Multiple Sclerosis and Related Disorders 29 (2019) 157–167 Contents lists available at ScienceDirect Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard Safety of cladribine tablets in the treatment of patients with multiple T sclerosis: An integrated analysis Stuart Cooka, , Thomas Leistb, Giancarlo Comic, Xavier Montalband,e, Gavin Giovannonif, ⁎ Axel Noltingg, Christine Hickingg, Andrew Galazkah, Elke Sylvesterg a Rutgers, The State University of New Jersey, New Jersey Medical School, Department of Neurology & Neurosciences, 185 South Orange Avenue, Newark, NJ 07101-1709, United States b Division of Clinical Neuroimmunology, Jefferson University, Comprehensive MS Center, 900 Walnut Street, Philadelphia, PA 19107, United States c Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Via Olgettina 48, Milan 20132, Italy d Division of Neurology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada e Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Passeif de la Vall d'Hebron 119- 129, 08035 Barcelona, Spain f Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK g Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany h Merck, Zone Industrielle de L'Ouriettaz, Aubonne, 1170, Switzerland, a division of Merck KGaA, Darmstadt, Germany ARTICLE INFO ABSTRACT Keywords: Background: Treating patients with relapsing multiple sclerosis (MS) with cladribine tablets (two times 4 or 5 Cladribine tablets days of treatment each year for 2 years) results in long-lasting efficacy, with continued stability in many patients Safety for 4 or more years. Safety and tolerability outcomes from individual clinical studies with cladribine tablets have Tolerability been reported previously. Risk:benefit Objective: Report safety data from an integrated analysis of clinical trials and follow-up in patients with MS to Combined analysis further characterize the safety profile of cladribine tablets. Methods: Data for patients treated with cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) as monotherapy (n = 923) or placebo (n = 641) in Phase III clinical trials (CLARITY, CLARITY Extension and ORACLE-MS) and followed up in the PREMIERE registry were aggregated (Monotherapy Oral cohort). To better characterize rare events, additional data from earlier studies which involved the use of parenteral cladribine in patients with MS, and the ONWARD study, in which patients were given cladribine tablets in addition to interferon (IFN)-β or placebo plus IFN-β were in- cluded in an All Exposed cohort (cladribine, n = 1926; placebo, n = 802). Adjusted adverse events incidences per 100 patient-years (Adj-AE per 100 PY) were calculated for the integrated analyses. Results: The incidence rate of treatment-emergent adverse events (TEAEs) in the Monotherapy Oral cohort was 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo. TEAEs that occurred more frequently with cladribine tablets were mainly driven by the TEAEs of lymphopenia (Adj-AE per 100 PY 7.94 vs. 1.06 for placebo) and lymphocyte count decreased (Adj-AE per 100 PY 0.78 vs. 0.10 for placebo) as anticipated due to the mode of action of cladribine. An increase in TEAE incidence rate was also observed in the cladribine tablets 3.5 mg/kg group vs. placebo for herpes zoster (Adj-AE per 100 PY 0.83 vs. 0.20, respectively). There were no cases of systemic, serious disseminated herpes zoster attributed to treatment with cladribine tablets. In general there was no in- crease in the risk of infections including opportunistic infections with cladribine tablets versus placebo, except for herpes zoster. Periods of severe lymphopenia (< 0.5 × 109 cells/L) were associated with an increased fre- quency of infections, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. Within the constraints of a limited sample size, malignancy rates in the overall clinical program for cladribine in MS did not show evidence of an increase compared to placebo-treated patients and there was no increase in the incidence of malignancies over time in cladribine-treated patients. Conclusion: The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy has been well-characterized in a pooled population of patients from early to more advanced relapsing MS. There was no increased risk for in- fections in general except for a higher incidence of herpes zoster. Lymphopenia was amongst the most frequently ⁎ Corresponding author. E-mail address: cooksd@ca.rutgers.edu (S. Cook). https://doi.org/10.1016/j.msard.2018.11.021 Received 25 July 2018; Received in revised form 9 November 2018; Accepted 19 November 2018 2211-0348/ © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 observed TEAEs that occurred at a higher incidence with cladribine relative to placebo. There was also no increase in malignancy rates for cladribine relative to placebo. 1. Introduction tablets and for patients receiving treatment for more than 2 courses. A companion publication in this journal issue (Comi et al., 2018) Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative provides more detailed information on lymphocyte count changes. The dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) have protocols of clinical trials involving treatment with cladribine specified shown efficacy across the spectrum of patients with relapsing multiple the use of contraception in study participants. Some pregnancies sclerosis (MS), including those at a higher risk of disease progression or nevertheless occurred in some female study participants or female with active disease while on a disease modifying drug (DMD) partners of male study participants. Available data from exposure (Giovannoni et al., 2010; Giovannoni et al., 2011; Comi et al., 2013; during pregnancy will be reviewed in a separate publication. Rammohan et al., 2012; Giovannoni et al., 2018; Giovannoni et al., 2017; Leist et al., 2014; Freedman et al., 2017; Montalban et al., 2016). 