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`
`Hopewell EX1015
`
`1
`
`

`

`1752 Current Opinionin Investigational Drugs 2001 Vol 2 No 12
`
`Pharmacology
`Cladribine, like other antimetabolite cytotoxic drugs such as
`pentostatin (Pfizer
`Inc),
`fludarabine
`(Southern Research
`Institute/Schering AG) and cyatarabine, are prodrugs requiring
`phosphorylation to becomebiologically 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 deaminates 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 quiescentcells
`[17808], [64003].
`
`such as
`in cells,
`Cladribine activity is very efficient
`levels
`of
`high
`lymphocytes
`and monocytes, with
`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 CD8+ T-
`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 factorfor cell apoptosis [17808].
`
`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.
`
`Twodifferent cladribine formulations have been used in MS
`studies: a 1 mg/ml formulation was used in the double-
`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 dose 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 somaticcells. 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-
`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
`Metabolism
`cladribine/day for 7 days. The typical hematologic response
`The bioavailability of orally administered cladribine ranges
`consisted of an acute transient monocytopenia, a prolonged
`from 37 to 51%, while that of subcutaneous (sc) preparations
`and severe lymphopenia (mainly affecting CD4+ cells), and
`is 100%. [122098], [423910]. As a consequence, a double dose
`a modest
`lowering of granulocytes and hemoglobin,
`of orally administered cladribine can substitute for a sc
`followed by a long-lasting macrocytosis. Two patients
`injection, which, in turn, results in a high peak concentration
`developed
`severe
`aplastic
`anemia, which
`required
`of short duration, with an area underthe curve identical to
`transfusion. One of these patients, however, had previously
`that obtained for intravenous (iv) administration [122098].
`received chlorambucil, while the other had previously
`Following the sc administration of a single dose,
`the
`received carbamazepine and was
`receiving phenytoin
`
`absorption of rapid and_peak-plasmacladribine is
`
`
`during cladribine therapy [241296].
`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 h and the apparent volumeof distribution ranges
`from 54 to 357 1/m/ [105448], [423910].
`
`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 somewhatgreater 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
`MSpatients by Selby et al [423894], who did not report any
`significant myelosuppression or
`infections, despite the
`
`In MSpatients, 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
`
`2
`
`

`

`3==x9<
`
`Pa
`Ee
`
`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 corticosteroids and purine analogs
`has been associated with an increased risk of opportunistic
`infections [423912]. Further studies are needed to establish
`whether cladribine is safe when used with or soon after
`other immunomodulating or immunosuppressive therapies,
`such
`as
`f-interferon,
`glatiramer
`acetate
`(Teva
`Pharmaceutical
`Industries Ltd), mitoxantrone (Immunex
`Corp), azathioprine or cyclophosphamide.
`
`PhaseIl
`Two randomized, double-blind, placebo-controlled, phase II
`trials have been conducted to evaluate the efficacy and safety
`of cladribine 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 wasthe proportion of subjects with
`contrast-enhancing lesions on magnetic resonance imaging
`(MRI)
`scans obtained during the double-blind phase.
`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 T2-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.
`
`lasted for two years,
`The MS-Scripps double-blind trial
`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 cladribine 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, subjects 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-
`enhanced MRI activity and slowing the increase in T2-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 III trial
`and might be, in part, due to a type I (false positive) error.
`This is suggested by the following characteristics of the MS-
`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.
`
`Cladribine Tortorella et a/ 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 wasstill 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-
`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 consideredit
`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.
`
`PhaseIll
`A multicenter, randomized, double-blind, parallel-group,
`placebo-controlled phase III 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 weresimilar 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 T1-
`hypointense lesion load [422567]. These two MRI-derived
`parameters
`are
`considered markers
`of MS-related
`irreversible tissue loss [423916], [423918].
`
`Nosignificant 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-
`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 volumeof contrast-enhanced
`lesions, which were on average 90% lower at months 6 and
`12 of the double-blind phase. T2-lesion load modestly
`improved in treated patients and worsened in placebo
`
`3
`
`

