ADIS DRUG EVALUATION
`
`BioDrugs 1998 May; 9 (5): 419-433
`1173-8804/98/0005-0419/$07.50/0
`
`© Adis International Limited. All rights reserved.
`
`Cladribine
`A Review of its Use in Multiple Sclerosis
`
`Heather D. Langtry and Harriet M. Lamb
`Adis International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`E. Beutler, The Scripps Research Institute, La Jolla, California, USA; M. Boggild, The Walton Centre for
`Neurology & Neurosurgery, NHS Trust, Liverpool, England; P. Grieb, Laboratory of Experimental
`Pharmacology, Polish Academy of Sciences Medical Research Centre, Warsaw, Poland; G. Konwalinka, Stem
`Cell Laboratory, Leopold-Franzenz-Universität, Universitätsklinik für Innere Medizin, Innsbruck, Austria;
`J. Liliemark, Department of Oncology, Karolinska Hospital, Stockholm, Sweden; E. McDonald, Multiple
`Sclerosis Society of Victoria, Toorak, Victoria, Australia; H. Panitch, Department of Neurology, Maryland
`Center for Multiple Sclerosis, Baltimore, Maryland, USA; B.J. Pleuvry, Department of Physiological Sciences,
`Neuropharmacology Research Group, University of Manchester, Manchester, England; M. Schirmer, Stem
`Cell Laboratory, Leopold-Franzenz-Universität, Universitätsklinik für Innere Medizin, Innsbruck, Austria.
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
`Summary
`1. Rationale for the Use of Cladribine in Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . 420
`2. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
`2.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
`2.1.1 Pharmacodynamic Effects and Mechanism of Action . . . . . . . . . . . . . . . . . . 421
`2.1.2 Effects in Patients with Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
`2.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
`2.2.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
`2.2.2 Metabolism and Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
`3. Therapeutic Potential in Multiple Sclerosis
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
`3.1 Effects on Neurological Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
`3.1.1 Chronic Progressive Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
`3.1.2 Relapsing-Remitting Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
`3.2 Effects on CNS Lesions and Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
`3.2.1 Chronic Progressive Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
`3.2.2 Relapsing-Remitting Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
`4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
`4.1 Haematological Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
`4.2 Fever, Neutropenia and Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
`4.3 Other Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
`4.4 Long Term Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
`5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
`6. Place of Cladribine in the Management of Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . 430
`
`Summary
`
`Cladribine is a deaminase-resistant deoxyadenosine analogue that selectively
`reduces lymphocyte counts. The drug is an effective therapy for selected haemato-
`logical malignancies and is being tested in patients with multiple sclerosis (MS),
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`Langtry & Lamb
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`in whom the antilymphocytic effects of the drug may reduce the autoimmune
`destruction of myelin.
`With activity against resting and dividing cells that express high deoxycytidine
`kinase activity, cladribine causes prolonged, profound suppression of lymphocyte
`counts. Subcutaneous cladribine is 100% bioavailable and has no local tissue
`toxicity. Dosages used in clinical trials in patients with MS are in the range of
`0.05 to 0.07 mg/kg/day subcutaneously for 5 days each month for 2 to 6 months.
`Temporary improvement or no change in neurological functioning and im-
`provements in CNS lesions detected by gadolinium-enhanced magnetic reso-
`nance imaging (MRI) have been seen after cladribine use in patients with chronic
`progressive (CPMS) and relapsing-remitting (RRMS) forms of MS. In a random-
`ised double-blind study of 24 pairs of patients, improvement or stabilisation of
`CPMS for » 2 years was observed in cladribine-treated patients, whereas the dis-
`ease progressed in placebo recipients. Another study of 159 patients found no
`progression in either the treated or placebo control group. In both studies, marked
`improvements were seen in gadolinium-enhanced CNS lesions. Cladribine-
`associated improvements in neurological functioning were also seen in some
`patients with RRMS in one study, which also noted a reduction in the frequency
`and severity of relapses. In this and a separate RRMS study, cladribine resulted
`in the regression of CNS lesions on MRI.
