Cladribine Ortho Biotech Inc
`Carla Tortorella, Marco Rovaris & Massimo Filippi*
`
`1751
`
`Address
`Neuroimaging Research Unit
`Department of Neuroscience
`Scientific Institute and University Ospedale San Raffaele
`Via Olgettina
`20132 Milan
`Italy
`Email: m.filippi@hsr.it
`
`•
`
`"To whom correspondence should be addressed
`
`Current Opinion In lnvestlgatlonal Drugs 2001 2( 12): 1751-1756
`<C> PharmaPress Ltd ISSN 1472-4472
`
`Cladribine, an adenosine deaminase inhibitor, has been develaped
`and launched by Ortho Biotech in collaboration with The Scripps
`Research Institute for
`the
`treatment of several neaplasms,
`including acute myelogenous leukemia, chronic lymphocytic
`leukemia, chronic myelogenous
`leukemia, cutaneous T-cell
`lymphoma, hairy-cell leukemia and non-Hodgkin's lymphoma. It
`was first launched in the US in February 1993 [224609]. Ortho
`Biotech and The Scripps Research Institute have since been
`develaping the compound for its potential use in multiple sclerosis
`(MS) [203216].
`
`In 1997, Ortho filed an NDA in the US fer the use of cladribine in
`the treatment of relapsing-remitting and secondary progressive
`MS [309586], [351798]. An FDA drug advisory committee was
`planning to meet in January 1999 to discuss the NDA [309586].
`However, Ortho cancelled the meeting [313428]. Following an
`FDA inspection during December 1998 and January 1999, the
`Scripps Clinic received a warning letter from the FDA in April
`1999 regarding violations in the clinical studies of cladribine for
`MS, and Ortho withdrew the NDA after concluding that further
`clinical studies would be necessary [337358].
`
`Cladribine has been known since the 1960s as an intermediate for
`the synthesis of 2-deoxynucleotides and its potential fer the
`treatment of leukemia was disclosed in 1984 [65313]. The Scripps
`Research Institute and the Johnson & Johnson group hold several
`patents claiming preparation methods (US 05208327), and
`additional indications, such as multiple sclerosis (WO-09316706)
`and rheumatoid arthritis (US-05316732). The associated patent,
`WO-09323508, is the only one among those patents that claims
`the use of unmodified cladribine fer the treatment of leukemia, but
`it focuses particulli.rly on a specific ferm of the disease, chronic
`myelogenous leukemia [224609].
`
`Analysts at UBS Warburg predicted in October 2001, that the
`product would make US sales of $50 million in 2004 for its MS
`indication [427553].
`
`Introduction
`Multiple sclerosis (MS) is ronsidered to be an organ-specific, T(cid:173)
`cell-mediah:rl, autoimmune disorder of the central nervous
`system (CNS). In MS, CNS myelin components are thought to
`represent the target of the immunological attack, which leads to
`the formation of lesions with heterogeneous pathological
`substrates, ranging from reversible inflammatory changes to
`irreversible demyelination and axonal loss. In most MS cases,
`the progressive accumulation of irreversible neurological
`disability starts after an initial relapsing-remitting (RR) phase.
`
`Originator Ortho Biotech Inc
`
`Licensees IVAX Corp, Scripps Research Institute
`
`Status Phase Ill Clinical
`
`Indication Multiple Sclerosis, Leukemia, Rheumatoid
`Arthritis
`
`Action Adenosine deaminase inhibitor
`
`Biotechnology Oral formulation
`
`Synonym 2-CdA, Leustat, Leustatin, NSC-105014F, RWJ-
`26251
`
`CAS Adenosine, 2-chloro-2'-deoxy(cid:173)
`Registry No: 4291-63-8
`
`However, in about 10% of the cases a progressive clinical
`deterioration occurs following the onset of the disease.
`Given the pathogenesis of MS, several immunomodulating
`and immunosuppressive therapies have been used in an
`attempt to favorably modify the disease course.
`
`Cladribine is a highly specific lymphocytotoxic agent which
`has become the first-line treatment for hairy-cell leukemia
`and which is also used to treat lymphoid malignancies. The
`potent and
`long-lasting
`lymphocytotoxic activity of
`cladribine has also suggested its potential for influencing
`favorably the autoimmune process underlying the evolution
`ofMS.