`

`1754 Current Opinion in Investigational 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-
`blind phase. This wasalso the case for SPMSpatients during
`the first year of the study extension phase. No significant
`treatmenteffect of either dose of cladribine on brain volume
`or T1l-hypointense lesion load changes over time was
`observed [422447], [422567].
`
`The discrepancy between the lack of effect of cladribine on
`MSdisability 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 treatmentis
`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
`lymphocytotoxicity 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 III 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 immunomodulating or immunosuppressive drugs that
`have been approved for the treatment of RR and SPMS,such
`as B-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 phase 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 SPMSpatients.
`
`Considering that conflicting results have been obtained as
`regards the efficacy of B-interferon in SPMS [423922], [423925]
`and that the use of mitoxantroneis limited by its cardiotoxicity
`[423939], the results of available studies suggest that a further
`assessment of cladribine efficacy in selected subgroups of
`patients, such as those with SPMS or rapidly deteriorating
`RRMS, could prove useful. The known immunosuppressive
`action of cladribine also makes it a potential rescue therapy for
`MS patients whoare unresponsiveto other first-line treatments.
`Finally, the possibility of combination treatments of cladribine
`and other immunomodulating drugs also deserves further
`consideration.
`
`Licensing
`IVAX Corp
`In December 2000, IVAX 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 separate
`agreementrelating to cladribine [224373].
`
`Developmenthistory
`Devel
`Orthe Biotech Inc
`
`Scripps Research
`
`IVAX Gorp
`
`Coun
`US.
`
`us
`
`us
`
`Status
`C3
`
`C3
`
`Indication
`MS
`
`MS
`
`MS
`
`Date
`01-DEC-95
`
`01-APR-99
`
`O1-MAY-01
`
`Reference
`172942
`
`337356
`
`420751
`
`Literature classifications
`Biology
`Reference
`Result
`ntal Model
`Effect Studied
`Stu
`
`
`
`in vitro Selective toxicity of cladribine on both=©664003Growth inhibition. Non-divicing and proliferating human
`lymphocytes.
`dividing and resting lymphocytes.
`
`In vive
`
`Antileukemic and
`immunosuppressive
`activity.
`
`Patients with a T-cell leukemia
`lymphoma and chronic myelogenous
`leukemia in blast crisis.
`
`Cladribine lowered blast count in
`leukemic patients and terminated
`hemolytic process in a patient with
`severe autoimmune hemolytic anemia.
`
`65313
`
`4
`
`

`

`Biology (continued)
`Study T
`Effect Studied
`In vitra
`Effect on clonal
`growth.
`
`In-vive
`
`Toxicity.
`
`rimental Model
`Myeloid progenitors and T-
`lymphocyte colony-forming cells
`from normal human bone marrow
`and peripheral blood.
`
`NormalbonemarrowfromMS
`
`patients.
`
`Claaribine lortorelia ef af 1755
`
`Result
`Marked inhibition of myeloid progenitor
`and lymphecyte colony forming cells in
`a dose-dependent manner.
`
`Acuteandtransientmonocytopenia,
`
`prolonged, profound lymphopenia
`especially of COd+ cells, modest
`lowering of granulocyte count and
`hemoglobin.
`
`Reference
`106552
`
`241206
`
`=
`=
`L
`be
`-
`|
`
`
`
`
`
`.
`
`i
`cae
`=
`_ .
`
`In vive
`
`Lymphaoyle count.
`
`Lymphocytes from MS patients.
`
`Longasting 4-fold reduction in CD44
`to CD8+ T-cell ratio.
`
`429894
`
`Metabolism
`@
`
`in vivo
`
`in vive
`
`Effect Studied
`Pharmacokinetics:
`rates of
`administration.
`Pharmacokinetics,
`
`ental Model
`Ex
`High-performance liquid
`chromatography.
`
`High-pertormance liquid
`chromatography.
`
`Results
`Oral bioavailability 37 to 51%;
`subcutaneous biovailability 100%.
`
`Reference
`122098
`
`Lo= 57 to 18.7 h,
`Apparent volume of distribution = 54 to
`357 Wm",
`
`105448
`
`z
`2
`a
`a
`a |
`fo}
`a
`
`Clinical
`Effect Studied
`Toxlcity.
`
`Toxicity.
`
`tal Model
`Ex
`Cladribine 0,1 mg/kg/day as a 7-day
`continuous fv infusion every 26 to 35 daysin
`patients with previously untreated chronic
`lymphocytic leukemia,
`
`Results
`Myelosuppression was the primary toxicity,
`20% of patients daveloped grade IIL
`thrombocytopenia.
`
`Reference
`181788
`
`31% OF the patients sustained early toxicityand
`Cladribine 0.1 mg/kg/day as a 7-day
`continuous ty infusion for Sor? days every 28 most died before the first re-evaluation of
`days fora maximum of six cycles trial in
`infection; no nausea, vomiting, renal, hepatic or
`patients with either relapsed or refractory
`cardiac toxicity observed.
`chronic lymphocytic leukemia.
`
`181838
`
`Salety and efficacy in Double-blind, randomized, placabo- Cladribine (2.8 mg/kg lv) was effective on MAl=241294
`
`chronic progressive
`controlled, parallel group design.
`{T1-anhancing lesions, T24esion load) and
`MS patients.
`clinical endpoints (EDSS and Scripps scale
`scores), Bone marrow suppression was the
`main adverse event.
`
`Safety and efficacy in Double-blind, randomized, placebo-
`RA MS patients.
`controlled, parallel-group design.
`
`Gladnibine (2.1 mo/kg sc) was eifectiveon MRl
`(7 1-anhancing lesions) but not.on clinical
`endpoints (EDSS and SNAS scores). Mild
`segmental hares zoster was the only adverse
`event.
`
`422449
`
`Safety and efficacy in Double-blind, randomized, multicenter,
`chronic progressive
`placebo-controlied, parallel-group design.
`MS patients.
`
`Gladnibine (0.7 to 2.1 mg/kg Sc) was effective
`on MAI (T1-enhancing lesions, T24asion load),
`but not on dini¢al endpoints (EDSS and SNRS
`scores). The affect on T2easion load was dose-
`related as well as the treatment emergent
`gSle}
`adverse event
`
`Effects of cladribine=Double-blind, randomized, multicenter, No significant difference between placebo and 422567 ey
`
`onthe accumulation
`placebo-controlled, parallel-group design.
`treated ains, or when PP and SPMS patients
`iS
`of ‘black holes",
`were considered separately.
`a
`
`d22627
`
`
`
`Effects of cladribine
`on the changes in
`brain volurre,
`
`Double-blind, randomized, multicenter,
`placebo-contralled, parallel-group design.
`
`No significant difference between Placebo and
`treated arms. No correlation in the placebo
`group between brain atrophy and other MAI
`measure at baseline (enhancing lesion number
`and volume, T2-hyperintense and T1-
`hypointense lesion volume).
`
`422447
`
`5
`
`