`Bone marrow suppression is the main dose-related toxicity; in patients with
`MS, use of low total cladribine dosages appears to limit myelosuppression. Al-
`though thrombocytopenia is of concern with higher-dose regimens (i.e. 2.8 mg/kg
`total dose) in patients with MS, granulocyte counts and haemoglobin levels ap-
`pear to be largely unaltered. Cladribine treatment is also associated with culture-
`negative fever and a risk of infections in patients with haematological malignan-
`cies.
`Conclusions: Further study of cladribine is needed to confirm present results
`in wider numbers of patients treated or followed up for longer durations, define
`optimum treatment and retreatment schedules for the drug and compare it with
`other agents. Nonetheless, cladribine therapy appears to have the potential to slow
`the progression of MS, reduce CNS lesions in patients with either the chronic
`progressive or relapsing-remitting forms of the disease and improve neurological
`functioning in some of these patients.
`
`1. Rationale for the Use of Cladribine in
`Multiple Sclerosis
`
`Multiple sclerosis (MS) is characterised by clin-
`ical signs and symptoms of CNS demyelination in-
`cluding optic neuritis, diplopia, muscle weakness,
`spasticity and eventual loss of ambulatory func-
`tion. The disease may have relapsing and remitting
`stages (RRMS) or can be chronic and progressive
`(CPMS).[1,2] However, progressive disease may
`occur without a relapsing-remitting stage (primary
`progressive) or may follow a relapsing-remitting
`stage (secondary progressive).[3] The disease is
`
`highly variable in its course, and although it causes
`considerable disability, it does not greatly reduce
`life expectancy, except in patients with severe dis-
`ability.[4]
`A diagnosis of MS must be based on symptoms
`characteristic of at least 2 CNS lesions. Tests that
`assist in diagnosis and evaluation of the progres-
`sion of MS include examination of the CSF for the
`presence of oligoclonal bands of IgG and magnetic
`resonance imaging (MRI) for CNS lesions.[5] Neu-
`rological impairment is often assessed using the
`Kurtzke extended disability status scale (EDSS),
`although the Scripps neurological rating scale
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`Cladribine in Multiple Sclerosis
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`(SNRS) and other similar tests have also been
`used.[2] For a more detailed description of the func-
`tions of these tests, see section 3 and the review by
`Waubant and Goodkin.[2]
`Cladribine (2-chloro-2¢ -deoxyadenosine) is an
`adenosine deaminase–resistant analogue of deoxy-
`adenosine. After phosphorylation to cladribine tri-
`phosphate within cells by the enzyme deoxycytid-
`ine kinase (dCK), it is incorporated into DNA,
`where it takes the place of adenosine triphosphate
`and effectively halts cell replication.[6] Phosphoryl-
`ated cladribine can be dephosphorylated (and
`therefore inactivated) by 5¢ -nucleotidase (5-NT).
`Of various cells of the body, lymphocytes are most
`subject to the effects of cladribine because they
`have a higher ratio of dCK to 5-NT than other cells.
`This and other mechanisms confer on cladribine
`specific antilymphocytic effects that are of clinical
`utility in the treatment of haematological malig-
`nancies (reviewed by Bryson & Sorkin[6]).
`Although MS is thought to be a lymphocyte-de-
`pendent autoimmune disease, the specific antigens
`and triggering agents involved in the disease are
`unknown, so treatments are nonspecific.[7] The ra-
`tionale for the use of cladribine in MS is that au-
`toantigen-specific T lymphocytes are thought to be
`activated peripherally before migrating to the
`CNS, where they mediate damage to myelin.[8]
`This suggests that a cladribine-induced reduction
`in the number of lymphocytes may help to slow
`progression of the disease. The efficacy of cladri-
`bine in the treatment of MS has been studied and
`the evidence relating to its potential use in this dis-
`ease is reviewed here.
