Drugs (2020) 80:1901–1928
`https://doi.org/10.1007/s40265-020-01422-9
`
`REVIEW ARTICLE
`
`The Development of Cladribine Tablets for the Treatment of Multiple
`Sclerosis: A Comprehensive Review
`
`Kottil Rammohan1 · Patricia K. Coyle2 · Elke Sylvester3 · Andrew Galazka3 · Fernando Dangond4 · Megan Grosso5 ·
`Thomas P. Leist6
`
`Published online: 28 November 2020
`© The Author(s) 2020
`
`Abstract
`Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to
`the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the
`treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be
`delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the
`beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3
`and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the
`efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS),
`the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinat-
`ing event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were
`administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data,
`including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, includ-
`ing the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years
`have been approved across the globe for various forms of relapsing MS.
`
`1 Introduction
`
`Multiple sclerosis (MS) is a chronic, inflammatory, immune-
`mediated demyelinating and neurodegenerative disease of
`the central nervous system (CNS). It is one of the most
`
`Enhanced Digital Features To view enhanced digital features for
`this article, go to https ://doi.org/10.1007/s4026 5-020-01422 -9
`
` * Kottil Rammohan
`krammohan@med.miami.edu
`
`1 Multiple Sclerosis Center, University of Miami, Miami, FL,
`USA
`
`2 Multiple Sclerosis Comprehensive Care Center, Stony Brook
`University, Stony Brook, NY, USA
`
`3 Merck KGaA, Darmstadt, Germany
`
`4
`
`5
`
`EMD Serono Research & Development Institute, Inc.,
`Billerica, MA, USA, an affiliate of Merck KGaA, Darmstadt,
`Germany
`
`EMD Serono, Inc., Rockland, MA, USA, an affiliate
`of Merck KGaA, Darmstadt, Germany
`
`6 Comprehensive MS Center, Jefferson University,
`Philadelphia, PA, USA
`
`common causes of serious neurological disability in young
`adults, and one of the most prevalent neurological disor-
`ders in the world [1]. In 2016, the estimated global preva-
`lence of MS was 2.2 million, an increase of 10.4% from the
`age-standardized MS prevalence in 1990 [2]. Among the
`more than 2 million people with MS, more than 900,000 are
`thought to reside in the United States (US) [3]. About 85%
`of patients with MS present with relapsing–remitting MS
`(RRMS), which is characterized by periodic acute exacerba-
`tions of disease activity (relapses) punctuated by periods of
`clinical stability. Relapses may be associated with partial or
`complete recovery [4].
`MS is associated with poor health-related quality of
`life and can have a profound effect on social functioning,
`employment status, and healthcare costs [5, 6]. The mean
`age at onset of symptoms is 30 years, and approximately
`75% of patients are female [7]. Therefore, many patients
`are women of childbearing age, and MS can impact fam-
`ily planning due to risks associated with treatments that
`may affect pregnancy [8]. While there are no adequately
`controlled studies of disease-modifying drugs (DMDs) and
`pregnancy, there is a significant body of evidence on the
`safety of DMDs during pregnancy, generated primarily
`
`Vol.:(0123456789)
`
`Merck 2023
`TWi v Merck
`IPR2023-00049
`
`