2. Methods Treatment with cladribine tablets leads to a transient reduction of lymphocyte counts and a minimal effect on innate immune function, 2.1. Monotherapy Oral cohort followed by gradual reconstitution of the lymphocyte populations to- wards baseline levels (Giovannoni, 2017; Wiendl, 2017). By pre- Safety data relating to treatment with cladribine tablets 3.5 mg/kg ferentially targeting lymphocytes, cladribine tablets can interfere with as oral monotherapy were combined from three Phase III studies autoimmune processes underlying MS in which certain lymphocyte (CLARITY, CLARITY Extension, and ORACLE-MS) that involved treat- populations are considered to play a central role (Leist and ment with cladribine tablets 3.5 mg/kg and the PREMIERE registry Vermersch, 2007; Leist and Weissert, 2009). (Supplementary Table 1) (Giovannoni et al., 2010; Giovannoni et al., The lymphocyte count reduction produced by cladribine tablets 2017; Leist et al., 2014). This Monotherapy Oral cohort is the primary occurs earlier and to a greater extent in the case of CD19+ B cells than cohort as it evaluates the safety of oral cladribine given as monotherapy in CD4+ or CD8+ T cells (Baker et al., 2017; Ceronie et al., 2018). and includes long-term safety follow-up data. However, the degree and time profile of the lymphocyte count reduc- CLARITY was a 96-week, Phase III, double-blind, randomized, pla- tion seen with cladribine tablets is distinct from that for alemtuzumab, cebo-controlled, parallel-group, multicenter study which evaluated the where circulating lymphocytes are very significantly reduced after safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg (cumulative treatment (Baker et al., 2017; Dorr and Baum, 2016; Havrdova et al., dose) in patients with relapsing-remitting MS (RRMS) 2017; Willis and Robertson, 2014; Thomas et al., 2016). The gradual (Giovannoni et al., 2010). CLARITY Extension was a 96-week, Phase recovery of lymphocyte populations following cladribine tablets occurs IIIb, double-blind, randomized, parallel-group, multicenter, extension without the triggering of secondary autoimmunity observed following study which evaluated the safety, tolerability, and efficacy of treatment treatment with alemtuzumab (Zwang and Turka, 2014; Jones et al., with cladribine tablets for an additional 2.5 years (including supple- 2009). mental follow-up) beyond the 2-year CLARITY study. Eligibility for The mode of action of cladribine tablets is believed to be responsible entry into CLARITY Extension was based upon completion of the for a durable clinical effect in patients with relapsing MS despite an double-blind treatment period in CLARITY. Patients who received cla- only short-term presence of the therapeutic agent (Giovannoni et al., dribine tablets during the CLARITY study were randomized to receive 2017). With long-term efficacy comes the need to consider long-term an additional two courses of cladribine tablets or placebo. Patients who safety of cladribine tablets. Safety and tolerability outcomes from in- received placebo during CLARITY were assigned to two courses of dividual clinical studies with cladribine tablets have been reported cladribine tablets with a cumulative dose of 3.5 mg/kg previously (Giovannoni et al., 2010; Giovannoni et al., 2017; (Giovannoni et al., 2017). ORACLE-MS was a 96-week Phase III, Leist et al., 2014; Cook et al., 2011). To provide a more comprehensive double-blind, randomized, placebo-controlled multicenter study which characterization of the safety profile of cladribine tablets in MS, data evaluated the safety and efficacy of 2 doses of treatment with cladribine from these, and other relevant studies from the clinical development tablets 3.5 and 5.25 mg/kg (cumulative dose) in patients with a first program have been combined for the purposes of an integrated analysis. clinical demyelinating event, including patients who were subsequently This publication focuses on an integrated safety analysis of patients found to have met the 2010 McDonald criteria (Leist et al., 2014; receiving oral monotherapy of cladribine tablets (Monotherapy Oral Freedman et al., 2017). The PREMIERE registry is a prospective, ob- cohort) given as two courses of 4 or 5 days of treatment each year for 2 servational, long-term safety study of patients with MS that commenced years to the cumulative dose of 3.5 mg/kg (the dose approved in Europe in 2009 and is open to patients who had participated in one of the and other regions) (MAVENCLAD SmPC. 2017) or placebo. Data were clinical studies of cladribine tablets (CLARITY, CLARITY Extension, derived from the three Phase III clinical trials (CLARITY ORACLE-MS or ONWARD). To enter PREMIERE, patients had to pro- [NCT00213135], CLARITY Extension [NCT00641537] and ORACLE- vide written informed consent. MS [NCT00725985]) as well as the ongoing Prospective observational long-term safety registry of multiple sclerosis patients who have parti- cipated in cladribine clinical trials (PREMIERE) registry 2.2. All Exposed cohort (NCT01013350) in which patients continue to be followed up for long- term monitoring. Safety relating to rarer adverse events of special interest (AESI), In addition, aggregated safety data on all cladribine exposed pa- such as malignancies, was assessed in a larger All Exposed patient co- tients from studies and the on-going registry are also included (All hort. This cohort includes data from MS patients who received treat- Exposed cohort). This cohort includes data from all MS studies with ment with cladribine or placebo, regardless of the formulation or mode cladribine (tablets or parenteral administration) or placebo, and data of administration and includes doses of cladribine higher than those from ONWARD (NCT00436826) in which patients received cladribine recommended in the European Union (EU) Summary of Product tablets in combination with interferon (IFN)-β (Montalban et al., 2016). Characteristics (SmPC) (MAVENCLAD SmPC. 2017). This All Exposed It also includes data from patients receiving other doses of cladribine cohort analysis is most suitable for identifying and characterizing rare events but includes a more heterogeneous population than that 158 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 included in the trials studying cladribine tablets in relapsing MS pa- censored at the time of re-exposure. Analysis of the All Exposed cohort tients. The All Exposed cohort additionally includes ONWARD which used a conservative approach. Data from patients initially treated with compared cladribine tablets or placebo in combination with IFN-β, and cladribine and subsequently with placebo (i.e. in CLARITY Extension), 5 other smaller trials in which patients were treated with placebo or were analyzed from the time of entry into the program as part of the parenteral cladribine (Supplementary Table 1). cladribine group and never as part of the placebo group (Supplementary Table 2). 