`
`2. Pharmacology
`
`2.1 Pharmacodynamics
`
`2.1.1 Pharmacodynamic Effects and
`Mechanism of Action
`The major pharmacodynamic effects of cladri-
`bine are on blood cells and blood progenitor cells,
`which express high levels of dCK. dCK levels,
`which correlate with the degree of cladribine phos-
`phorylation, are high in normal leucocytes (120ng
`dCK/mg protein) and low in other tissues such as
`
`stomach mucosa (6 ng/mg).[9] Cladribine also
`markedly and dose-relatedly inhibits lymphocyte
`colony-forming and myeloid progenitor cells from
`normal human peripheral blood and bone marrow
`in vitro.[10] Bone marrow suppression is a dose-
`limiting adverse effect of cladribine (see section 4).
`Cladribine is active against both resting and di-
`viding cells; therefore, at least 2 mechanisms are
`thought to be involved in its activity.
`In dividing cells, cladribine is believed to be
`incorporated into DNA in its triphosphate form af-
`ter phosphorylation by dCK. Cladribine appears in
`much higher concentrations within blood cells than
`in blood plasma (see section 2.2.1) and its cyto-
`toxic effects on leukaemic cells correlate with the
`efficiency of its transport across the cell mem-
`brane.[11] Within cells, it is phosphorylated by dCK
`and dephosphorylated by 5-NT; thus, it is not sur-
`prising that hairy cell leukaemia (HCL) and
`chronic lymphocytic leukaemia (CLL) cells from
`patients with leukaemia who responded to cladri-
`bine exhibited higher dCK (p < 0.01) and lower
`5-NT (p < 0.05) levels than those from non-
`responders.[12] Cladribine is resistant to adenosine
`deaminase, so phosphorylated forms of the drug
`accumulate within cells; 80% of a radiolabelled
`dose was identified as cladribine monophosphate
`and 10% as the triphosphate in human tonsillar
`lymphocytes in vitro.[13] Incorporation of cladri-
`bine triphosphate into the DNA of dividing cells
`appears to arrest cell division.[6]
`In resting cells, cladribine is believed to induce
`apoptosis, or programmed cell death. DNA frag-
`mentation is known to occur in a dose-related man-
`ner when cells from patients with CLL are exposed
`to cladribine in vitro.[14] Cladribine also appears to
`induce expression of the p53 protein and its down-
`stream target WAF1/CIP1 protein, which have
`been implicated in the apoptosis response to DNA
`damage.[15] Apoptosis has also been measured in
`peripheral blood cells from 3 patients with HCL
`before and after intravenous cladribine (0.09
`mg/kg/day infused for 7 days),[16] rising from 2 to
`3.4% at baseline to 20 to 32% after 5 to 14 days.
`
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`Langtry & Lamb
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`Table I. Effects of cladribine (CdA) on blood cell counts in patients with multiple sclerosis of the chronic progressive (CPMS) or
`relapsing-remitting (RRMS) forms
`
`Parameter
`
`Dosage
`
`Scripps IV CPMS
`(n = 29; 30mo
`observation)[19-21]
`CdA 0.087-0.1 mg/kg/day IV ·
`7 days q1mo · 4mo
`
`Scripps SC RRMS
`(n = ?; 10mo
`observation)[20]
`CdA 0.07 mg/kg/day SC ·
`5 days q1mo · 6mo
`
`Lymphocytes
`
`Prolonged profound
`lymphopenia (especially of
`CD4+ cells) affecting both T
`(CD3+) and B (CD19+) cells;
`decreased CD4+/CD8+ ratio
`
`Prolonged profound
`lymphopenia
`
`Monocytes
`
`Granulocytes
`
`Acute transient
`monocytopenia
`Modest decrease
`
`?
`
`?
`
`Haemoglobin
`Cell size
`
`Modest decrease
`Prolonged macrocytosis
`
`Modest decrease
`No macrocytosis
`
`Platelets
`
`Variable platelet counts, no
`major change from
`baseline at 10mo
`
`Polish SC or PO RRMS
`(n = 11; 18mo
`observation)[22]
`CdA 5 mg/day SC or 10
`mg/day PO · 5 days q1mo ·
`6mo, plus 1 or 2 additional
`courses at 3mo or 6mo
`intervals in some patients
`Prolonged and profound
`decrease (from » 2.5 · 109 to
`1 · 109 cells/L), no
`correlation between
`decrease at 6mo and CdA
`dosage
`?