`

`
`
`1902
`
`Key Points
`
`Multiple sclerosis (MS) is a neurodegenerative disease
`that affects more than 2 million people globally and
`is associated with poor quality of life. MS involves an
`aberrant immune system attacking the central nervous
`system, and disease-modifying drugs are thought to act
`by suppressing or modulating the immune system.
`
`Cladribine tablets are the first oral therapy with a short-
`course, limited cycle dosing schedule approved for
`patients with relapsing forms of MS (RMS). In clinical
`studies, cladribine tablets have demonstrated efficacy in
`patients across the RMS spectrum.
`
`The safety profile of cladribine tablets monotherapy at
`the recommended dosage of 3.5 mg/kg includes data
`from > 3700 patient-years of cladribine exposure at this
`dose, and from > 2200 patient-years of placebo expo-
`sure in clinical trials. The most common adverse events
`reported with cladribine tablets include headaches and
`lymphopenia. Additional adverse events examined
`include malignancy and infections.
`
`from clinical experience and pregnancy registries. Large
`interferon (IFN)-β registry studies have found no evidence
`for differences in infant size [9], congenital anomalies, or
`miscarriages [10], and recently updated IFN-β Summaries
`of Product Characteristics recommend to continue treat-
`ment during pregnancy and while breastfeeding if clinically
`needed [11, 12]. Glatiramer acetate is also generally consid-
`ered to be safe for use during pregnancy [13, 14]. However,
`the labels for the majority of DMDs for patients with MS
`either state to use ‘only if clearly needed’ [15], to avoid these
`therapies unless the benefits outweigh the risks [16–19], or
`not to use at all, and a washout period is recommended prior
`to pregnancy [20–26]. Longitudinal studies indicate that life
`expectancy is shorter for patients with MS compared with
`the general population (approximately 7 years shorter in a
`Norwegian population studied over a 60-year period) [27],
`but rising prevalence without parallel changes in incidence,
`and a shift in peak age towards older age groups, suggest
`that survival is improving (based on Canadian data col-
`lected over 2 decades) [28]. An aging MS population may
`be associated with significant disability; in a self-reporting
`postal survey conducted in a Canadian cohort of MS patients
`aged > 55 years who had been living with MS for a mean of
`approximately 33 years, 28% either required a wheelchair or
`were bedridden [29].
`Lymphocytes play a central role in the pathogenesis of
`MS, with the actions of both B and T cells in the periphery
`and in the CNS implicated from an early stage in the disease
`
`K. Rammohan et al.
`
`process. Immune cells activated in the periphery enter the
`CNS, facilitated by chemokines [30, 31]. Autoreactive T
`cells are present in acute CNS lesions in early MS [30, 32];
`their reaction to myelin protein-derived antigens [32] con-
`tributes to direct cytotoxic effects and stimulation of mac-
`rophages [31, 33]. B cells have a role in the proliferation and
`reactivation of T cells, acting as antigen-presenting cells,
`and fully differentiated B cells further contribute to demyeli-
`nation via the production of antibodies to myelin by plasma
`cells [30, 31, 33, 34]. Thus, the combined actions of T cells,
`B cells, and macrophages contribute to demyelination and
`axonal damage, triggering neurodegenerative processes from
`disease onset [30, 31]. Later in the course of the disease,
`chronic CNS inflammation drives ongoing neurodegenera-
`tion, possibly via neurotoxic inflammatory mediators pro-
`duced by activated microglia and astrocytes [32].
`Treatment options for relapsing forms of MS (RMS) com-
`prise a number of immunosuppressive and immunomodu-
`latory agents. The first DMD, IFN-β-1b, was approved by
`the US Food and Drug Administration (FDA) for RMS in
`1993 [19] and by the European Medicines Agency (EMA) in
`1995 [35]. Alternative forms of IFN-β (subcutaneous [SC]
`and intramuscular [IM] IFN-β-1a) and glatiramer acetate
`entered the market between 1996 and 2002, becoming stand-
`ard treatment over the ensuing years [36]. The introduction
`of natalizumab, a recombinant monoclonal antibody against
`cell adhesion molecule α4-integrin [23] (initially approved
`in 2004, withdrawn from the market, then reintroduced in
`2006 [37]), marked a shift in the treatment paradigm for MS
`[38]. While this molecule was perceived to be more effective
`than the IFNs and glatiramer acetate [39], it is associated
`with greater risks, including progressive multifocal leukoen-
`cephalopathy (PML), which is rare but carries significant
`morbidity and a mortality rate of approximately 23% [40].
`After a span of nearly 20 years of injectable therapies, oral
`DMDs became available. While patients have generally pre-
`ferred oral DMDs over injections when given the choice
`[41], most approved oral DMDs, including fingolimod, terif-
`lunomide, dimethyl fumarate and siponimod, require regular
`and ongoing dosing once- or twice-daily [20–22].
`More recently, therapies with different hypothesized
`mechanisms of action (MOA) that require less frequent dos-
`ing have become available. Ocrelizumab is an anti-CD20
`antibody, administered via intravenous (IV) infusion every
`6 months (after the initial dose, which is split across two
`infusions 2 weeks apart) [25, 42]. Alemtuzumab is an anti-
`CD52 antibody with an infrequent dosing regimen, involv-
`ing infusions over a course of 5 days in year 1, followed
`by 3 days in year 2, with further 3-day courses adminis-
`tered as needed thereafter, separated by intervals of at least
`12 months [24, 43]. Both antibodies are thought to deplete
`lymphocytes via cytolysis and complement-mediated lysis,
`with different profiles based on expression of their respective
`
`