`
`Synthesis and SAR
`Cladribine (2-chloro-2'-deoxyadenosine) has been known for
`four decades as an intermediate for the synthesis of 2'(cid:173)
`deoxynucleotides. It is a chlorinated purine analog derived
`from deoxyadenosine by substituting chlorine for hydrogen
`at the 2'-position of the purine ring. This substitution
`renders 2-cladribine resistant to the action of adenosine
`deaminase [65313].
`
`Cladribine was first synthesized chemically and shown to
`be an inhibitor of Ll210 leuke~ in mice. Subsequently,
`Carson et al detailed a method utilizing a stereospecific
`enzymatic
`transfer of a deoxyribosyl moiety
`from
`thyrnidine to 2-chloroadenine [64003]. This reaction is
`catalyzed by a partially purified transdeoxyribosylase from
`Lactobacillus helveticus and the drug was isolated using ion
`exchange chromatography [64003].
`
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`

`1752 Current Opinion in lnvestlgational Drugs 2001 Vol 2 No 12
`
`Pharmacology
`Cladribine, like other antimetabolite cytotoxic drugs such as
`(Southern Research
`pentostatin (Pfizer Inc),
`fludarabine
`Institute/Schering AG) and cyatarabine, are prodrugs requiring
`phosphorylation to beco~e biologically active. Deoxypurine
`nucleosides, such as cladribine, enter cells through an efficient
`transport system and are phosphorylated by deoxycytidine
`kinase to the corresponding mononucleotide. Deoxyadenosine
`concentration is maintained at a low level by adenosine
`deaminase (ADA), which dearninates the compound to
`deoxyinosine [17808). Administration of cladribine, which is
`resistant to the action of ADA, causes a toxic concentration
`of deoxynucleotides, which are then incorporated into the
`DNA. This impairs DNA synthesis and cellular metabolism
`and causes the death of both dividing and quiescent cells
`[17808), [64003).
`
`Cladribine activity is very efficient in cells, such as
`levels of
`lymphocytes and monocytes, with high
`deoxycytidine kinase and low deoxynucleotidase activity,
`since
`the
`latter
`enzyme usually dephosphorylates
`deoxyadenosine monophosphate nucleotides, and, as a
`consequence, prevents the action of deoxycytidine kinase
`and
`ribonucleotide accumulation. For
`these
`reasons,
`cladribine concentrations, which are not harmful to normal
`bone marrow cells and other cell types, can selectively
`damage lymphocytes, particularly of the CD4+ subset
`[241296), and monocytes [64003),
`[106552). Cladribine
`treatment can induce a 4-fold decrease in CD4+ to CDS+ T(cid:173)
`cell ratio which may persist for several months [423894] and
`which
`is 2-times higher
`than
`those
`caused by
`cyclophosphamide [423896) or chlorambucil [423908). The
`immunosuppressive efficacy of cladribine is, therefore, at
`least equal to that of cyclosporine [241277). To explain the
`toxicity of cladribine against resting lymphocytes, it has also
`been suggested that the accumulation of an abnormal
`concentration of deoxyribonucleotides may act as a
`triggering factor for cell apoptosis [17808).
`
`Metabolism
`The bioavailability of orally administered cladribine ranges
`from 37 to 51 %, while that of subcutaneous (sc) preparations
`is 100%. [122098), [423910). As a consequence, a double dose
`of orally administered cladribine can substitute for a sc
`injection, which, in turn, results in a high peak concentration
`of short duration, with an area under the curve identical to
`that obtained for intravenous (iv) administration [122098).
`Following the sc administration of a single dose, the
`absorption of cladribine
`is
`rapid and peak-plasma
`concentrations (C .. ..) are achieved in most subjects 60 to 70
`min after dosing. The disposition kinetics are similar
`following administration of single or multiple sc doses and
`only a minimal accumulation has been observed after
`repeated daily dosing for 5 days. Cladribine is mainly
`excreted in the urine; the renal clearance is 51 % of total
`clearance, and 21 to 35% of an iv dose is excreted unchanged
`in the urine. The terminal half-life of cladribine varies from
`5.7 to 19.7 hand the apparent volume of distribution ranges
`from 54 to 357 l/m2 [105448), [423910).