`
`Little mean change (small
`decrease at 18mo)
`No change
`Slight macrocytosis in ‘some
`patients’, change in average
`MCV NS except at 18mo
`Decrease, but none <100 ·
`109 cells/L
`
`Polish SC RRMS
`(n = 90; » 18mo
`observation)[23]
`CdA 5mg od SC · 5 days
`q1mo · 6mo; then 5mg od ·
`5 day 3mo later
`
`Decrease to one-third of
`original counts
`
`?
`
`‘Not reduced significantly’
`
`?
`‘Some macrocytosis’
`
`‘Mild’ thrombocytopenia ‘of
`no clinical significance’
`
`Sharp decrease in counts for
`6mo, nadir at 8mo, counts
`were <100 · 109 cells/L in 7 of
`29 patients (24%)
`Abbreviations and symbol: IV = intravenous; MCV = mean corpuscular volume; NS = not statistically significant; od = once daily; PO = oral;
`q1mo = every month; SC = subcutaneous; ? = not reported.
`
`Additional in vitro effects that may contribute
`to the mechanisms of action of cladribine include
`modification of the activity of DNA polymer-
`ase[17,18] and ribonucleotide reductase[18] and in-
`duction of dCK activity.[13] For further discussion
`of the mechanism of activity of cladribine, see the
`review by Bryson and Sorkin.[6]
`
`2.1.2 Effects in Patients with Multiple Sclerosis
`Cladribine has a clear profile of effects on lym-
`phocytes and other blood cell counts in patients
`with MS (table I).
`A marked and sustained reduction in lympho-
`cyte counts appears to occur regardless of the total
`cladribine dose, type of MS or route of drug admin-
`istration. In 4 trials (1 in patients with CPMS and
`3 in patients with RRMS),[20-23] subcutaneous, oral
`or intravenous cladribine use was associated with
`reductions in lymphocyte counts to »1 ·
` 109 cells/L
`or to at least one-half and up to one-third of base-
`
`line counts, and these reductions lasted throughout
`the 10- to 30-month observation periods.
`Effects of cladribine on other haematological
`parameters (e.g. platelet counts, cell size) appear to
`be related to the total dose and/or exposure period.
`They are greatest in patients with CPMS who re-
`ceived total doses of 2.8 mg/kg as 7-day intra-
`venous courses (table I).[20-22] The lesser effects
`seen in studies of patients with RRMS are not
`thought to be related to the disease type or the route
`of administration, but to the lower dosages (0.07
`mg/kg or 5mg once daily subcutaneously or 10mg
`once daily orally) and the shorter courses (5 vs 7
`days) adopted in the RRMS trials. Indeed, although
`thrombocytopenia and prolonged macrocytosis oc-
`curred with the higher total dose (2.8 mg/kg) in the
`patients with CPMS, only modest effects on plate-
`let counts and cell size were observed in patients
`with RRMS receiving lower total doses (2.1
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`Cladribine in Multiple Sclerosis
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`423
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`mg/kg) or lower daily dosages for shorter courses
`(5mg subcutaneously or 10mg orally for 5 days).
`Little or no effect was seen on mean granulocyte
`counts or mean haemoglobin levels in these studies
`(table I). Monocytopenia was reported in the intra-
`venous study, but was not discussed in reports of
`the other trials. For a discussion of other adverse
`effects of cladribine, see section 4.
`
`2.2 Pharmacokinetics
`
`As yet, no pharmacokinetic studies of cladri-
`bine have been conducted in patients with MS, but
`the kinetics of the drug are well studied in patients
`with haematological malignancies and solid tu-
`mours. Most of the pharmacokinetic research has
`been conducted in Sweden, and the kinetics of
`cladribine have been reviewed recently by Liliem-
`ark.[24] An overview of cladribine pharmacokinet-
`ics based on the review of Liliemark is presented
`in table II.