`

`Development of Cladribine Tablets
`
`1903
`
`target antigens on B cells, T cells, and other immune cells
`[24, 25, 44–46].
`Cladribine tablets are the first oral therapy with an infre-
`quent dosing schedule, administered in two yearly treatment
`courses, each divided into two treatment cycles compris-
`ing 4–5 days of treatment [12, 26]. Cladribine tablets are
`thought to exert their clinical effects via a transient reduction
`of selective lymphocyte subtypes, followed by a recovery
`period during which cell numbers return to the normal range
`[47, 48]. While immune function is restored as cell num-
`bers recover, cell subtype ratios are thought to be altered,
`resulting in a reduction in autoreactive lymphocytes [47–49].
`Thus, a short dosing period is thought to achieve sustained
`effects on lymphocytes that persist for an extended period
`after the treatment period has ended.
`Cladribine tablets have been approved worldwide by
`many different regulatory authorities, including the EMA
`in 2017 [50] and the FDA in 2019 [51]. In this review, we
`provide an overview of the development of cladribine tablets
`as a therapy for patients with MS, from initial discovery and
`development of the molecule to its putative MOA in MS. We
`also review the pertinent efficacy data from clinical studies,
`and an integrated safety analysis of > 3700 patient-years’
`clinical trial experience with cladribine tablets monotherapy
`at the recommended dosage.
`
`1.1 Discovery and Development
`
`Cladribine (2-chlorodeoxyadenosine [2-CdA]) was first
`synthesized nearly 50 years ago [52] (Fig. 1). It is a syn-
`thetic purine nucleoside analog of deoxyadenosine that was
`developed to selectively target lymphocytes in lymphopro-
`liferative diseases (e.g. hairy cell leukemia) and autoimmune
`disorders [53–55]. The design of cladribine was inspired
`by the consequences of adenosine deaminase (ADA) defi-
`ciency in children [55, 56]. The selective vulnerability of
`lymphocytes in this autosomal recessive genetic disorder
`was described by Carson and colleagues as resulting from
`the preferential accumulation of cytotoxic deoxyadenosine
`nucleotides in lymphocytes, causing lymphocytopenia [54,
`57]. Based on this understanding, several nucleoside analogs
`were synthesized, including cladribine in the early 1970s
`[54, 58, 59]. Following the efficacy observed in lymphoid
`leukemias and the ability of cladribine to selectively target
`lymphocyte populations, the drug was considered for poten-
`tial use in MS [53].
`
`1.2 Mechanism of Action
`
`Cladribine (2-CdA) is a small molecule (molecular mass
`285.7  g/mol [60]) prodrug that is taken up by cells via
`nucleoside transporter proteins and becomes active in cer-
`tain cells upon phosphorylation to 2-chlorodeoxyadenosine
`
`triphosphate (2-Cd-ATP). 2-CdA undergoes sequential intra-
`cellular phosphorylation, first to 2-chlorodeoxyadenosine
`monophosphate (2-Cd-AMP) mediated by deoxycytidine
`kinase (DCK), and subsequently to 2-chlorodeoxyadenosine
`diphosphate (2-Cd-ADP) and 2-Cd-ATP by other kinases.
`De-phosphorylation by 5(cid:397)-nucleotidases (5(cid:397)-NTases) pre-
`vents accumulation of 2-Cd-ATP in most cells [31]. Phos-
`phorylation preferentially occurs in B and T lymphocytes
`due to their unique constitutively high DCK and relatively
`low 5(cid:397)-NTase levels, compared with other cell types. DCK
`is a rate-limiting enzyme in the nucleoside salvage path-
`way that provides deoxyribonucleosides (dNTPs). The high
`DCK level is thought to be important for lymphocyte clonal
`expansion during development and immune reactions [61,
`62]. Lymphocytes are therefore susceptible to accumulation
`of 2-Cd-ATP (Fig. 2). In cells where 2-Cd-ATP accumulates,
`it incorporates into deoxyribonucleic acid (DNA) strands,
`disrupting DNA synthesis and cell cycle progression, and
`inhibits enzymes involved in DNA synthesis, leading to cell
`death in both proliferating and quiescent lymphocytes [31,
`59, 63].
`While the precise mechanisms by which cladribine exerts
`its therapeutic effects in patients with MS is not known, its
`effects on B and T lymphocytes are thought to play a central
`role. Cladribine preferentially reduces cells of the adaptive
`immune system, while leaving the innate immune system
`relatively spared. Absolute lymphocyte counts (ALC) and
`B- and T-cell subset counts rapidly reach nadir following
`administration of cladribine tablets, and gradual lymphocyte
`count recovery begins soon after treatment and continues
`for months afterwards [64]. In the phase III CLARITY and
`CLARITY Extension studies [65, 66], median ALC reached
`nadir, at the lower limit of normal (LLN) at week 13, and
`was followed by recovery of cell counts back to the nor-
`mal range (Fig. 3). In year 2, median ALC fell below the
`LLN but recovered into the normal range by week 84, or
`approximately 30 weeks postdose after completion of the
`second treatment cycle in year 2. Reduction of CD19+ B
`cells in year 1 also reached nadir at about week 13 (below
`LLN and approximately 80% change from baseline), fol-
`lowed by recovery towards baseline values (Fig. 4). CD19+
`B-cell counts also fell below LLN in year 2, and recovered
`to LLN by week 84. CD4+ T-cell median counts showed a
`lesser decline from baseline to nadir (approximately 50%
`change from baseline, also reached at week 13) in year 1, fol-
`lowed by a more gradual recovery towards baseline (Fig. 5).
`While CD4 + T cells did not reach the LLN in year 1, they
`fell below the LLN in year 2 and reached threshold values
`for recovery by week 96, approximately 43 weeks post last
`therapy dose. Median CD8 + T cells never dropped below
`LLN (Fig. 6) [64]. Analysis of CD4 + T-cell subtypes in
`ORACLE-MS showed that subpopulations displayed dif-
`ferent repopulation dynamics, leading to changes in the
`
`

