
`Sections to be
`reviewed:
`
`
`
`
`
`
`Page 3 of 59
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`
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`Thank you in advancefor youraction.
`
`Kind regards.
`
`Isabelle Emery
`
`
`
`Page 4 of 59
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`Cladribine
`
`(2-chloro-6-amino-9-(2-deoxy-B-D-erythropento-furanosyl) purine)
`
`Briefing Document December2003
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`
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`Cladribine
`Briefing Document
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`Page 5 of 59
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`TABLE OF CONTENTS
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`Page 1
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`Briefing Document
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`5.
`5.1
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`CLINICAL DEVELOPMENTPLAN...........cceecccccessseesessesssecesesesessesesceeesseeees 43
`PHASE 3: ORAL CLADRIBINE IN THE TREATMENT OF RELAPSING
`FORMSOF MS 0.0. ecceceececccceeesceeeeeeceseeeeeeceeeeneeeeneeeseseeeeaeeseeeeseseeseeseetenseeeeneeeeeees 43
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`Briefing Document
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`CladribinedalUd
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`CladribinedllWal
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`Briefing Document
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`bioavailability of three tablet and capsule oral formulations of cladribine are currently being
`
`Serono partnered with IVAXResearch Inc. (IVAX) in 2002 to develop an oral formulation
`of cladribine for the treatment of MS. Twoclinical studies to study the pharmacokinetics and
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`‘ladribine
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`Cladribine
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`Briefing Document
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`Cladribine
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`Briefing Document
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`Briefing Document
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`Cladribine
`Briefing Document
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`Research Inc)
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`Ongoingstudies
`Protocol No.
`IXR 101-09-
`186 (IVAX
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`Cladribine
`Briefing Document
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`Protocol No.
`IXR 102-09-
`186 (IVAX
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`Research Inc)
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`treatment of MS.
`
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`4.2.3.
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`Ongoing Pharmacokinetic Studies
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`Serono has partnered with IVAX to develop
`
`
`an oral formulation of cladribine for the
`
`The pharmacokinetics and bioavailability of this formulation are currently
`being investigatedin a Phase I studyin MSpatients (Protocol No. [IXR 102-09-186). Another
`Phase I study in MS
`patients
`is also being conducted with alternative formulations
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`
`
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`— No. [XR 101-09-186).
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`inl
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`Briefing Document
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`ee
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`|as
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`Table 5.1-1: Synopsis of the Proposed Phase 3 Study
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`Oral cladribine in the treatment of relapsing forms of MS
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`Project Phase
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`Phase 3
`
`SE
`|———s
`ee.
`og
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`
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`
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`2.1mg/kg and 0.7mg/kg)
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`StudyDesign
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`Study design summary: Randomised, double-blind, placebo-controlled, multi-centre
`trial
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`Target population: RRMS & relapsing SPMS
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`Treatment group(s): 2 doses (high and lowapproximating cumulative doses of
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`Duration of treatment: 1phase - 6 cycles (high/low/placebo). 2" phase /re-treatment-
`6 cycles (low/low/placebo). 3% phase/re-treatment- 6 cycles (low/low/low). One cycle
`= 5-day course of treatment during a 28 dayperiod.
`
`Duration of study: First 24 months includes 6 cycles (months 1-6) followed by repeat
`treatmentforactive patients only at 12-18 months based on lymphocyte counts.
`Months 24-30 are re-treatmentto all patients who qualify (adequate lymphocyte
`counts), including placebopatients, followed by a safety follow-up phase ending at
`
`month36.
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`Briefing Document
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`Assignmentto
`treatment groups
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`Assignment of subject ID numbers: Central randomisation
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`Randomisation: Equally randomisedto all treatment groups (1:1:1)
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`
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`Blinding: double-blind, central MRI blinded to treatment assignment,all patients
`receive same numberoftabs(i.e., low dose patients receive placebo tofill out high
`dose cycles, any decrease inactive treatment dose is replaced with placebo, and any
`ify
`for re-treatment will receive placebo
`
`Study Treatment
`
`Strength: 0, 3 and 10 mg
`Route of administration: PO
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`
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`Treatment regimens: 3 phases, 5-day consecutive dosing within 28-daycycles x 6
`cycles/phase
`Duration of study: 36 months
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`Re-treatment/crossover: Active treatment patients with adequate (TBD) lymphocyte
`counts will receive blinded re-treatment at 12-18 months at the lower dose. All
`patients with adequate lymphocyte counts will receive open-label re-treatmentat 24-
`30 monthsat the lower dose. DSMB will determine whichpatients receive re-
`treatment based on pre-determined lymphocyte countcriteria.
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`1 P
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`age 47
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`Briefing Document
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` 1 P
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`age 49
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`ne
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