`The only commercially available form of
`cladribine is an intravenous injectable solution (1
`
`Table II. Overview of cladribine pharmacokinetic parameters in
`adult patients with haematological malignancies (data from the
`review by Liliemark[24] unless otherwise noted)
`
`mg/ml in normal sodium chloride and phosphate
`buffer),[26,27] but the kinetics of the drug have been
`tested after intravenous, oral, subcutaneous and
`rectal administration. Other solutions have been
`prepared for subcutaneous administration (buf-
`fered 2.5 mg/ml at pH 7.4) or oral use (isotonic 1
`mg/ml),[22] and the drug has been formulated into
`enteric-coated capsules for oral testing.[28] Al-
`though the kinetics of the drug after oral and rectal
`administration have been examined in patients
`with malignancies[24] and the oral drug has been
`tested in clinical trials of patients with MS,[22] bio-
`availability of these 2 forms is low (£51% oral;
`»20% rectal) and variable, so their use in patients
`with MS is not generally recommended (see sec-
`tion 5). Also, although originally used as a contin-
`uous 24-hour intravenous infusion, intravenous
`cladribine is now usually administered to patients
`with MS as 2-hour infusions once daily or as sub-
`cutaneous injections; these regimens/routes appear
`to result in pharmacokinetics and efficacy similar
`to those seen with use of the intravenous route.[24]
`
`2.2.1 Absorption and Distribution
`Having no local tissue toxicity and 100% bio-
`availability, cladribine is suitable for administra-
`tion as a subcutaneous injection.[24] Variability in
`the area under the plasma concentration-time curve
`(AUC) is high between individuals, but is similar
`after oral and intravenous administration (coeffi-
`cient of variation 38 vs 36%).[24] Oral cladribine
`has low (37 to 51%) bioavailability. Food slowed
`and reduced oral absorption of cladribine. Al-
`though cladribine is unstable at low pH, oral bio-
`availability was not substantially increased by rais-
`ing stomach pH with omeprazole.[24]
`Cladribine has a short distribution half-life of 8
`to 11.9 hours and is widely distributed in the body
`cells, with a steady-state volume of distribution of
`up to 368 L/m2. Concentrations of the drug and its
`nucleotides within cells are several hundred times
`higher than concentrations of the parent drug in
`plasma, but cannot be predicted by plasma concen-
`trations. Cladribine and its metabolites are also re-
`tained in leukaemic cells, with a half-life of up to
`30 hours, making the drug suitable for intermittent
`
`SC
`100
`268 after
`0.12 mg/kg
`
`PO
`37-51
`165 after 0.24
`mg/kg
`
`Route
`IV
`
`142 after 2h
`0.12 mg/kg
`infusion
`8-11.9
`0.7-1.5
`5.7-13.4
`54-368
`26-45
`0.25
`
`Parameter
`
`F (%)
`Cmax (nmol/L)
`
`t1⁄2a (min)
`t1⁄2b (h)
`t1⁄2g (h)
`Vss (L/m2)
`CL (L/h/m2)
`CSF : plasma
`concentration
`ratio
`PB (%)[25]
`
`Patients with haematological malignancies: 25
`Healthy volunteers: 21.1
`Human serum albumin in vitro: 24.3
`Abbreviations: CL = clearance; Cmax = peak plasma concentration;
`F = bioavailability; IV = intravenous; PB = plasma protein binding;
`PO = oral; SC = subcutaneous; t1⁄2a = distribution half-life;
`t1⁄2b = elimination half-life; t1⁄2g = terminal elimination half-life;
`Vss = volume of distribution at steady-state.
`
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`424
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`Langtry & Lamb
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`rather than continuous administration. Cladribine
`also distributes to the CSF, and although concen-
`trations are lower there than in the plasma, the time
`course of CSF pharmacokinetics is roughly similar
`to that in plasma.[24]
`
`2.2.2 Metabolism and Excretion
`Much of an orally administered dose may be
`deglycosylated to chloroadenine before absorp-
`tion, resulting in the lower systemic availability of
`oral than intravenous cladribine.[29] Chloroadenine
`is a major inactive catabolite of cladribine; its AUC
`is similar to that of cladribine after intravenous ad-
`ministration of 5 mg/m2 (530 vs 508 nmol/L • h),
`but it has a 4.4-fold greater AUC than cladribine af-
`ter oral administration (1863 vs 423 nmol/L • h).[29]
`Renal clearance is 51% of total systemic clear-
`ance of cladribine.[24] 21 to 32% of an intra-
`venously administered cladribine dose was ex-
`creted in the urine within 24 hours as unchanged
`drug[24] and <10% was excreted as chloroaden-
`ine.[24,29]
`There are no data on the pharmacokinetics of
`cladribine in patients with impaired renal or he-
`patic function.