`

`
`
`1904
`
`K. Rammohan et al.
`
`Clinical Development of Cladribine Tablets
`
`CLINICAL MILESTONES
`
`Discovery of
`ADA deficiency52
`
`2-CdA first synthesized
`by Christensen
`and colleagues122
`
`Global Phase 4
`program initiated
`
`Phase 3 CLARITY
`results published65,a
`
`Phase 3 ORACLE-MS
`results published94,b
`
`US Phase 4
`program initiated
`Integrated safety
`results published102,d
`
`Phase 3
`CLARITY-
`EXT results
`published66
`
`Phase 2 ONWARD
`results published100,c
`
`Completion of
`PREMIERE long-term
`safety registry study123
`
`1972
`
`1993
`
`2010
`
`2011
`
`2014
`
`2016
`
`2017
`
`2018
`
`2019
`
`IV formulation approved
`by FDA as an orphan
`drug for the treatment
`of hairy cell leukemia124
`
`First reviewed
`by EMA126
`FDA grants priority
`review for relapsing MS127
`
`REGULATORY MILESTONES
`
`Approved in
`Russia and
`Australia for
`RRMS but later
`withdrawn125
`
`CRL issued
`by the FDA
`for US
`approval128
`
`Marketing
`authorization
`application
`resubmitted to
`EMA with new
`clinical data from
`CLARITY-EXT,
`ORACLE-MS,
`and PREMIERE129
`
`EMA
`approval130
`
`NDA
`resubmitted to
`FDA with
`additional safety
`clinical data and
`analyses (no new
`efficacy data was
`submitted)131
`
`approval51
`
`Approved
`in more than
`75 countries
`as of July 2020
`
`Cladribine tablets were approved by the EMA in 2017 and the FDA in 2019
`
`Fig. 1 Cladribine tablets development milestones [51, 52, 65, 66, 94,
`100, 102, 122–131]. aNaive and treatment-experienced patients with
`RRMS. bTreatment-naive patients at high risk for developing MS.
`cPatients with active RRMS in combination with IFN-β. dIncluding
`patients from CLARITY, CLARITY–EXT, ORACLE-MS, and PRE-
`
`MIERE. ADA adenosine deaminase, 2-CdA 2-chlorodeoxyadenosine
`deaminase, CRL complete response letter, EMA European Medicines
`Agency, FDA Food and Drug Administration, IFN interferon, IV
`intravenous, MS multiple sclerosis, NDA new drug application, RRMS
`relapsing–remitting MS
`
`relative proportions of the CD4 +  T-cell subpopulations
`[67]. Median monocyte and neutrophil counts remained
`within the normal range throughout the CLARITY and
`CLARITY Extension studies (Figs. 7, 8), while the effects
`on natural killer (NK) cells were moderate and transient,
`with a 30–44% median decrease in NK cells followed by a
`recovery towards pretreatment levels by week 24 (Fig. 9).
`These findings support the view that the impact of cladribine
`on the innate immune system is relatively minor [67]. The
`preferential reduction of lymphocyte subpopulations, fol-
`lowed by the pattern of lymphocyte count recovery (termed
`immune reconstitution), may ‘reset’ the immune system to a
`less autoreactive state [64], a putative mechanism with con-
`siderable potential in the long-term treatment of MS [48].
`
`was required. Phase II and III studies that were ongoing at
`the time were completed, and a long-term safety registry
`was continued. The additional data served to support the
`thorough characterization of the safety profile of cladrib-
`ine tablets in MS. Evaluation of these additional data and
`analyses of the compound’s longer-term benefit–risk profile
`supported new submissions to regulatory authorities. Clad-
`ribine tablets received EMA approval in August 2017 [50]
`and FDA approval in March 2019 [26]. As of July 2020,
`cladribine tablets have gained marketing authorization in
`more than 75 countries for the treatment of patients with
`various forms of RMS.
`
`1.4 Dosing Schedule
`
`1.3 Approvals
`
`Cladribine tablets were developed as a potential treatment
`for MS in response to the efficacy seen in early studies of
`parenteral cladribine and the need for additional treatment
`options [53, 68, 69]. The pivotal CLARITY trial was com-
`pleted in 2009 and published in 2010; however, some regu-
`latory authorities indicated in 2011 that improved under-
`standing of safety risks and the overall benefit–risk profile
`
`Two dosages were investigated during the clinical develop-
`ment of cladribine tablets: 3.5 mg/kg and 5.25 mg/kg (cumu-
`lative doses over 2 years). In addition, in certain study arms,
`patients received retreatment in years 3 and 4 (cumulative
`doses over 4 years of 7.0 mg/kg and 8.75 mg/kg). The 3.5 mg/
`kg and 5.25 mg/kg doses appeared to be equally efficacious,
`but the 5.25 mg/kg dose was associated with an increased
`rate of higher-grade lymphopenia [65]. The 3.5 mg/kg dose
`was considered to have the most favorable benefit–risk profile.
`
`