`
`In MS patients, cladribine was administered iv in the first
`trial (MS-Scripps [241294)) and sc in the following studies
`[422449), [422627). In two placebo-controlled, double-blind
`
`studies of subjects with chronic progressive [422627) or
`RRMS [422449), cladribine was administered sc at 0.07
`mg/kg for 5 consecutive days for 2 to 6 monthly courses, ie,
`at a total dose of 0.7 to 2.1 mg/kg. Even though a higher
`dose (2.8 mg/kg) was found to be effective in a previous
`study [241294), this regimen was abandoned because of the
`increased degree of myelosuppression and incidence of
`infections.
`
`Two different cladribine formulations have been used in MS
`studies: a 1 mg/ml formulation was used in the double(cid:173)
`blind phase of the placebo-controlled studies [241294),
`[422627) and a 5 mg/ml formulation was used in the
`retreatment phase of the phase III study [422449). The
`pharmacokinetics of the two cladribine formulations were,
`however, similar.
`
`Oral cladribine has been used in MS patients only in a
`preliminary study. The cff>se was of 10 mg once a day for 5
`consecutive days in six monthly courses, followed by one or
`two additional courses at 3 or 6 month intervals. Oral
`cladribine treatment was well-tolerated and relatively safe
`[241271).
`
`Toxicity
`Although the analogs of deoxyadenosine are more specific
`for lymphocytes than other cell types, they can potentially
`harm normal somatic cells. Since their toxicity is correlated
`with sustained increases in the plasma concentration of
`endogenously generated deoxyadenosine and adenosine,
`both toxicity and therapeutic response are dose-related.
`
`The use of cladribine in MS was considered after the drug
`was used to test lymphoid leukemias and autoimmune
`hemolytic anemia [181788), [181838). The primary toxicity
`caused by the drug is myelosuppression, which is a dose(cid:173)
`limiting factor. Long-term hematologic observations of the
`effect of cladribine on 'normal' bone marrow have been
`made on 29 patients with MS undergoing experimental
`therapy with monthly courses of 0.07 to 0.1 mg/kg
`cladribine/ day for 7 days. The typical hematologic response
`consisted of an acute transient monocytopenia, a prolonged
`and severe lymphopenia (mainly affecting CD4+ cells), and
`a modest lowering of granulocytes and hemoglobin,
`followed by a long-lasting macrocytosis. Two patients
`developed
`severe aplastic
`anemia, which
`required
`transfusion. One of these patients, however, had previously
`received chlorambucil, while the other had previously
`received carbamazepine and was receiving phenytoin
`during cladribine therapy [241296).
`
`Clinical Development
`Phase/
`The recommended cladribine doses for MS treatment (0.7
`and 2.1 mg/kg) have similar safety profiles, as regards the
`incidence of infections. However, 2.1 mg/kg cladribine
`seems to cause a somewhat greater degree of lymphopenia
`and myelosuppression. The dose of 2.8 mg/kg used during
`the first year of the MS-Scripps trial was subsequently
`lowered because of dose-related myelosuppression [241294).
`Cladribine safety and tolerability have also been tested in
`MS patients by Selby et al [423894), who did not report any
`significant myelosuppression or infections, despite the
`
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`

`

`presence of a profound lymphocytopenia in treated patients.
`In this study, which used a 2.1 mg/kg dose, the rate of
`decline in CD4+ cells was less rapid than that previously
`reported with a higher dose [241296), although after 6
`months CD4+ cell blood levels were comparable in the two
`studies. However, a partial recovery of CD4+ levels was
`found one year after treatment in the patients treated with
`lower doses, whereas CD4+ cell counts remained markedly
`decreased in patients treated with higher doses [423894).
`The concomitant use of corticosteroid9 and purine analogs
`has been associated with an increased risk of opportunistic
`infections [423912). Further studies are needed to establish
`whether dadribine is safe when used with or soon after
`other immunomodulating or immunosuppressive therapies,
`as
`~interferon,
`glatiramer
`acetate
`(f eva
`such
`Pharmaceutical Industries Ltd), mitoxantrone (Immunex
`Corp), azathioprine or cyclophosphamide.