2.3. Adverse events of special interest (AESI) All integrated analyses were performed using SAS® Software version 9.2 or later. AEs and Medical Histories in all studies were recoded using Three main categories of adverse events were defined as AESI; the Medical Dictionary of Regulatory Activities (MedDRA) v17.1 in lymphopenia, infections and malignancies. Cladribine selectively re- order to assure a common basis for the safety database. In addition, duces lymphocyte counts which may lead to lymphopenia (as expected data from the Merck pharmacovigilance database were reconciled with from its mode of action). There is potential concern for an increase in the clinical database and the most current information was used in the the incidence of infections or malignancies associated with lympho- analyses described. Data on AEs were based on treatment emergent penia-associated immunosuppression and reduction of cell-mediated adverse events (TEAEs), which were absent prior to treatment, but immunity. Malignancies, however, are generally observed only with started during the treatment and observation period relative to the pre- profound and long-lasting immunosuppression (Comi et al., 2018; treatment state. An AE was treatment-emergent if the AE occurred on or Oliveira Cobucci et al., 2012). after day 1 during the treatment and observation period. Crude AE incidence rate was expressed as the sum of all patients with at least one 2.4. Analyses occurrence of the AE of interest divided by the analysis population; Crude incidence rate = 100*(Number of patients with at least one AE/ All analyses were based on the safety analysis set for the relevant number of patients). cohort (Monotherapy Oral or All Exposed), which comprised all pa- Assessments of AEs mainly used observation-adjusted incidence tients receiving study treatment at least once (cut-off date of 20 rates (Adj-AE), including Adj-AE per 100 patient-years (PY), the time- February 2015). This corresponds to the data used as the basis of reg- adjusted AE incidence rate which can be interpreted as the number of ulatory filings that supported the approval of cladribine tablets by the events occurring in 100-patient-years, calculated as 100*(Number of European Commission and other authorities, and the respective pre- patients with at least one AE)/(Sum of observation time in days among scribing information (MAVENCLAD SmPC. 2017). Patients who re- patients at risk for initial occurrence of an AE or time on study/365.25). ceived IFN-β per protocol as rescue therapy (CLARITY) or after con- This presentation of AE incidence accounts for different observation version to clinically definite MS (ORACLE-MS) were included in the periods between treatment groups and provides rates with reasonable analyses. decimal places based on the observation time and the number of events. All safety analyses were performed using the "as treated principle”. Observation time until occurrence was calculated in a similar way to For the Monotherapy Oral cohort, if patients received only placebo or time on study but was limited to time to occurrence of the first AE of were in the observational follow-up period without having switched interest. For patients with no events, the time on study was used. subsequently to cladribine tablets, then their data became part of the Analysis of malignancy events in the All Exposed cohort included all placebo group. Patients who switched treatment from placebo to cla- events in the clinical trial databases, irrespective of cladribine dose or dribine tablets in subsequent studies/periods (i.e. in CLARITY route of administration. For the analysis of malignancies, data from the Extension), had their time on placebo censored at the time of the switch integrated clinical database (cut-off date 20 February 2015) were re- (Supplementary Table 2). Patients who switched treatment from pla- conciled with the Merck pharmacovigilance database (cut-off date 05 cebo to cladribine tablets 3.5 mg/kg had their time on cladribine tablets November 2015). All cases with a reported preferred term within the 3.5 mg/kg initiated at the time of switching. Patients who were treated Standardized MedDRA Query “Malignant or Unspecified Tumors” with cladribine tablets 3.5 mg/kg in CLARITY and were then re-exposed (MedDRA version 17.1) were identified, reviewed and assessed. In ad- to cladribine tablets 3.5 mg/kg in a subsequent study/period (i.e. in dition, all cases were adjudicated by an independent tumor review CLARITY Extension) had their time on cladribine tablets 3.5 mg/kg board on a case-by-case basis in a blinded fashion. Risk differences Table 1 Demographic information for patients included in the Monotherapy Oral cohort. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) Patient-years 2026 3433 Time on study in weeks, mean (SD) 164.92 (105.97) 194.05 (110.50) Time on study ≥ 24 weeks (∼6 months), n (%) 617 (96.3) 900 (97.5) Time on study ≥ 48 weeks (∼1 year), n (%) 595 (92.8) 875 (94.8) Time on study ≥ 96 weeks (∼2 years), n (%) 486 (75.8) 772 (83.6) Time on study ≥ 192 weeks (∼4 years), n (%) 181 (28.2) 395 (42.8) Time on study ≥ 384 weeks (∼8 years), n (%) 60 (9.4) 93 (10.1) Age (years), mean (SD) 36.6 (9.8) 36.5 (10.3) Median 36.0 36.0 Min; max 18; 64 18; 65 Age ≤ 40 years, n (%) 415 (64.7) 592 (64.1) Age > 40 years, n (%) 226 (35.3) 331 (35.9) Male, n (%) 217 (33.9) 311 (33.7) Female, n (%) 424 (66.1) 612 (66.3) Prior treatment with DMD, n (%) 131 (20.4) 184 (19.9) Disease duration in years, mean (SD) 8.91 (7.39) 7.90 (6.91) Original study, n (%) CLARITY 435 (67.9) 685 (74.2) ORACLE-MS 206 (32.1) 238 (25.8) DMD, disease modifying drug; SD, standard deviation. The Monotherapy Oral cohort includes data from CLARITY, CLARITY Extension, ORACLE-MS and PREMIERE. 159 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 (cladribine tablets vs. placebo) were presented with corresponding two- the cut-off date of 20 February 2015. sided 95% confidence intervals (CIs) on Adj-AE per 100 PY, estimated by the Miettinen and Nurminen method (Miettinen and Nurminen, 1985) unless otherwise specified. Standardized Incidence 3. Results Ratios (SIR) for adjudicated malignancies were calculated in relation to the GLOBOCAN 2012 reference population, (GLOBOCAN 2012) using In both the Monotherapy Oral cohort and the All Exposed cohort the number of patients exposed to cladribine tablets at a cumulative dose of Table 2 Summary of AEs for Monotherapy Oral cohort. See also Table 4 for infections and infestations. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) n Total PY Adj-AE per 100 PY n Total PY Adj-AE per 100 PY Patients with ≥ 1 TEAE 515 546.3 94.26 773 748.4 103.29 Patients with ≥ 1TEAE related to study drug 291 1162.8 25.03 542 1605.5 33.76 Patients with ≥ 1 serious‡ TEAE 67 1876.3 3.57 124 3096.8 4.00 Patients with TEAE leading to treatment discontinuation 21 1993.7 1.05 67 3229.0 2.07 Patients with ≥ 1 severe TEAE reported in ≥ 2 patients 57 1912.5 2.98 115 3111.2 3.70 Patients with TEAE leading to death† 5 2024.7 0.25 9 3431.0 0.26 *Most commonly reported TEAEs (Adj-AE per 100 PY of ≥1.0 in either group) Nervous system disorders 226 1429.5 15.81 327 2346.7 13.93 Headache 144 1631.9 8.82 230 2641.9 8.71 Dizziness 36 1944.4 1.85 47 3268.0 1.44 Multiple sclerosis relapse a 11 2014.0 0.55 21 3404.9 0.62 Gastrointestinal disorders 197 1454.9 13.54 278 2482.0 11.20 Nausea 62 1845.6 3.36 86 3134.4 2.74 Diarrhea 44 1915.9 2.30 68 3202.0 2.12 Abdominal pain, upper 22 1969.2 1.12 42 3283.1 1.28 Toothache 22 1957.5 1.12 35 3335.8 1.05 Abdominal pain 23 1966.2 1.17 30 3346.2 0.90 Constipation 22 1968.7 1.12 24 3368.3 0.71 Vomiting 24 1982.6 1.21 21 3363.7 0.62 Blood and lymphatic system disorders 47 1901.6 2.47 276 2543.4 10.85 Lymphopenia 21 1985.0 1.06 217 2731.8 7.94 Leukopenia 8 2008.4 0.40 43 3276.9 1.31 Neutropenia 4 2015.0 0.20 27 3362.8 0.80 Musculoskeletal and connective tissue disorders 153 1608.0 9.51 245 2654.5 9.23 Back pain 46 1890.0 2.43 102 3115.8 3.27 Arthralgia 38 1938.8 1.96 63 3236.0 1.95 Pain in extremity 33 1965.6 1.68 50 3283.6 1.52 Myalgia 21 1966.3 1.07 28 3356.9 0.83 Musculoskeletal pain 16 1989.1 0.80 19 3375.9 0.56 General disorders and administration site conditions 168 1558.5 10.78 213 2717.1 7.84 Influenza-like illness 61 1857.4 3.28 75 3167.6 2.37 Fatigue 47 1897.2 2.48 54 3252.1 1.66 Pyrexia 20 1980.8 1.01 36 3341.5 1.08 Asthenia 25 1941.8 1.29 33 3311.5 1.00 Investigations 83 1802.4 4.61 145 2939.6 4.93 Lymphocyte count decreased 2 2023.1 0.10 26 3337.4 0.78 Psychiatric disorders 85 1787.8 4.75 121 3009.3 4.02 Insomnia 32 1938.7 1.65 46 3285.5 1.40 Depression 23 1960.6 1.17 46 3298.1 1.39 Anxiety 12 2002.3 0.60 37 3312.1 1.12 Respiratory, thoracic and mediastinal disorders 95 1770.8 5.36 118 3065.2 3.85 Oropharyngeal pain 35 1929.2 1.81 44 3278.8 1.34 Cough 27 1968.3 1.37 34 3336.6 1.02 Vascular disorders 45 1909.6 2.36 72 3231.2 2.23 Hypertension 25 1965.3 1.27 35 3338.5 1.05 Ear and labyrinth disorders 35 1930.6 1.81 53 3269.0 1.62 Vertigo 22 1966.4 1.12 35 3317.9 1.05 Injury, poisoning and procedural complications 81 1830.4 4.43 115 3090.3 3.72 Fall 13 1985.9 0.65 24 3371.1 0.71 Most commonly reported serious‡ TEAEs (Adj-AE per 100 PY of ≥ 0.10 in either group) Blood creatine phosphokinase increased 4 2022.6 0.20 7 3414.4 0.21 Pneumonia 3 2019.7 0.15 6 3403.4 0.18 Uterine leiomyoma 2 2020.9 0.10 5 3409.7 0.15 Lymphopenia 0 2026.0 0 4 3421.4 0.12 Urinary tract infection 1 2024.4 0.05 4 3419.4 0.12 n is the number of patients with events; T is the total patient's time on study in years. If a patient has multiple events, the time to first event is considered. For a patient with no event the time is censored at the last follow-up time for that patient. Adj-AE per 100 PY is the time adjusted AE incidence rate which can be interpreted as the number of events occurring in 100 patient-years. *System organ class and preferred terms are presented in descending order of Adj-AE per 100 PY rate in the cladribine tablets 3.5 mg/kg group. ‡Serious was defined as resultant in death; life-threatening; required inpatient hospitalization; congenital anomaly or birth defect; or was otherwise considered as medically important. †Narratives for deaths in the Monotherapy Oral and All Exposed cohorts are shown in Supplementary Table 4 a Preferred term “Multiple sclerosis relapse” was reported in PREMIERE where relapse was not an efficacy endpoint. 160 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 3.5 mg/kg was larger and had a longer average time period of follow up adjusted rate of ≥0.05 per 100 PY are shown in Supplementary compared to the number who received placebo (Table 1). The larger Table 5. numbers of patients exposed to cladribine tablets reflects the fact that in both cohorts patients may have switched from placebo to cladribine 3.2. Effects of cladribine tablets on lymphocyte counts tablets in CLARITY Extension; additionally, in the All Exposed cohort several large studies included a higher number of patients exposed to Lymphocyte count reductions are expected due to the mechanism of cladribine (at all doses) than placebo. In the Monotherapy Oral cohort, action of cladribine. The effects of cladribine tablets on lymphocyte the median age of patients who received placebo and those who were counts in the Monotherapy Oral cohort are shown in Table 3. In the treated with cladribine tablets 3.5 mg/kg was similar, at about 36 years CLARITY and CLARITY Extension studies, Grade 3 lymphopenia (ab- at the time of enrollment into the respective trial. The majority of pa- solute lymphocyte count [ALC] 0.2– < 0.5 × 109 cells/L) was experi- tients in each group were women. Disease characteristics were balanced enced by 25% of patients and Grade 4 lymphopenia (< 0.2 × 109 cells/ in both groups. A similar pattern of patient characteristics was seen in L) was experienced by < 1% of patients treated with cladribine tablets the demographics of the All Exposed cohort (Supplementary Table 3). 3.5 mg/kg (Giovannoni et al., 2010; Giovannoni et al., 2017). It is of note that the Monotherapy Oral cohort included patients with IFN-β as 3.1. Summary of adverse events rescue medication (patients who received IFN-β as rescue medication were not excluded or censored). The companion publication The incidence rate of TEAEs in the Monotherapy Oral cohort was (Comi et al., 2018) provides more detailed information on lymphocyte 103.29 vs. 94.26 Adj-AEs per 100 PY for placebo (Table 2). There was a changes in relation to treatment using a cohort of patients that does not trend for a higher rate of drug-related TEAEs with cladribine tablets include those from ORACLE-MS (Leist et al., 2014). That analysis de- 3.5 mg/kg vs. placebo (33.76 vs. 25.03 Adj-AEs per 100 PY, respec- monstrates that after rapid reductions in the lymphocyte count, lym- tively). The rate of TEAEs leading to treatment discontinuation was low phocyte count recovery begins soon after treatment with cladribine across both the cladribine tablets 3.5 mg/kg and placebo groups (2.07 tablets 3.5 mg/kg in year 1 and year 2. In patients that met the treat- and 1.05 Adj-AE per 100 PY, respectively). The number of patients with ment guidelines specified in the EU SmPC for cladribine tablets TEAEs leading to death was very low, and was similar in the cladribine (MAVENCLAD SmPC. 2017), severe (Grade 3/4; < 0.5 × 109 cells/L) tablets 3.5 mg/kg and placebo groups (0.26 and 0.25 Adj-AE per 100 lymphopenia was uncommon (MAVENCLAD SmPC. 2017; Cook et al., PY, respectively). Listings and brief narratives for deaths in the 2017). Monotherapy Oral and All Exposed cohorts including those occurring during the registry phase are shown in Supplementary Table 4. 