`

`Development of Cladribine Tablets
`
`1905
`
`B and T lymphocytes
`
`HIGH
`kinase-to-phosphatase ratio
`
`Cladribine
`molecule
`
`Phosphatase
`Inactivation by
`5’NTase
`
`Kinase
`Activation
`by DCK
`
`High levels of
`activated cladribine
`molecule
`
`Other cells
`
`LOW
`kinase-to-phosphatase ratio
`
`Cladribine
`molecule
`
`Phosphatase
`Inactivation by
`5’NTase
`
`Kinase
`Activation
`by DCK
`
`Low levels of
`activated cladribine
`molecule
`
`CD4+ lymphocytes
`CD8+ lymphocytes
`Skin
`Heart
`Brain
`Ovary
`Liver
`Kidney
`Lung
`Testis germ cell
`Testis
`
`mRNA Expression of
`Inactivating Phosphatase
`
`mRNA Expression of
`Activating Kinase
`
`Fig. 2 Ratios of DCK to 5(cid:397)-NTase mRNA expression in T cells
`and various non-hematologic cells [58]. 5(cid:397)-NTase 5(cid:397)-nucleotidases,
`DCK deoxycytidine kinase, mRNA messenger RNA. *Calculated
`
`using data from the BioGPS website (available at https ://biogp
`s.org/#goto=welco me). Adapted with permission from Giovannoni
`[58]
`
`In countries where approved, the recommended cumu-
`lative dose of cladribine tablets is 3.5 mg/kg given over
`2 years (one treatment course is 1.75 mg/kg/year) [12, 26].
`Each course consists of two treatment weeks or cycles—one
`cycle at the beginning of the first month and one cycle at
`the beginning of the second month. Each treatment cycle
`lasts 4 or 5 consecutive days, depending on the patient’s
`weight, and patients receive one or two 10 mg tablets per
`
`day. Lymphocytes must be within normal limits prior to ini-
`tiating the first course and at least 800 cells/mm3 prior to
`initiating the second course. Modeling simulations suggest
`that 92% of patients would not require a delay in receiving
`the second treatment course and < 1% would be ineligible
`for treatment in year 2 due to a delay in recovery of more
`than 6 months [70]. No further treatment with cladribine
`tablets may be required in years 3 and 4; a patient cohort
`
`