`
`Phase II
`Two randomized, double-blind, placebo-controlled, phase II
`trials have been conducted to evaluate the efficacy and safety
`of dadribine in MS (MS-Scripps [241294); Scripps C [422449)).
`These trials enrolled patients with chronic progressive MS
`[241294) and RRMS [422449), respectively. In both studies, the
`primary efficacy measure was the proportion of subjects with
`contrast-enhancing lesions on magnetic resonance imaging
`the double-blind phase.
`(MRI) scans obtained during
`Secondary outcomes
`included changes
`in neurological
`disability scores, as measured by the Expanded Disability
`Status Scale (EDSS) [423913) and Scripps Neurological Rating
`Scale (SNRS) [423914], and changes in the total volume of
`contrast-enhanced and TI-hyperintense MRI
`lesions. In
`addition, the time to disease progression and the annualized
`exacerbation
`rate were considered
`secondary clinical
`outcomes for chronic progressive MS [241294) and for RRMS
`[422449), respectively.
`
`The MS-Scripps double-blind trial lasted for two years,
`during which time 49 patients were studied [241294).
`During the first 4 months of the study, each subject received
`seven daily infusions of 0.1 mg/kg of dadribine each month
`(total dosage: 2.8 mg/kg) or placebo over a 1 month period,
`followed by an 8-month interval without treatment. In the
`second year of the study, s u~ initially randomized to
`placebo received four monthly courses of cladribine at a
`total dosage of 1.4 mg/kg and subjects who received the
`drug in the first year received placebo with the same
`regimen.
`
`Cladribine 2.8 mg/kg was effective in suppressing contrast(cid:173)
`enhanced MRI activity and slowing the increase in TI-lesion
`volume over the double-blind period. In addition, evidence
`of a reduced neurological deterioration was observed in
`cladribine-treated patients but not in placebo patients. Such
`clinical efficacy has not been confirmed by the phase ill trial
`and might be, in part, due to a type I (false positive) error.
`This is suggested by the following characteristics of the Ms(cid:173)
`Scripps trial: (i) the replacement of cladribine dropout
`patients in such a small-sized cross-over study; (ii) the lack
`of confirmation after 3 to 6 months of the observed clinical
`deterioration; (iii) the use of means of ordinal scores (EDSS)
`as an outcome measure; (iv) the rapid worsening of the
`placebo group.
`
`Cladrlblne Tortorella et at 1753
`
`The Scripps C study was designed to evaluate the efficacy
`and safety of cladribine 2.1 mg/kg in 52 patients with
`RRMS. Again, the drug was effective in reducing the
`proportion of subjects with contrast-enhanced MRI lesions.
`This effect appeared to be significant 3 months after study
`initiation and was still present one year after treatment
`ceased. No significant treatment effect on neurological
`disability was observed. On the contrary, the treatment
`effect on exacerbation rate was statistically significant and
`its dynamics mirrored the delayed effects on contrast(cid:173)
`enhanced MRI lesions. A correct interpretation of the clinical
`data is made difficult by the high dropout rate (25% in the
`placebo patients) during the second and third semester of
`the treatment period, and by the fact that there was no
`significant clinical worsening in the placebo group.
`
`In both phase II trials, the most common treatment emergent
`adverse events were due to the known pharmacological
`effects of the drug on bone marrow and lymphocytes. In the
`MS-Scripps study, only four chronic progressive MS patients
`in the cladribine 2.8 mg/kg group withdrew from the study
`during the first year. This was because of injury, aplastic
`anemia, hepatitis and thrombocytopenia, respectively. The
`subject with hepatitis died, but the investigator considered it
`unlikely that the event was drug-related [241294). The
`observed changes in liver and renal functions, vital signs
`and physical examination were not considered clinically
`significant in any of the study subjects.