`

`1756 Current Opinion in Investigational Drugs 2001 Vol 2 No 12
`
`Associated patent
`
`Titie Use of substituted adenine derivatives for treating multiple sclerosis.
`
`Assignee Scripps ResearchInstitute
`
`Publication WO-09316706 01-SEP-93
`
`Priority US-00838546 19-FEB-92
`
`Inventor Beutler E.
`
`Associated references
`
`17808 Cladribine (2-chlorodeoxyadenosine). Beutler E LANCET 1992 340
`8825 952-956
`e Review on drug profile of cladribine.
`
`64003 Specific toxicity of 2-chlorodeoxyadenosine toward resting and
`proliferating human lymphocytes. Carson DA, Wasson DB,Taetle R, YuA
`BLOOD 1983 62 4 737-743
`
`65313 Antileukemic and immunosuppressive activity of 2-chloro-2'-
`deoxyadenosine. Carson DA, Wasson DB, Beutler E PROC NATL ACAD
`SCI USA 1984 81 7 2232-2236
`
`105448 On the pharmacokinetics of 2-chloro-2'-deoxyadenosine in
`humans.Liliemark J, Juliusson G CANCER RES 1991 51 20 5570-5572
`
`106552 Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic,
`erythroid, and T-lymphocytic colony growth. Petzer AL, Bilgeri R, Zilian U,
`Haun M, Geisen FH, Pragnell |, Braunsteiner H, Konwalinka G BLOOD 1991
`78 10 2583-2587
`
`392111 IVAX to develop new drug for multiple sclerosis IVAX licenses
`cladribine,
`in advanced clinical development,
`from The Scripps
`ResearchInstitute. IVAX Corp PRESS RELEASE 2000 December04
`
`420751 US Specialty Pharmaceuticals: Monthly Dose - May. MEARIL
`LYNCH CAPITAL MARKETS 2001 May
`¢ This report contains financial analysis and pipeline information for Allergan,
`Andrx, Forest Laboratories, (VAX, SangStat, Sepracor and Watson.
`
`422447 Whole brain volume changes In patients with progressive MS
`treated with cladribine. Filippi M, Rovaris M,
`lannucci G, Mennea S,
`Sormani MP, Comi G NEUROLOGY2000 55 11 1714-1418
`e Ancillary phaseIil study for the evaluation of the effect of cladribine on brain
`atrophy.
`
`422449 Cladribine and progressive MS:clinical and MRI outcomesof a
`multicenter controlled trial. Cladribine MRI Study Group. Rice GP,Filippi
`M, Comi G NEUROLOGY2000 54 5 1145-1155
`¢ PhaseIf trial of cladribine in RRMS.
`
`‘black hole' changes in
`422567 The effect of cladribine on T(1)
`progressive MS.Filippi M, Rovaris M, Rice GP, Sormani MP, lannucci G,
`Giacomotti L, Comi G J NEUROL SC/ 2000 176 1 42-44
`e Ancillary phaseIII study for the evaluation of the effect of cladribine on the
`accumulation of T1-hypointenselesion.
`
`422627 A double-blind, placebo-controlled, randomized trial of cladribine in
`relapsing-remitting multiple sclerosis. Romine JS, Sipe JC, Koziol JA, Zyroff J,
`Beutler E PROC ASSOCIATION AM PHYSICIANS 1999 111 1 35-44
`e PhaseIif trial of cladribine in chronic MS.
`
`423894 Safety and tolerability of subcutaneous cladribine therapy in
`progressive multiple sclerosis. Selby R, Brandwein J, O'Connor P CAN J
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