`

`Weeks 1 & 5
`
`Weeks 48 & 52
`
`K. Rammohan et al.
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`No additional placebo
`Cladribine administration
`
`LLN 1.0 x 109/L
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`0
`
`24
`
`48
`
`72
`
`96
`
`120
`
`144
`
`168
`
`192
`
`216
`
`240
`
`264
`
`288
`
`312
`
`Week
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`Median (Q1–Q3) lymphocyte counts
`
`(109/L)
`
`
`
`1906
`
`Fig. 3 Adaptive immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/kg
`or placebo—absolute lympho-
`cyte counts [58]. LLN lower
`limit of normal, Q1–Q3 inter-
`quartile range, RMS relapsing
`multiple sclerosis. Pooled data
`from CLARITY, CLARITY
`EXT, and PREMIERE. Visits
`with a sample size ≥ 30 are
`displayed. Adapted with permis-
`sion from Giovannoni [58]
`
`Number of patients
`434
`
`683
`
`415
`
`645
`
`263
`
`437
`
`378
`
`624
`
`358
`
`574
`
`86
`
`298
`
`94
`
`265
`
`69
`
`167
`
`34
`
`147
`
`131
`
`116
`
`106
`
`66
`
`32
`
`LLN 0.1 x 109/L
`
`Weeks 1 & 5
`
`Weeks 48 & 52
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`Cladribine administration
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`Median (Q1–Q3) CD19+
`
`counts (109/L)
`
`Fig. 4 Adaptive immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/
`kg or placebo—B (CD19+)
`cells [64]. LLN lower limit of
`normal, Q1–Q3 interquartile
`range, RMS relapsing multiple
`sclerosis. Pooled data from
`CLARITY, CLARITY EXT,
`and PREMIERE. Visits with a
`sample size ≥ 30 are displayed.
`Adapted with permission from
`Comi et al. [64]
`
`0.0
`
`0
`
`24
`
`48
`
`Number of patients
`79
`
`220
`
`81
`
`203
`
`61
`
`137
`
`72
`
`74
`
`191
`
`96
`Week
`
`78
`
`195
`
`120
`
`144
`
`168
`
`192
`
`38
`
`56
`
`68
`
`64
`
`that received additional treatments in years 3 and 4 had
`comparable clinical efficacy compared with a study cohort
`that received placebo in years 3 and 4 [66]. The safety and
`efficacy of additional treatment courses after year 4 have not
`been studied. There are no current definitions of treatment
`failure with cladribine tablets. Any definition would need to
`be on a case-by-case basis, most likely taking into account
`disease activity prior to commencing cladribine tablets [71].
`
`1.5 Clinical Pharmacology
`
`Following oral administration, cladribine is rapidly
`absorbed, reaching maximal plasma concentrations after
`approximately 0.5 h (in the fasted state). Food delays absorp-
`tion but does not affect overall exposure [72]. Oral bioa-
`vailability is approximately 40% compared with parenteral
`administration; reduced bioavailability is likely due to gas-
`trointestinal efflux mediated by the breast cancer resistance
`
`