3.3. Summary of infections Headache was the most common TEAE (8.71 per 100 PY for cla- dribine tablets 3.5 mg/kg and 8.82 per 100 PY for placebo). The incidence rate for infections overall, severe infections, infec- Hematologic TEAEs occurring at a higher rate with cladribine tablets tions leading to discontinuation, or opportunistic infections, was com- (≥0.5 Adj-AE per 100 PY) were, in decreasing order of frequency, parable following cladribine tablets 3.5 mg/kg and placebo (Table 4). lymphopenia, leukopenia and neutropenia (Table 2). TEAEs that were The incidence of herpes zoster and herpetic infections was increased less frequent with cladribine tablets than placebo (≥0.5 Adj-AE per 100 following cladribine tablets 3.5 mg/kg versus placebo. For the AESI PY) included urinary tract infection (2.40 for placebo vs. 1.69 for cla- herpetic infections, herpes zoster was the most frequently reported dribine tablets 3.5 mg/kg), and influenza-like illness (3.28 for placebo preferred term for patients randomized to cladribine tablets 3.5 mg/kg, vs. 2.37 for cladribine tablets 3.5 mg/kg) which may be related to IFN-β followed by oral herpes and herpes simplex (see Table 4). A time to rescue therapy being required more frequently in patients randomized event analysis indicated that more events occurred shortly after treat- to placebo. ment with cladribine tablets 3.5 mg/kg in years 1 and 2, but the low Serious AEs (SAEs) were reported with an Adj-AE per 100 PY rate of number of overall events does not allow conclusions to be drawn 4.00 in the cladribine tablets 3.5 mg/kg group vs. 3.57 for placebo. (Supplementary Fig. 1). Except for lymphopenia (Adj-AE per 100 PY 0.12 vs. 0 for placebo; Herpes zoster cases were all dermatomal and followed a normal Table 2) the rate of SAEs with cladribine tablets was comparable to that course. There were no cases of post herpetic neuralgia reported in pa- for placebo. Details of the most frequently reported SAEs with an tients treated with cladribine tablets. The Adj-AE per 100 PY for serious Table 3 Effects of cladribine tablets on lymphocyte counts for the Monotherapy Oral cohort. Time point Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) Baseline N (missing) 640 (1) 921 (2) Median (IQR) cell count, 109/L 1.918 (1.560; 2.330) 1.870 (1.520; 2.300) Week 9 (nadir year 1) N (missing) 607 (25) 873 (43) Median (IQR) cell count, 109/L 1.890 (1.560; 2.280) 1.030 (0.790; 1.300) 9 Median (IQR) cell count reduction from baseline, 10 /L −0.005 (− 0.300; 0.260) −0.830 (− 1.155; −0.515) Week 48 N (missing) 395 (205) 587 (290) Median (IQR) cell count, 109/L 1.880 (1.530; 2.270) 1.220 (0.960; 1.500) Median (IQR) cell count reduction from baseline, 109/L −0.030 (−0.320; 0.280) −0.660 (−940; −0.400) Week 55 (nadir year 2) N (missing) 280 (306) 538 (330) Median (IQR) cell count, 109/L 1.900 (1.565; 2.345) 0.815 (0.600; 1.070) 9 Median (IQR) cell count reduction from baseline, 10 /L 0.010 (− 0.360; 0.300) −1.075 (− 1.440; − 0.730) Week 96 N (missing) 438 (104) 668 (155) Median (IQR) cell count, 109/L 1.900 (1.525; 2.280) 1.043 (0.810; 1.340) Median (IQR) cell count reduction from baseline, 109/L −0.065 (− 0.320; 0.290) − 0.800 (−1.110; − 0.500) 161 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 Table 4 Summary of infections and infestations for the Monotherapy Oral cohort. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) n Total PY Adj-AE per 100 n Total PY Adj-AE per 100 PY PY *Most commonly reported TEAEs in SOC Infections and Infestations (Adj-AE per 100 PY 314 1160.8 27.05 478 1917.5 24.93 of ≥ 1.0 in either group) Nasopharyngitis 97 1764.5 5.50 158 2951.0 5.35 Upper respiratory tract infection 61 1869.1 3.26 109 3112.0 3.50 Influenza 51 1898.1 2.69 87 3169.5 2.74 Bronchitis 22 1964.4 1.12 55 3234.1 1.70 Urinary tract infection 46 1916.8 2.40 55 3249.7 1.69 Herpes zoster 4 2019.0 0.20 28 3360.2 0.83 Pharyngitis 31 1961.4 1.58 27 3348.0 0.81 Rhinitis 22 1962.3 1.12 24 3354.0 0.72 Serious‡ TEAEs in SOC Infections and infestations (Adj-AE of ≥ 0.05 in either group) 10 2003.4 0.50 23 3357.6 0.69 Appendicitis 2 2023.5 0.10 1 3426.8 0.03 Chronic Hepatitis C 1 2019.4 0.05 0 3432.7 0 Chronic sinusitis 1 2024.1 0.05 0 3432.7 0 Erysipelas 1 2022.1 0.05 0 3432.7 0 Herpes zoster 0 2026.0 0 2 3425.6 0.06 Myocarditis bacterial 1 2024.2 0.05 0 3432.7 0 Pneumonia 3 2019.7 0.15 6 3403.4 0.18 Pyelonephritis 0 2026.0 0 2 3423.1 0.06 Urethral abscess 1 2025.9 0.05 1 3430.3 0.03 Urinary tract infection 1 2024.4 0.05 4 3419.4 0.12 Infections and infestations SOC leading to treatment discontinuation (Adj-AE of ≥ 0.01 in 3 2020.8 0.15 4 3415.5 0.12 either group) Hepatitis B 0 2026.0 0 1 3427.9 0.03 Herpes zoster 0 2026.0 0 1 3424.8 0.03 Pneumonia bacterial 0 2026.0 0 1 3428.2 0.03 Urinary tract infection 0 2026.0 0 1 3432.6 0.03 Appendicitis 1 2025.8 0.05 0 3432.7 0 Gardnerella infection 1 2025.8 0.05 0 3432.7 0 Varicella 1 2021.0 0.05 0 3432.7 0 AESI severe infection (Adj-AE of ≥ 0.05 in any group) 17 1983.4 0.86 28 3336.2 0.84 Pneumonia 3 2109.7 0.15 6 3403.4 0.18 Urinary tract infection 2 2023.4 0.10 4 3419.4 0.12 Herpes zoster 1 2024.4 0.05 3 3424.1 0.09 Gastroenteritis 0 2026.0 0 2 3423.8 0.06 Pyelonephritis 0 2026.0 0 2 3423.1 0.06 AESI Opportunistic infections 23 1965.5 1.17 36 3321.9 1.08 Axillary candidiasis 1 2018.3 0.05 0 3432.7 0 Fungal infection 2 2023.4 0.10 8 3398.3 0.24 Fungal skin infection 2 2018.4 0.10 3 3430.8 0.09 Mastitis fungal 1 2025.6 0.05 0 3432.7 0 Onychomycosis 3 2023.1 0.15 4 3419.0 0.12 Oral candidiasis 1 2021.6 0.05 1 3431.0 0.03 Oral fungal infection 2 2013.9 0.10 1 3431.5 0.03 Pulmonary tuberculosis 0 2026.0 0 1 3429.6 0.03 Skin candida 1 2025.4 0.05 0 3432.7 0 Tonsillitis fungal 1 2022.0 0.05 0 3432.7 0 Tuberculosis 0 2026.0 0 1 3432.7 0.03 Upper respiratory fungal infection 0 2026.0 0 1 3431.7 0.03 Urinary tract infection fungal 0 2026.0 0 1 3424.1 0.03 Vulvovaginal candidiasis 3 2013.3 0.15 7 3416.9 0.20 Vulvovaginal mycotic infection 7 2016.4 0.35 9 3402.0 0.26 AESI Herpetic infections 19 1969.9 0.96 60 3262.7 1.84 Herpes zoster 4 2019.0 0.20 28 3360.2 0.83 Oral herpes 11 1996.9 0.55 20 3381.3 0.59 Herpes simplex 1 2018.1 0.05 5 3416.6 0.15 Herpes virus infection 1 2020.6 0.05 4 3416.9 0.12 Varicella 2 2020.6 0.10 3 3422.6 0.09 Herpes zoster disseminated 1 2023.7 0.05 2 3427.5 0.06 Genital herpes 0 2026.0 0 1 3429.0 0.03 AESI Herpes zoster** 4 2017.7 0.20 29 3356.2 