`
`Phase Ill
`A multicenter, randomized, double-blind, parallel-group,
`placebo-controlled phase ill trial has also been conducted to
`evaluate the safety and efficacy of two different doses of
`cladribine in patients with primary progressive (PP) and
`secondary progressive (SP) MS [422627]. 159 MS patients
`(30% with PP and 70% with SPMS) randomly received 2.1
`mg/kg or 0.7 mg/kg of cladribine or placebo. The lowest
`dose was chosen to minimize bone marrow toxicity. After a
`one-year, double-blind phase, a
`six-year, open-label
`extension was planned. MRI evaluation was carried out at
`baseline and every 6 months for the first two years. The
`primary outcome measure was the mean change in EDSS
`score at the final evaluation. Secondary clinical and MRI
`outcome measures were similar to those used for the phase
`II cladribine MS studies [241294), [422449). In addition, two
`ancillary studies [422447], [422567], assessed the treatment
`efficacy on MRI-measured brain volume [422447] and Tl(cid:173)
`hypointense lesion load [422567]. These two MRI-derived
`parameters are
`considered markers of MS-related
`irreversible tissue loss [423916), [423918].
`
`No significant treatment effects on disability were found.
`However, the mean changes of EDSS and SNRS scores were
`minor in all three of the treatment groups. Subgroup
`analysis suggested a stabilization of disability in cladribine(cid:173)
`treated patients with SPMS, but not in those with PPMS.
`Exacerbations, steroid use and hospitalizations did not differ
`among the treatment subgroups compared to the placebo
`group. Both of the cladribine treatment groups had a
`significant reduction of MRI-measured disease activity, as
`expressed by the number and volume of contrast-enhanced
`lesions, which were on average 90% lower at months 6 and
`12 of the double-blind phase. TI-lesion load modestly
`improved in treated patients and worsened in placebo
`
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`1754 Current Opinion in lnvestigational Drugs 2001 Vol 2 No 12
`
`patients. Lesion load percentage changes were significantly
`lower in patients who received cladribine 2.1 mg/kg
`compared to patients receiving placebo during the double(cid:173)
`blind phase. This was also the case for SPMS patients during
`the first year of the study extension phase. No significant
`treatment effect of either dose of cladribine on brain volume
`or Tl -hypointense lesion load changes over time was
`observed (422447], [422567].
`
`The discrepancy between the lack of effect of cladribine on
`MS disability and its efficacy on MRI measures of MS
`activity can be explained by the relatively short duration of
`this phase III trial, combined with the clinical characteristics
`of the patients studied. At study entry, the mean level of
`disability was relatively high in all three arms. This might
`have prevented
`the detection of additional disease
`progression over such a relatively short follow-up period in
`the placebo patients. Clearly, follow-up is an essential
`prerequisite
`to demonstrate any
`treatment effect.
`In
`addition, PPMS patients
`typically have
`low degree
`inflammatory changes (423919]. This might have rendered
`clinical and MRI measures of disease activity uninformative
`in these patients. However, the results of the ancillary MRI
`studies indicate that an alternative explanation might be that
`cladribine does not affect
`the progression of severe
`demyelination and axonal loss, which are likely to be
`responsible for the increasing irreversible disability in MS.
`
`The phase III study confirmed that cladribine treatment is
`not related to serious adverse events. Herpes infections
`occurred rarely and had a similar frequency in the three
`treatment groups. Furthermore, doses used in this study
`reduced the hematopoietic effects of the drug, which were
`previously reported for higher doses (241294].
`
`Side Effects and Contraindications
`from
`apart
`Treatment-emergent
`adverse
`events,
`myelosuppression, are not treatment-limiting and include
`
`nausea, infections, muscle weakness, hypertonia, purpura,
`ataxia and skin reactions (422627]. There is no known drug
`interaction with cladribine. However, given the marked
`lyrnphocytotoxicity and the moderate myelosuppressive
`activity of the drug, particularly at high doses, caution
`should be exercised when administering cladribine
`concomitantly with other immunosuppressive agents.
`
`Current Opinion
`Phase II and ID trials have demonstrated that the effect of
`cladribine on MRI surrogate markers of MS inflammatory
`activity is similar, if not more pronounced, to that found for
`other irnmunomodulating or irnmunosuppressive drugs that
`have been approved for the treatment of RR and SPMS, such
`as ~-interferon, glatiramer acetate and mitoxantrone.
`
`That cladribine was not found to be effective against MS
`clinical deterioration might be due to the characteristics of
`the only available phii,e III trial, which was based on
`patients in an advanced phase of the disease, and of which a
`relevant proportion were affected by PPMS. Both these
`factors might have prevented
`the
`investigators
`from
`detecting any drug effect, as suggested by the results of the
`subgroup analysis, which demonstrated a trend toward a
`positive response for SPMS patients.