`

`1907
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`Cladribine administration
`
`LLN 0.35 x 109/L
`
`72
`
`74
`
`191
`
`96
`Week
`
`78
`
`195
`
`120
`
`144
`
`168
`
`192
`
`38
`
`56
`
`68
`
`64
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`Cladribine administration
`
`LLN 0.2 x 109/L
`
`72
`
`74
`
`191
`
`96
`Week
`
`78
`
`195
`
`120
`
`144
`
`168
`
`192
`
`38
`
`56
`
`68
`
`64
`
`Weeks 1 & 5
`
`Weeks 48 & 52
`
`0
`
`24
`
`48
`
`1.2
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Median (Q1–Q3) CD4+
`
`counts (109/L)
`
`Development of Cladribine Tablets
`
`Fig. 5 Adaptive immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/kg
`or placebo—T helper (CD4+)
`cells [64]. LLN lower limit of
`normal, Q1–Q3 interquartile
`range, RMS relapsing multiple
`sclerosis. Pooled data from
`CLARITY, CLARITY EXT,
`and PREMIERE. Visits with a
`sample size ≥ 30 are displayed.
`Adapted with permission from
`Comi et al. [64]
`
`Number of patients
`79
`
`220
`
`81
`
`203
`
`61
`
`137
`
`Weeks 1 & 5
`
`Weeks 48 & 52
`
`0
`
`24
`
`48
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Median (Q1–Q3) CD8+
`
`counts (109/L)
`
`Number of patients
`79
`
`220
`
`81
`
`203
`
`61
`
`137
`
`Fig. 6 Adaptive immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/
`kg or placebo—T cytotoxic
`(CD8+) cells [64]. LLN lower
`limit of normal, Q1–Q3 inter-
`quartile range, RMS relapsing
`multiple sclerosis. Pooled data
`from CLARITY, CLARITY
`EXT, and PREMIERE. Visits
`with a sample size ≥ 30 are
`displayed. Adapted with permis-
`sion from Comi et al. [64]
`
`protein (BCRP), a transporter with affinity for cladribine
`[72]. Cladribine is rapidly taken up by lymphocytes, where
`it or its phosphorylated products accumulate, and reach
`intracellular concentrations that are approximately 30- to
`40-fold greater than in plasma within 1 h of administration
`[72]. No measurable accumulation of cladribine in plasma
`has been observed following repeated once-daily oral dosing
`[72]. The estimated terminal half-life is approximately 1 day
`[26]. About 50% of cladribine is cleared renally. Non-renal
`clearance occurs largely in lymphocytes; accumulated 2-Cd-
`AMP and 2-Cd-ATP are cleared via lymphocyte elimination
`
`pathways and their intracellular half-life is approximately
`10–15 h [72].
`Due to the risk of additive effects on the immune sys-
`tem, concomitant immunosuppressive or myelosuppressive
`therapy (e.g. cyclosporine, methotrexate) with cladribine is
`contraindicated. Previous immunomodulatory or immuno-
`suppressive therapy use, including washout periods, should
`be considered when initiating cladribine tablets [12, 26].
`Cladribine pharmacokinetics was not altered when used
`concomitantly with the proton pump inhibitor pantopra-
`zole or with IFN-β. However, the risk of lymphopenia may
`
`

`

`Weeks 1 & 5
`
`Weeks 48 & 52
`
`K. Rammohan et al.
`
`LLN 0.2 x 109/L
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`No additional placebo
`Cladribine administration
`
`0
`
`24
`
`48
`
`72
`
`96
`Week
`
`120
`
`144
`
`168
`
`192
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Median (Q1–Q3) monocyte
`
`counts (109/L)
`
`
`
`1908
`
`Fig. 7 Innate immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/kg
`or placebo—monocytes [132].
`LLN lower limit of normal,
`Q1–Q3 interquartile range, RMS
`relapsing multiple sclerosis.
`Pooled data from CLARITY,
`CLARITY EXT, and PRE-
`MIERE. Visits with a sample
`size ≥ 30 are displayed
`
`Number of patients
`435
`
`683
`
`415
`
`645
`
`263
`
`437
`
`378
`
`624
`
`358
`
`574
`
`85
`
`293
`
`93
`
`249
`
`65
`
`148
`
`30
`
`116
`
`LLN 2.03 x 109/L
`
`Cladribine tablets 3.5 mg/kg
`Placebo
`No additional active treatment
`No additional placebo
`Cladribine administration
`
`72
`
`378
`
`624
`
`120
`
`144
`
`168
`
`192
`
`96
`Week
`
`358
`
`574
`
`85
`
`293
`
`93
`
`249
`
`65
`
`148
`
`30
`
`116
`
`Weeks 1 & 5
`
`Weeks 48 & 52
`
`0
`
`24
`
`48
`
`6.0
`
`5.0
`
`4.0
`
`3.0
`
`2.0
`
`1.0
`
`0.0
`
`Median (Q1–Q3) neutrophil
`
`counts (109/L)
`
`Fig. 8 Innate immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/kg
`or placebo—neutrophils [132].
`LLN lower limit of normal,
`Q1–Q3 interquartile range, RMS
`relapsing multiple sclerosis.
`Pooled data from CLARITY,
`CLARITY EXT, and PRE-
`MIERE. Visits with a sample
`size ≥ 30 are displayed
`
`Number of patients
`435
`
`683
`
`415
`
`645
`
`263
`
`437
`
`increase with concomitant use of IFN-β. Cladribine may also
`result in hematological adverse events (AEs) when admin-
`istered with hematotoxic drugs (e.g. carbamazepine). As a
`substrate of BCRP, equilibrative nucleoside transporter 1
`(ENT1) and concentrative nucleoside transporter 3 (CNT3),
`coadministration with cladribine may interfere with cladrib-
`ine exposure. A decrease in cladribine exposure is possible
`when coadministered with potent inducers of BCRP (e.g.
`corticosteroids) or P-glycoprotein (e.g. rifampicin); however,
`
`acute short-term corticosteroid therapy can be concomitantly
`administered. Antivirals/antiretrovirals that require intracel-
`lular phosphorylation to become active (e.g. lamivudine,
`ribavirin) could potentially compete with cladribine over
`phosphorylation, affecting both cladribine and competing
`compound activity. The hydroxypropyl betadex component
`in cladribine may interact with active ingredients of other
`drugs to increase bioavailability, therefore a gap of at least
`3 h between administrations is recommended. Cladribine is
`
`