0.86 Herpes zoster 4 2019.0 0.20 28 3360.2 0.83 Herpes zoster disseminated 1 2023.7 0.05 2 3427.5 0.06 *System organ class and preferred terms are presented in descending order of Adj-AE per 100 PY rate in the cladribine tablets 3.5 mg/kg group. ‡Serious was defined as resultant in death; life-threatening; required inpatient hospitalization; congenital anomaly or birth defect; or was otherwise considered as medically important. n is the number of patients with events; Total PY is the total patient's time on study in years. If a patient has multiple events, the time to first event is considered. For a patient with no event the time is censored at the last follow-up time for that patient. AESI = Severe infection is a custom grouping defined by any serious or severe event belonging to the MedDRA SOC Infections and infestations. AESI = Medical Concept Opportunistic Infection is a custom query containing all PTs belonging to the medical concept of opportunistic infections excluding the PTs belonging to the HLT Herpes viral infections. ** From AESI = Medical concept herpetic infection, which is a custom grouping defined by PTs with the term ‘herpes zoster’. 162 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 Table 5 Incidence rates, risk difference and risk ratio for malignancies in patients treated with cladribine or placebo. Monotherapy Oral cohort Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) n/ PY at risk 3/2022.11 10/3414.20 Incidence per 100 PY 0.14836 0.29289 95% CI of incidencea 0.0478–0.4600 0.1576–0.5444 Risk Difference per 100 PY 0.1445 95% CI of Risk Difference per 100 PYb −0.1656–0.4141 Risk Ratio 1.9742 95% CI of Risk Ratioc 0.5433–7.1733 All Exposed cohort Placebo (N = 802) Cladribine (N = 1976) n/ PY at risk 4/2357.09 32/8579.39 Incidence per 100 PY 0.16970 0.37299 95% CI of incidencea 0.0637–0.4522 0.2638–0.5274 Risk Difference per 100 PY 0.2033 95% CI of Risk Difference per 100 PYb −0.0785–0.3947 Risk ratio 2.1979 95% CI of Risk Ratioc 0.7773–6.2148 CI, confidence interval; n, number of patients with events; PY, patient year. a CI computed with the exact Clopper–Pearson formula. b CI computed using the Miettinen and Nurminen method. c CI computed with the Wald method for the number of subject with events using a Poisson regression model with fixed effect for treatment group and log of time at risk as an offset. or severe herpes zoster was 0.09 with cladribine tablets 3.5 mg/kg and SAEs occurring during periods of Grade 3 or 4 lymphopenia in patients 0.05 with placebo. The incidence rate of serious or severe infections treated with cladribine tablets 3.5 mg/kg. Periods of Grade 3 or 4 was low in the cladribine tablets 3.5 mg/kg group and no relevant lymphopenia were defined as the onset of the Grade 3 or 4 lymphopenia differences vs. placebo were observed at the preferred term level (ALC < 0.5 × 109 cells/L) until recovery to ALC > 0.5 × 109 cells/L, (Table 4; AESI Severe infection is a custom grouping defined by any plus 2 weeks. serious or severe event belonging to the MedDRA SOC Infections and During periods of Grade 3 and 4 lymphopenia infections occurred infestations). with increased frequency. The type of infectious events reported during The incidence of opportunistic infections was similar for cladribine Grade 3 and 4 lymphopenia did not differ from those occurring outside tablets 3.5 mg/kg (1.08 Adj-AE per 100 PY) and placebo (1.17 Adj-AE of these periods (Supplementary Table 6). Herpes zoster occurred more per 100 PY). More than half of the opportunistic infections were mu- frequently during these periods (Adj AE per 100 PY 4.50 vs. 0.73 cocutaneous and cutaneous fungal infections, which resolved on stan- without Grade 3 or 4 lymphopenia). The clinical profile of herpes zoster dard treatments. Opportunistic infections that could be life-threatening was uncomplicated, consistent with findings for the overall (e.g., progressive multifocal leukoencephalopathy, cryptococcosis, Monotherapy Oral cohort. toxoplasmosis, pneumocystis jirovecii pneumonia, cytomegalovirus in- Upper respiratory tract infections were reported more frequently fection or listeriosis) were not observed in the cladribine trials or during during periods of Grade 3 or 4 lymphopenia. Overall, there was a low the subsequent registry period. incidence of opportunistic infections during severe lymphopenia; the incidence was similar for patients in the cladribine tablets 3.5 mg/kg and placebo groups. The only opportunistic infections reported during 3.4. Infections during periods of grade 3 or 4 lymphopenia Grade 3 or 4 lymphopenia were single occurrences in the preferred terms ‘Urinary tract infection fungal’ and ‘Fungal infection’ . None of A post-hoc analysis specifically examined the infectious AEs and Fig. 1. Malignancy incidence for cla- dribine compared with external re- ference populations. aSIR calculated against the GLOBOCAN reference po- pulation (non-melanoma skin cancer excluded due to inconsistent reporting in GLOBOCAN). Reference population (GLOBOCAN 2012), http://globocan. iarc.fr/default.aspx. PY, patient-years; SIR, standardized incidence ratio. 163 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 these events were severe or serious. of malignancy was assessed by examining the risk difference. Risk dif- ference (RD) per 100 PY and risk ratios (RR) are shown in Table 5. The 4. Malignancy risk 95% confidence intervals of RD and RR include 0 and 1, respectively, supporting the conclusion that the current evidence does not indicate Cladribine is a prodrug which is phosphorylated intracellularly to its an increased risk of malignancies with cladribine treatment. active form, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), by deox- Hematologic or lymphoproliferative cancers were not observed ycytidine kinase, and Cd-ATP is degraded by 5′-nucleotidase. B and T following exposure to cladribine in either the Monotherapy Oral or All lymphocytes contain a higher deoxycytidine kinase to 5′-nucleotidase Exposed cohorts as might have been expected from an agent activated activity ratio than other cells types, which means Cd-ATP accumulates in lymphocytes, and there was no clustering of specific tumor types as selectively to high levels in these cells, leading to their apoptosis might have been expected if cladribine were carcinogenic (See (Leist and Vermersch, 2007; Carson et al., 1986; S. Seto et al., 1986; Supplementary Table 7). S. Seto et al., 1986; Saven and Piro, 1994). Cladribine's clinical efficacy is thought to be due to selective reduction and subsequent repopulation 