`
`3. Therapeutic Potential in
`Multiple Sclerosis
`
`The results of 2 pilot studies suggested that pa-
`tients with CPMS[30,31] and RRMS[32,33] might ben-
`efit from cladribine treatment and that benefits may
`be due to immunological mechanisms. In 4 patients
`with clinically or laboratory-supported definite
`CPMS of ‡ 2 years’ duration, cladribine 0.087
`mg/kg/day intravenously for 7 days once a month
`for 6 months (total cumulative dose 3.7 mg/kg) re-
`sulted in reported improvements in clinical mani-
`festations of the disease (assessed using the SNRS)
`and the disappearance of oligoclonal bands from
`the CSF.[30,31] In 10 patients with RRMS and
`‘seemingly irreversible clinical deficits’ on the
`EDSS, cladribine 5 mg/day subcutaneously or 10
`mg/day orally was administered for 5 days once
`monthly for 6 months followed by 2 additional
`courses at 3-month intervals.[32,33] The number of
`relapses was unchanged in 3 patients and reduced
`
`markedly in the other 7, and EDSS scores de-
`creased from a mean of 4.3 at baseline to 2.4 after
`15 months’ observation before gradually returning
`to baseline by 24 months.[33]
`None of the published reports of studies exam-
`ined in this review differentiated between patients
`with primary progressive or secondary progressive
`forms of CPMS. To the extent that it is known, this
`information should be provided in reports of future
`clinical trials.
`Additional and longer term trials examined dif-
`ferent cladribine dosage schedules versus placebo
`in patients with confirmed CPMS or RRMS (see
`table III for study design details), and one retreat-
`ment study is also under way (results unavailable).
`Major study end-points were neurological func-
`tioning, MRI evidence of CNS lesions and clinical
`relapse. For effects of cladribine on haematological
`end-points, see section 2.1.2.
`The EDSS and SNRS are semiquantitative
`scales that were used to test neurological function-
`ing. In general, higher SNRS and lower EDSS
`scores indicate better functioning. EDSS and
`SNRS scores may not correlate in individual pa-
`tients.[39] The SNRS tends to show more gradual
`changes in disease course, and in a sample of 48
`patients with CPMS it was nearly normally distrib-
`uted about a mean of »70. The EDSS shows more
`abrupt changes, and, in the same sample of pa-
`tients, exhibited bimodal distribution with modes
`of 3.5 and 6 to 6.5.[39] MRI techniques can deter-
`mine the extent of MS lesions in the CNS and the
`frequency of new disease activity, both of which
`assist prediction of the clinical course of the dis-
`ease.[40] In particular, gadolinium-enhanced MRI,
`which was used in studies examined in this review,
`may be up to 10 times more sensitive as a marker
`of disease activity than clinical data.[40] In clinical
`trials, however, effects of drugs used to treat MS
`may be seen on MRI where no change may be seen
`in clinical findings.[41] Thus, once it has been used
`to show the effects of agents in pilot studies, MRI
`is best kept for use only as a secondary end-point
`in controlled clinical trials.
`
` Adis International Limited. All rights reserved.