`

`1909
`
`Week 48
`
`LLN 0.09 x 109/L
`
`48
`
`83
`
`89
`
`116
`
`Weeks 1 & 5
`
`CLARITY cladribine tablets 3.5 mg/kg
`CLARITY EXT cladribine tablets 3.5 mg/kg*
`CLARITY placebo
`Cladribine administration
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`Median (Q1–Q3) NK
`
`counts (109/L)
`
`Development of Cladribine Tablets
`
`Fig. 9 Innate immune cell
`counts in patients with RMS
`receiving cladribine 3.5 mg/
`kg or placebo—natural killer
`(CD16 + /CD56 +) cells [67].
`LLN lower limit of normal,
`Q1–Q3 interquartile range, RMS
`relapsing multiple sclerosis.
`Visits with a sample size ≥ 30
`are displayed. *Patients who
`received placebo in CLARITY
`and cladribine tablets 3.5 mg/
`kg in CLARITY EXT. Adapted
`from Stuve et al. [67] under a
`Creative Commons CC-BY-NC
`license
`
`0.0
`
`0
`
`Number of patients
`77
`
`81
`
`122
`
`5
`
`84
`
`88
`
`110
`
`13
`
`83
`
`89
`
`116
`
`24
`Week
`
`81
`
`87
`
`124
`
`not a substrate of the cytochrome P450 (CYP) pathway and
`has no known inductive effect on CYP1A2, CYP2B6, and
`CYP3A4 enzymes [12, 26].
`It is not known whether cladribine can reduce the effec-
`tiveness of hormonal contraceptives; however, a clinical
`trial to examine this is ongoing (ClinicalTrials.gov identi-
`fier: NCT03745144). A barrier method is currently recom-
`mended during treatment with cladribine tablets and for at
`least 4 weeks after the last dose in each treatment course
`[26]. In humans, cladribine has a half-life of < 24 h and is
`rapidly eliminated [73]. However, in supratherapeutic doses,
`teratogenicity has been observed in mice and rabbits, and
`short-term effects have been observed in male mice germ
`cells [74]. Cladribine tablets should therefore not be admin-
`istered to pregnant women; pregnancy should be prevented
`using effective contraception during treatment and 6 months
`after the last dose in each treatment course in women and
`men of reproductive potential [26].
`As a small molecule, cladribine has been demonstrated
`to cross the blood–brain barrier (BBB) in animal [75] and
`human studies [76, 77]. In a study of parenteral cladribine
`in children with acute myeloid leukemia, cerebrospinal
`fluid (CSF) concentrations reached approximately 25%
`of those in plasma [76]. CNS penetration of cladribine
`may allow for a treatment effect on lymphocytes that have
`migrated into the CNS, possibly also affecting lymphoid
`follicles in the meninges of patients and reducing intrathe-
`cal immunoglobulin G (IgG) synthesis. In a study of 29
`patients with RRMS who had received parenteral cladrib-
`ine, 55% of patients tested negative for oligoclonal bands
`(OCBs) in CSF post-treatment, despite all patients testing
`
`positive for OCB and demonstrating raised Ig concentra-
`tions in CSF at baseline [78]. Furthermore, in a 10-year
`follow-up, Expanded Disability Status Scale (EDSS) pro-
`gression was significantly delayed in the OCB-negative
`patients despite both cohorts demonstrating equal charac-
`teristics at baseline.
`
`2 Clinical Studies in Relapsing Forms of