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`12/17/2003 11:23:17 AM
`Gordon Fran'siii ; Varia Lopez-Bresnahan
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`david.browEN ; kate.bentleI; Dodie Frankx
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`
` Subject: Cladribine - draft forBD
`Attachments: Clabribine Briefing Document 17 Dec 2003.doc;xy
`
`Cc:
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`mm
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`Dear All,
`
`Please find hereunderthefirst draft of the Briefing document[ix |
`In the table below, the namesof the reviewersis indicated with section(s) to be reviewed.
`OOe—SSCSC‘CSCiés
`
`
`
`a,
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`
`
`
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`aPS
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` a R
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`eview Brief
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`Briefing docuneniiiiiii
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`Document:
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`Merck 2078
`TWi1v Merck
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`IPR2023-00050
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`Page 2 of 59
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`Reviewers1
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`A. Jaber, Y. Dandiker
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`Sections
`.
`.
`reviewed:
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`to
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`be
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`CMCsection (Section 2)
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`
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`Germano Oberto, Steve Marcus
`Reviewers 2
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`Sections
`reviewed:
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`to
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`Nonclinical section (Section 3)
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`oe ClabribineBriefingDocument1%Dec2003.doc
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`
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`Alain Munafo, Steve Marcus
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`Sections to be
`reviewed:
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`PK and PD humaninfo (Section 4.2)
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`
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`Maria Lopez-Bresnahan, Gordon Francis, Alain Micaleff, Samir Shah, Nazih Ammoury,
`Isabella Cei Martini, Alison Ernst, Paola Ricci, Steve Marcus
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`Sections to be
`reviewed:
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`Page 3 of 59
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`Thank you in advancefor your action.
`
`Kind regards.
`
`Isabelle Emery
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`
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`Page 4 of 59
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`Cladribine
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`(2-chloro-6-amino-9-(2-deoxy-B-D-erythropento-furanosyl) purine)
`
`Briefing Document December2003
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`Cladribine
`Briefing Document
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`TABLE OF CONTENTS
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`Page i
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`Briefing Document
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`5.
`5.1.
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`CLINICAL DEVELOPMENTPLAN...........csccscsssssssssscsssessesscsssssssnsssesssesseesoeees 43
`PHASE3: ORAL CLADRIBINE IN THE TREATMENT OF RELAPSING
`FORMS OF MS oo cccccccceeccceseescescceseceeeesecsseseesneenecaeceseesaeeseeaeeseceeeseeeaeeneeeneeatens 43
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`Briefing Document
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`Serono partnered with IVAX Research Inc. (IVAX) in 2002 to develop an oral formulation
`of cladribine for the treatment of MS. Twoclinical studies to study the pharmacokinetics and
`bioavailability of three tablet and capsule oral formulations of cladribine are currently bein
`conducted in MS patients
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`Ongoing studies
`Protocol No.
`TXR 101-09-
`186 IVAX
`Research Inc)
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`Protocol No.
`TXR 102-09-
`186 IVAX
`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
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`an oral formulation of cladribine for the
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`The pharmacokinetics and bioavailability of this formulation are currently
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`being investigated in a Phase I study in 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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`Protocol No. IXR 101-09-186).
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`Project Phase
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`Oral cladribine in the treatment of relapsing forms of MS
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`2.1mg/kg and 0.7mg/kg)
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`Study design summary: Randomised, double-blind, placebo-controlled, multi-centre
`trial
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`Study Design
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`Target population: RRMS & relapsing SPMS
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`Treatment group(s): 2 doses (high and low approximating cumulative doses of
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`Duration oftreatment: 1‘' phase - 6 cycles (high/low/placebo). 2phase /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 day period.
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`Duration of study: First 24 monthsincludes 6 cycles (months 1-6) followed by repeat
`treatment for active patients only at 12-18 months based on lymphocyte counts.
`Months 24-30 are re-treatmentto all patients who qualify (adequate lymphocyte
`counts), including placebo patients, followed by a safety follow-up phase ending at
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`month 36.
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`Assignmentto
`treatment groups
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`Study Treatment
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`Assignment of subject ID numbers: Central randomisation
`Randomisation: Equally randomisedto all treatment groups (1:1:1)
`Blinding: double-blind, central MRI blindedto treatment assignment,all patients
`receive same numberoftabs (i.e., low dose patients receive placeboto fill out high
`dose cycles, any decrease in active treatment dose is replaced with placebo, and any
`patient who does not
`i
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`treatment based on pre-determined lymphocyte countcriteria.
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`Strength: 0,3 and 10 mg
`Route of administration: PO
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`Treatment regimens: 3 phases, 5-day consecutive dosing within 28-day cycles 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 monthsat the lower dose. All
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`patients with adequate lymphocyte counts will receive open-label re-treatment at 24-
`30 monthsat the lower dose. DSMB will determine whichpatients receive re-
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