4.1. Comparison with external reference populations of both B and T cells. In view of cladribine's mechanism of action the risk of malignancy was thoroughly evaluated in the clinical program. In For the Monotherapy Oral cohort, the analysis of the malignancy the integrated analysis of the clinical trials and the registry follow-up of SIR showed that the rate of malignancies observed with cladribine ta- cladribine in MS, no significant increase of malignancies has been ob- blets 3.5 mg/kg was almost identical (0.97, 95% CI 0.44–1.85) to the served. In particular there was no increase in the types of malignancies expected rate of malignancies from the GLOBOCAN matched reference known to be associated with severe immunosuppression (e.g. non population (Fig. 1). Analysis of the malignancy SIR for the All Exposed melanoma skin cancer, virally associated tumors and hematological cohort showed that the rate of malignancies compared to the GLOBO- malignancies). CAN matched reference population was similar following cladribine While there was an imbalance in the total number of cases of ma- exposure (1.06, 95% CI 0.70–1.55) (Fig. 1). The GLOBOCAN database lignancies observed in the cladribine tablets 3.5 mg/kg group compared does not include data on non-melanoma skin cancers (NMSCs), there- to placebo, this was not meaningful after adjustment for number of fore, an epidemiologic database from Denmark, a country with low patients, risk and different follow-up times. For estimation of any in- NMSC incidence rates, was used for external comparison (Birch- cremental effect of cladribine tablets 3.5 mg/kg over placebo, the risk Johansen et al., 2010). This showed no increase in incidence of NMSC Fig. 2. Risk of malignancy over time for cladribine in the Monotherapy Oral cohort (A) or All Exposed cohort (B). 164 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 for cladribine compared to the reference database (data not shown). 100 patient years of exposure and follow-up time. This is done to ac- count for different follow-up times in the treatment arms. In this con- 4.2. Risk of malignancies over time text, estimates for some events which have occurred in the short term after drug exposure may be diluted by accounting for longer exposure There was no increase in the risk of malignancy over time (Fig. 2). times. However, previous publications of individual studies (e.g. In the Monotherapy Oral cohort, the malignancy rate for cladribine CLARITY) have described adverse events in comparison to placebo in tablets 3.5 kg/mg during years 1–4 (0.29 Adj-AE per 100 PY) was very the short term (2 year) context (Giovannoni et al., 2010; close to the rate during years 5–8+ (0.28 Adj-AE per 100 PY), in- Giovannoni et al., 2017; Leist et al., 2014) and the results from these dicating that the malignancy incidence rate was constant during these 2 short-term analyses were broadly similar to those from the analyses periods. In contrast, the malignancy rate in the placebo group was presented here. The long-term analyses in this report are particularly higher during years 5–8+ (0.60 Adj-AE per 100 PY) than during years useful in analyzing the incidence of rare events and events that take 1–4 (0.06 Adj-AE per 100 PY), but the overall number of events was time to be observed, and comparison with other safety databases was small. In the All Exposed cohort, the malignancy rate for cladribine useful in providing context for these data. during years 1–4 (0.38 Adj-AE per 100 PY) was identical to the rate Lymphopenia is an expected effect of treatment with cladribine during years 5–8 + , demonstrating that the malignancy rate remained tablets due to the mechanism of action. In a companion paper, pro- constant over time (Fig. 2). In the placebo group, the malignancy rate in viding details of lymphocyte changes over time, it is shown that after years 1–4 was 0.10 and during years 5–8+ it was 0.57. the initial reduction in lymphocyte count numbers, their recovery be- gins soon after treatment with cladribine tablets in year 1 and year 2 (Comi et al., 2018). The majority of patients treated with cladribine 4.3. Comparison of overall experience for cladribine and other disease tablets 3.5 mg/kg in clinical trials (around 75%) did not experience modifying drugs Grade 3/4 lymphopenia (ALC < 0.5 × 109 cells/L) over the 2 years of treatment and Grade 4 (ALC < 0.2 × 109 cells/L) at any time over the 2 The overall malignancy incidence rate of cladribine (both years was experienced by < 1% of patients (MAVENC- Monotherapy Oral and the All Exposed cohort) was compared with data LAD SmPC. 2017). In general, there was no increase in the risk of in- for other DMDs (using mainly regulatory sources except in the case of fections including opportunistic infections with cladribine tablets fingolimod) (Table 6). This showed that the incidence rate for the versus placebo, except for herpes zoster. There were no cases of sys- Monotherapy Oral and All Exposed cohorts is similar to the rates re- temic, serious or disseminated herpes zoster attributed to treatment ported for other DMDs. with cladribine tablets. Occurrences of severe lymphopenia (ALC < 0.5 × 109 cells/L) resulted in an increased frequency of infec- 5. Discussion tions, but the nature of these was not different to that observed in the overall patient group treated with cladribine tablets 3.5 mg/kg. In The integrated analyses reported here show that the AE profile and general, patients with Grade 4 lymphopenia are more susceptible to safety for cladribine tablets 3.5 mg/kg as monotherapy are favorable infections, but these actually occurred infrequently in patients treated overall. This safety profile should be considered in the context of the with cladribine tablets 3.5 mg/kg. The EU SmPC for cladribine tablets clinical efficacy and its durable effect. Given the unique treatment states that if lymphocyte counts drop to < 0.2 × 109 cells/L during schedule of cladribine tablets, an important consideration is subsequent treatment, anti-herpes prophylaxis according to local standard practice therapy. A post-hoc analysis of patients with relapsing MS treated with should be considered during the time of Grade 4 lymphopenia (MAV- cladribine tablets 3.5 mg/kg as monotherapy (in CLARITY, CLARITY ENCLAD SmPC. 2017). Extension or ORACLE-MS and followed up in PREMIERE) suggested Analysis of malignancy rates in the overall clinical program of cla- that only a minority received a subsequent DMD (for any reason) after dribine in MS does not indicate an increase compared to placebo- treatment with cladribine