Multiple Sclerosis and Related Disorders 46 (2020) 102572 Contents lists available at ScienceDirect Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard Original article Long-term safety data from the cladribine tablets clinical development T program in multiple sclerosis T. Leista, , S. Cookb, G. Comic, X. Montalband, G. Giovannonie, A. Noltingf, D. Damiang, S. Syedg,1, ⁎ A. Galazkah a Division of Clinical Neuroimmunology, Jefferson University, Comprehensive MS Center, Philadelphia, PA, USA b Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, USA c Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy d Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain e Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK f Merck KGaA, Darmstadt, Germany g EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, a business of Merck KGaA, Darmstadt, Germany h Merck, Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Germany ARTICLE INFO ABSTRACT Keywords: Background: Long-term safety data are of particular interest for any newly approved treatment in multiple Cladribine tablets sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as Multiple sclerosis;, Safety cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the Long-term integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. Methods: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. Results: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cla­ dribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cla­ dribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference po­ pulation (standardized incidence ratio, 0.88; 95% CI, 0.44–1.69). Conclusion: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cla­ dribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis. Abbreviations: Adj-AE per 100 PY, observation-adjusted incidence rates per 100 patient-years; AE, adverse event; AESI, AEs of special interest; NMSC, non- melanoma skin cancer; RRMS, relapsing-remitting MS; SAE, serious adverse event; SIR, standardized incidence ratio; TEAE, treatment-emergent adverse event ⁎ Corresponding author. E-mail address: Thomas.Leist@jefferson.edu (T. Leist). 1 Present address: Sanofi US, Cambridge, MA, USA. https://doi.org/10.1016/j.msard.2020.102572 Received 3 July 2020; Received in revised form 6 October 2020; Accepted 7 October 2020 Available online 08 October 2020 2211-0348/ © 2020 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/). T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 1. Introduction In the CLARITY trial, there was a numerical imbalance in the malig­ nancy rate with cladribine tablets relative to placebo (Giovannoni et al., Cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative 2010), but the rate in the overall clinical program for cladribine in MS dose over 2 years, referred to as cladribine tablets 3.5 mg/kg) have was not significantly increased compared to placebo-treated patients been approved in Europe and many other countries, including the USA. and with no increase in the incidence of malignancies over time in Cladribine tablets 3.5 mg/kg are administered for 2 weeks over 2 cladribine-treated patients being apparent (Cook et al., 2019). months as two annual courses and show durable efficacy in patients Here we provide the final report on the integrated analysis of the with relapsing multiple sclerosis (MS) (Giovannoni et al., 2010; safety profile of cladribine tablets 3.5 mg/kg from the clinical devel­ Giovannoni et al., 2011; Rammohan et al., 2012; Comi et al., 2013; opment program, including final data from the PREMIERE registry. Leist et al., 2014; Freedman et al., 2017; Giovannoni, 2017; Giovannoni et al., 2018). The long-lasting therapeutic effect of the drug 2. Methods is believed to be related to transient reversible reductions in lympho­ cytes and certain lymphocyte subsets (Giovannoni, 2017; Baker et al., 2.1. Patients – monotherapy oral cohort 2017; Comi et al., 2019; Leist and Weissert, 2009; Stuve et al., 2019; Wiendl, 2017). In this final report from the clinical development program, safety Long-term safety data are of particular interest for any newly ap­ data for cladribine tablets 3.5 mg/kg and 5.25 mg/kg from the three proved treatment in MS and cladribine tablets 3.5 mg/kg is uniquely Phase III studies, CLARITY, CLARITY Extension and ORACLE-MS, and supported by long-term safety data from the clinical development the completed PREMIERE registry were combined (Fig. 1). Cladribine program. Indeed, the safety profile of cladribine tablets 3.5 mg/kg has tablets 5.25 mg/kg over 2 years is not an approved dose; data for pa­ been well characterized with prior publication of interim integrated tients who received this dose in the clinical development program are safety data from two earlier data cut-offs (cumulative to February 2015 shown in the supplementary tables. and May 2017, respectively), including interim data from the long- Full methodology for the integrated analysis has been described in running safety registry, PREMIERE (Cook et al., 2019; Cook et al., detail previously (Cook et al., 2019). Briefly: CLARITY (NCT00213135) 2018). was a 