`
`Considering that oonflicting results have been obtained as
`regards the efficacy of l,l-interferon in SPMS [423922], (423925]
`and that the use of mitoxantrone is limited by its cardiotoxicity
`[423939], the results of available studies suggest that a further
`asses.5ment of cladribine efficacy in selected subgroups of
`patients, such as those with SPMS or rapidly deteriorating
`RRMS, could prove useful. The known irnmunosuppressive
`action of cladribine also makes it a potential rescue therapy for
`MS patients who are unresponsive to other first-line treatments.
`Finally, the possibility of combination treatments of cladribine
`and other irnmunomodulating drugs also deserves further
`consideration.
`
`Licensing
`/VAX Corp
`In December 2000, IV AX entered into an exclusive agreement with The Scripps Research Institute to develop and market
`cladribine worldwide for the treatment of multiple sclerosis (392111]. The Institute and Ortho Biotech have a sep arate
`agreement relating to cladribine (224373].
`
`Development history
`___ ~ '" ""*' ...
`_ Develop£!:
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`
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`

`

`Cladribine Tortorella et al 1755
`
`Biology (continued)
`dy Typet Effect StudJed
`n Wtro
`Effec:I an elem
`
`m iiND
`
`To,:lolfy,
`
`&:.pe,lmemal ModeJ
`MyelOld ptogenilors mid T•
`lymphocyf ootony•'lor:m ng cells
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`ritt panptul!ral blood._
`
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`pali'6nm,
`
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`
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`
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`and lymphocyte colony ormfng · ls In
`a dose-depen(leol rn
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`
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`
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`
`2-41296
`
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`to COB+ T~I ratio,
`
`Results
`Oral DJoa.vallablltty 37 to .51%:
`suboutaAe{MJS biovalklbi i'\Y 100%.
`
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`122098
`
`rformance ~quid
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`chromatography.
`
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`re.n volume r lfislri: IJtlon; 54
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`
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`
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`
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`
`CladrOxna o. t l'(lqA<g/da.y ~ ~ 7-day
`cgnli LJl:lll Iv inl
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`days for :a ~mum of sbt cy(j!e-s-11'I I io
`pallents wM
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`
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`IV'e
`Ctlnllr011ed, parallel group design.
`c:fllQflic prow
`MS pa,lmits.
`
`. tx>-
`S I ty and: etffcacy in DQuble-bllnd, ranclQmtzed,
`AA MS .patiBC'lts.
`cootro!IOO
`-group lilesign.
`al
`
`Doll~~ -blincf1 randomged, mliltiteot r,
`plE!llebo-aomrolk:KI, paraJIEll-9ro~p des.1gn
`
`ribin
`I
`Elfeets o
`oo the accuT'(u~llon
`of 'bis holes',
`mm
`,r e~tibin~
`tio eohan~ n
`brain 110:lume.
`
`Oout:llirblind, randomiz,oo, 111lJHicenter,
`piacebo-cootrolted, paraltaliaroup design.
`
`Dou l&-1:ifirut randamiz-ed. rnuttlcent-er,
`plaoobo-oontrollad, parat
`-grovp.s design,
`
`Results
`Myelosuppr,ession was the primary to)dc_lty,
`2.0% <if p,atlemts'lileveloped gtild
`llltlV
`lhmmboo)'toPE!o1Q.
`
`R tere-nce
`
`a~ o/o O!
`pallei11s sostaioed eatfy 10>.Pcity and
`rnost ~loo ba:forf! ihe first Flil valua.fion of
`JOledton; !10 riausea1 Vornitlog, rEfl&I,. hf!PB.1:ie or
`imrdla.o toxicity obs1;1rv8d.
`
`81838
`
`Cladribln.e (2.8 mgtkg l'i) w effective on MRI
`(f1 ~a · Ilg lesl~!l. T.2'1esloo load) and
`dil cal e~d
`,(EDSS and Scflipps cale
`~ ). Bo!lil8' ltll,ll'l'OW SUPPf8Sollol:l was tie
`m n adVeise event
`
`2412,94
`
`.422449
`
`Oladribihe {2.1 mg'kg !:IC) was eft8cti~ Oil MRI
`(Tt~emanei.11g le1 em) but not oo cllflklal
`endpom~ (EDS$ and SNi:l:S scores). 11$Jd
`:s99m.enta1 ~ z: . 9rWas ltle only edVEl~
`~\/eJ'lf.