`
`BioDrugs 1998 May; 9 (5)
`
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`
`(cid:211)
`

`

`Cladribine in Multiple Sclerosis
`
`425
`
`Table III. Design of cladribine (CdA) clinical trials in patients with multiple sclerosis
`
`Trial and reference No. of
`patients
`
`Study design
`
`Drug and dosage
`
`Duration
`of study
`
`End-points
`
`Comments
`
`Chronic progressive multiple sclerosis (CPMS)
`CdA 0.087 mg/kg/day IV · 7 days
`Scripps pilot[30,34]
` 4
`nr, nb, nc
`q1mo · 6mo
`
`Scripps 2-year
`CPMS[19,20,35]
`
` 51
`
`r, db, pc, coa
`then 6mo nb;
`patients in initial
`PL vs CdA
`groups matched
`for disease
`severity
`
`Scripps CPMS
`retreatment[34]
`Multicentre North
`American
`CPMS[34,36]
`
`?
`
`‡ sb
`
`159
`
`r, pc, pg, db
`
`Relapsing-remitting multiple sclerosis (RRMS)
`Polish RRMS
` 10
`nr, nb
`pilot[32,33]
`
`Initial cladribine group: CdA 0.1
`mg/kg/day IV · 7 days q1mo · 4mo in
`year 1 then PL in year 2
`OR
`Initial placebo: PL in year 1 then CdA
`0.1 mg/kg/day IV · 7 days q1mo ·
`1mo, then 0.05 mg/kg/day IV · 7
`days q1mo · 2mo in year 2a
`CdA 0.05 mg/kg/day SC · 5 days
`q1mo · 4mo
`CdA 0.07 mg/kg/day SC · 5 days
`q1mo · 2mo (total dose 0.7 mg/kg)
`OR CdA 0.07 mg/kg/day SC · 5 days
`q1mo · 6mo (total dose 2.1 mg/kg)
`OR PL
`
`CdA 5mg SC · 5 days q1mo · 6
`courses
`OR CdA 10mg PO · 5 days q1mo · 6
`courses, then 2 further courses at
`3mo intervals
`
`Polish double-blind
`RRMS[23,32,37]
`
` 90
`
`r, db, pg
`
`CdA 5mg SC · 5 days q1mo · 6mo;
`plus 1 further course 3mo later
`OR PL
`CdA 0.07 mg/kg/day SC · 5 days
`q1mo · 6mo
`OR PL
`
`6mo
`
`2.5y
`
`Clinical
`manifestations
`CSF IgG
`EDSS
`SNRS
`MRI
`
`?
`
`1y
`
`2y
`
`?
`
`EDSS
`SNRS
`MRI
`
`EDSS
`Relapse rate
`MRI
`
`30mo
`
`EDSS
`Relapse rate
`
`6mo-20y illness
`duration at entry;
`also examined
`haematology
`(Beutler et al.;[20,21]
`see section 2.1.2)
`
`Study is ongoing
`
`Full final results not
`published
`
`Mean 1.8 relapses
`per year at entry;
`also examined
`haematology (Grieb
`et al.;[22] see section
`2.1.2)
`Study is ongoing;
`final results not
`published
`
`2y
`
`Scripps 2-year
`RRMS[38]
`
` 50
`
`r, db, pg
`
`EDSS
`SNRS
`MRI
`Relapse rate
`a Crossover took place after 1 year; patients receiving cladribine in year 2 (initial placebo group) were given a lower total dose
`(1.4 mg/kg) than those receiving it in year 1 (2.8 mg/kg, initial cladribine group).
`Abbreviations: co = crossover; db = double-blind; EDSS = Kurtzke extended disability status scale; IV = intravenous; MRI = magnetic
`resonance imaging; nb = nonblind; nc = noncomparative; nr = nonrandomised; pc = placebo-controlled; pg = parallel group; PL = placebo;
`PO = oral; qxmo = every x months; r = randomised; SC = subcutaneous; SNRS = Scripps neurological rating scale; ‡ sb = at least single-blind
`(details of blinding not reported).
`
`Guidelines for the design of studies of MS ther-
`apies recommend placebo controls, randomisation,
`investigator blinding and controls for or consider-
`ation of the severity of disability, type and duration
`of disease and adequate study size and duration.[42]
`Investigator blinding is an important design mea-
`sure, since nonblind evaluation of EDSS and other
`neurological function tests is a known source of
`bias in studies.[40] Considerations for study dura-
`
`tion and sample size must account for the slow pro-
`gression or remitting nature of the disease. Studies
`in patients with CPMS must be of sufficient dura-
`tion to show a deterioration of function in untreated
`patients, and randomised studies must enrol a large
`enough number of patients to be able to detect a
`difference between treatments.[40] Detection of dif-
`ferences in neurological function, in particular,
`may be complicated by the fact that the most
`
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`
`BioDrugs 1998 May; 9 (5)
`
`Petitioner TWi Pharms., Inc.