tablets. At 4 years after last dose of cladribine treated patients, either in the All Exposed cohort or the Monotherapy tablets, the Kaplan-Meier estimated proportion of patients who had Oral cohort. With regards to epidemiologic analyses, the standardized initiated another DMD was 26.8% (95% CI: 22.2–31.5%); see incidence rate of malignancies with cladribine approached unity, in- Supplementary Information for details. dicating no increase in the incidence of malignancies in the clinical Cladribine tablets are given over 2 weeks (each with 4 or 5 treat- program compared with matched reference populations. The malig- ment days) per year for 2 years (cumulative dose 3.5 mg/kg), followed nancies observed in the cladribine program were typical of those seen by no treatment with cladribine for the next 2 years. For a treatment in the general population with no increase in the incidence of malig- such as cladribine tablets with its durable efficacy, the relevant ob- nancies over time in cladribine-treated patients. There was no clus- servation period for safety extends well beyond the time when study tering of malignancies of any particular type, and no increase in ma- treatment is being administered. Therefore, observation periods are not lignancies commonly associated with immunosuppression were directly linked to periods of active treatment or placebo and incidence observed (hematologic, virally induced or non-melanoma skin cancers). rates may change during longer observation periods. The safety data Given the limitations of the clinical trial population on identifying rare analyzed here is presented as observation-adjusted incidence rates per Table 6 Comparison of overall malignancy incidence rate of cladribine (both Monotherapy Oral and the All Exposed cohort) and other disease modifying drugs in multiple sclerosis patient populations. Disease modifying drug Incidence rate (cases per 100 PY) Cladribine tablets 3.5 mg/kg – Monotherapy Oral cohort 0.29 Cladribine – All Exposed cohort 0.37 Alemtuzumab (Lemtrada CDER Background Package 2013) 0.37 Natalizumab (Tysabri FDA Medical Review 2004) 0.32 Fingolimod (Kappos et al., 2014) 1.19 Dimethyl fumarate (Tecfidera RMP v5. Biogen Idec 2013) 0.38 Ocrelizumab (Ocrevus CDER Medical Review 2016) 0.40 PY, patient-year 165 S. Cook et al. Multiple Sclerosis and Related Disorders 29 (2019) 157–167 adverse events and in order to further monitor and characterize the Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, long-term safety profile of cladribine tablets, an 8000-patient post-au- FivePrime, GlaxoSmithKline, GW Pharma, Merck, Pfizer Inc, Protein thorization safety study comparing cladribine tablets with fingolimod is Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi- being conducted. Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, 6. Conclusions Merck, Novartis, and Ironwood. AN, CH and ES are employees of Merck KGaA, Darmstadt, Germany The AE profile for cladribine tablets 3.5 mg/kg as a monotherapy AG is an employee of Merck, Aubonne, Switzerland, a division of has been well-characterized in a pooled population of patients from Merck KGaA, Darmstadt, Germany. early to more advanced relapsing MS. Lymphopenia is expected from the mode of action of cladribine tablets, and treatment guidelines re- Supplementary materials duce the incidence of severe and prolonged lymphopenia with cla- dribine treatment, while preserving durable efficacy. In general, there Supplementary material associated with this article can be found, in was no increased risk for infections with cladribine tablets 3.5 mg/kg the online version, at doi:10.1016/j.msard.2018.11.021. Monotherapy, except for a higher incidence of herpes zoster. Severe lymphopenia (ALC < 0.5 × 109 cells/L) resulted in an increased fre- References quency of infections. 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Cladribine treatment of multiple This study was sponsored by EMD Serono, Inc., a business of Merck sclerosis is associated with depletion of memory B cells. J. Neurol. 265 (5), 1199–1209. KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA – Comi, G., Cook, S.D., Giovannoni, G., et al., 2013. MRI outcomes with cladribine tablets Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW). The for multiple sclerosis in the CLARITY study. J. Neurol. 260 (4), 1136–1146. authors would like to thank patients and their families, investigators, Comi, G., Cook, S., Giovannoni, G., et al., 2018. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. co-investigators, and the study teams at each of the participating cen- Mult. Scleros. Relat. Disord. ters and at Merck KGaA, Darmstadt, Germany. Medical writing assis- Cook, S., Vermersch, P., Comi, G., et al., 2011. 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The sponsor patients retrospectively assigned the diagnosis of MS using modern criteria: results from the ORACLE-MS study. Mult. Scler. J. Exp. Transl. Clin. 3 (4). https://doi.org/ participated in the study design, collection, analysis and interpretation 10.1177/2055217317732802. of the data; in the writing of the report and in the decision to submit the Giovannoni, G., Comi, G., Cook, S., et al., 2010. A placebo-controlled trial of oral cla- article for publication. dribine for relapsing multiple sclerosis. N. Engl. J. Med. 362 (5), 416–426. Giovannoni, G., Cook, S., Rammohan, K., et al., 2011. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine Conflict of interest statements tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 10 (4), 329–337. Giovannoni, G., Soelberg Sorensen, P., Cook, S., et al., 2017. Safety and efficacy of cla- SC has received honoraria for lectures/consultations from Merck, dribine tablets in patients with relapsing-remitting multiple sclerosis: results from the Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, randomized extension trial of the CLARITY study. Mult. Scler. https://doi.org/10. Teva Pharmaceuticals, and Actinobac Biomed Inc.; has served on ad- 1177/1352458517727603. visory boards for Bayer HealthCare, Merck, Actinobac Biomed, Teva Giovannoni, G., Soelberg Sorensen, P., Cook, S., et al., 2018. Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple Pharmaceuticals, and Biogen Idec; and received grant support from sclerosis: a post hoc analysis of the CLARITY study. Mult. Scler. https://doi.org/10. Bayer HealthCare. 1177/1352458518771875. TL has received consultancy fees or clinical research grants from Giovannoni, G., 2017. Cladribine to treat relapsing forms of multiple sclerosis. 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