`a · rib
`(0.7 ® ,2..1 mg/kg sc) was effecl ve 4~7
`on MRI (Tl. haneing l&Sions, T2.-lesion load);
`but no on cl nleal endpoln
`(SOSS and SNFtS
`:oorea) The effect ori T2-li. ·on~ 111ratHlosa-
`1'81ated as y,rgll BS" e tre.mtiei:lt emeryent
`a<lverse aitenL
`
`No&agolllwll dl:IJerefiee b I.Ween placebo Md.
`treatecl.arms, orwtien.PP and SPMS p lfenls
`'We're CQl"ISk:lered se ately
`nt d erenoe betWeen placebo 8l1d'
`N9 ~g
`t.re led am'ls. No oor,etalion in the placebo
`VJ'OOP between .brar,n abqph and oH1or MRI
`measura al base ne !enhancing
`skl11 m.1rnb&.I'
`and 11olurne, 12.hypetin ans:e '1ioo n
`l'lypoin~1,inse ~ mo 11olumeJ,
`
`22.567
`
`4,!.2447
`
`Petitioner TWi Pharms., Inc.
`EX1026, Page 5 of 6
`
`

`

`1756 Current Opinion in tnvestigatlonat Drugs 2001 Vol 2 No 12
`
`Associated patent
`
`Title Use of substituted adenine derivatives for treating multiple sclerosis.
`
`Asalgnee Scripps Research Institute
`
`Publication WO-09316706 01-SEP-93
`
`Priority US-00838546 19-FEB-92
`
`Inventor Beutler E.
`
`Associated references
`
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`
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`BLOOD1983624 737-743
`
`65313 Antlleukemlc and lmmunosuppresslve activity of 2-chloro-2'·
`deoxyadenoslne. Carson DA, Wasson DB, Beutler E PROC NA TL ACAD
`SCI USA 1984 81 7 2232-2236
`
`105448 On the pharmacoklnetlcs of 2-chloro-2'-deoxyadenosine In
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`78 10 2583-2587
`
`392111 IVAX to develop new drug for muhiple sclerosis IVAX licenses
`from The Scripps
`cladrlblne,
`In advanced ctlnlcal development,
`Research Institute. IV AX Corp PRESS RELEASE 2000 December 04
`
`420751 us Speclalty Pharmaceuticals: Monthly Dose • May. MERRIL
`LYNCH CAPITAL MARKETS 2001 May
`• This report contains financial analysis and pipeline information for Allergan,
`Andrx, Forest Laboratories, IV AX, SangStat, Sepracor and Watson.
`
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`Sormani MP, Comi G NEUROLOGY200055111714-1418
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`
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`• Phase Ill trial of cladribine in chronic MS.
`
`423894 Safety and tolerablllty of subcutaneous cladrlblne therapy in
`progressive multiple sclerosis. Selby R, Brandwein J, O'Connor P CAN J
`NEUROL SCI 1998 25 295-299
`
`122098 On the bloavalabRlty of oral and subculaneous 2-c~•(cid:173)
`deoxyadenoslne in humans: Alternative routes of administration. Liliemark J,
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`
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`
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`
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`
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`
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`of
`Effect
`241271
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`
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`EXP199442111-12
`
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`344 8914~13
`• Phase II trial on cladribine in chronic progressive MS.
`
`241296 Marrow suppression produced by repeated doses of cladriblne.
`Beutler E, Koziol JA, McMillan R, Sipe JC, Romine JS, Carrera JS ACTA
`HAEMATOL 1994 91 1 10-15
`
`309586 In Brief. FDC REPORTS PINK SHEET 1998 60 49
`
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`
`337358 ClinCon monhortng of Lotrlslne and Floxln Otlc studies
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`
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`by monthly pulses of chlorambucll: studies In patients with chronic
`progressive multiple sclerosis. Chiapelli F, Myers L, Ellison GW, Liao D,
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`
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`
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`
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