`EX1018, Page 7 of 15
`
`(cid:211)
`

`

`426
`
`Langtry & Lamb
`
`widely used outcome measure, the EDSS, is not
`particularly sensitive to minor changes in disease
`severity.[40]
`Published information about the design of com-
`parative cladribine clinical trials suggests that most
`had appropriate study designs, despite the lack of
`detail about some trials (design details have been
`published in full only for the Scripps 2-year CPMS
`study).[19,20,35] Although pilot studies were non-
`blind, nonrandomised and of short duration, all
`comparative trials used randomisation, placebo
`control and both investigator and patient blinding.
`Most studies followed patients for at least 2 years
`and appeared to have enrolled adequate numbers of
`patients (although some studies are still ongoing).
`However, the North American multicentre study
`may have enrolled too few patients and/or followed
`patients for too short a duration (see section 6).
`
`3.1 Effects on Neurological Function
`
`3.1.1 Chronic Progressive Multiple Sclerosis
`A clear effect of cladribine on neurological
`functioning was seen in the Scripps 2-year CPMS
`study in 48 patients matched for disease sever-
`ity,[19] but no effect was observed in the 1-year
`multicentre North American trial that randomised
`159 patients to receive cladribine or placebo.[36]
`For a discussion of the effects of methodologi-
`cal factors on the results of these studies, see sec-
`tion 6.
`In the Scripps 2-year CPMS study, cladribine
`produced modest improvements in EDSS and
`SNRS scores that were sustained for 18 to 24
`months, whereas placebo was associated with de-
`teriorating neurological functioning. In addition,
`both the time-to-improvement and time-to-failure
`(indicated by changes of 1 EDSS or 10 SNRS
`points) showed statistically significant benefits of
`cladribine.[19]
`EDSS scores in the group randomised to receive
`cladribine in the first year of study (initial cladrib-
`ine group) improved from 4.8 at baseline to 4.4 at
`13 months, with deterioration from baseline values
`occurring only after 18 months. In the group re-
`ceiving placebo in year 1 (initial placebo group),
`
`EDSS scores increased from 4.7 at baseline to 5.6
`at month 13; low-dose cladribine therapy begun in
`this group in month 13 produced an improvement
`that peaked at EDSS scores of 5.1 at month 19 be-
`fore function deteriorated again.[19] Changes in
`EDSS from baseline in both patient groups are
`shown in figure 1a.
`SNRS scores (fig. 1b) showed more sustained
`improvements with cladribine than were seen in
`EDSS scores in the 2-year Scripps CPMS study. A
`score of 69.6 at baseline increased to a peak of 75.7
`at 18 months in the initial cladribine group and did
`not return to baseline until 30 months. However, in
`the initial placebo group, SNRS scores decreased
`from 68.3 to 62.1 at 12 months, then increased after
`the introduction of cladribine to 70.8 at month 19,
`after which they began a gradual decline.[19]
`Investigators in the Scripps 2-year CPMS study
`also noted a less durable therapeutic effect of the
`better-tolerated lower total dose of 1.4 mg/kg than
`of the higher 2.8 mg/kg dose.[19] However, al-
`though there was only a minor 1.292 point differ-
`ence in SNRS scores at the start of cladribine ther-
`apy, EDSS scores had already deteriorated by
`0.7292 points when the initial placebo group began
`the lower cladribine dose in the second year of the
`study. Thus, without a direct comparison control-
`ling for disease severity at the time of drug initia-
`tion, it is difficult to know if differences in durabil-
`ity of therapeutic effects are solely a sign of a
`dose-response relationship or may be attributable
`to disease factors.
`It is also interesting that the improvem