96-week, Phase III, double-blind, randomized, placebo-con­ Previous safety updates have shown that, in general, there was no trolled, parallel-group, multicenter study evaluating the safety and ef­ increase in the risk of infections with cladribine tablets 3.5 mg/kg ficacy of cladribine tablets with cumulative doses of 3.5 and 5.25 mg/ versus placebo during the clinical development program, except for kg in patients with relapsing-remitting MS (RRMS) (Giovannoni et al., herpes zoster (Cook et al., 2019). Periods of severe lymphopenia 2010). CLARITY Extension (NCT00641537) was a 96-week, Phase IIIb, (<0.5 × 109 cells/L) were associated with an increased frequency of double-blind, randomized, parallel-group, multicenter, extension study infections, but the pattern of infections was not different to that in an that evaluated the safety and efficacy of cladribine tablets for an ad­ overall group receiving cladribine tablets 3.5 mg/kg (Cook et al., 2019). ditional 2 years beyond the CLARITY study, with and without further Fig. 1. Overview of patients treated with cladribine tablets 3.5 mg/kg or placebo in the Monotherapy Oral cohort. *Patients with prior enrolment into selected clinical trials with cladribine tablets were eligible to enter PREMIERE once participation in the clinical trial had ended, but not all clinical trial participants were included in the registry as indicated by the dotted line. †The Monotherapy Oral cohort also contained a cladribine tablets (CT) 5.25 mg/kg treatment group; data not shown. All safety analyses were performed using the ‘as treated principle’. For the Monotherapy Oral cohort, if patients received only placebo or were in the observational follow-up period without having switched to CT (i.e. in CLARITY Extension [Ext]), then their data became part of the placebo group. Patients who switched treatment from placebo to CT in subsequent studies/ periods had their time on placebo censored at the time of the switch. Patients who switched treatment from placebo to CT 3.5 mg/kg had their time on CT 3.5 mg/kg initiated at the time of switching. Patients who were treated with CT 3.5 mg/kg in CLARITY and were then re-exposed to CT 3.5 mg/kg in a subsequent study/period (i.e. in CLARITY Ext) had their time on CT 3.5 mg/kg censored at the time of re-exposure. CP 3.5 mg/kg, CT 3.5 mg/kg in CLARITY followed by placebo in CLARITY Ext; CP 5.25 mg/kg, CT 5.25 mg/kg in CLARITY followed by placebo in CLARITY Ext; CC 7 mg/kg, CT 3.5 mg/kg in CLARITY followed by CT 3.5 mg/kg in CLARITY Ext; CC 8.75 mg/kg, CT 5.25 mg/kg in CLARITY followed by CT 3.5 mg/kg in CLARITY Ext; PC 3.5 mg/kg, placebo in CLARITY followed by CT 3.5 mg/kg in CLARITY Ext. 2 T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 treatment (Giovannoni et al., 2018). ORACLE-MS (NCT00725985) was AE)/(sum of observation time in days among patients at risk for initial a 96-week Phase III, double-blind, randomized, placebo-controlled, occurrence of an AE or time on study/365.25). Serious AEs were de­ multicenter study that evaluated the safety and efficacy of cladribine fined as AEs resulting in death, that were life-threatening, required tablets at cumulative doses of 3.5 and 5.25 mg/kg over 2 years in pa­ inpatient hospitalization, resulted in congenital anomaly or birth de­ tients with a first clinical demyelinating event (Leist et al., 2014; fect, or were otherwise considered as medically important. Freedman et al., 2017). The PREMIERE registry (NCT01013350), which ran from November 2009 to October 2018, was a prospective, ob­ 2.3. Serious adverse events of special interest servational, long-term safety study of patients who had participated in at least one of the four cladribine tablets interventional clinical trials Lymphopenia is an expected AE due to the mode of action of cla­ (CLARITY (Giovannoni et al., 2010), CLARITY Extension dribine, which causes selective, transient lymphocyte reduction. (Giovannoni et al., 2018), ORACLE-MS (Leist et al., 2014), or ONWARD Consequently, lymphopenia-associated immunosuppression and re­ (Montalban et al., 2018)). duction of cell-mediated immunity raises potential concerns about an Patients with prior enrolment into these trials were eligible, with increase in the incidence of infections or malignancies. Three categories written informed consent, to enter PREMIERE once participation in the of AEs – lymphopenia, infections, and malignancies – were therefore respective clinical trial had ended. The objective of the PREMIERE pre-defined as serious AEs of special interest (AESI). With regard to registry was to monitor long-term safety in the clinical trial population malignancies, standardized incidence ratios (SIRs) were calculated in in order to better characterize the potential safety risks of oral cla­ relation to the matched GLOBOCAN 2012 reference population (GLO­ dribine tablets 3.5 mg/kg. The total duration of follow-up was 8 years BOCAN, 2012). Risk differences (cladribine tablets versus placebo) after the patients’ first enrolment into a clinical trial or until October were presented with corresponding two-sided 95% confidence intervals 2018, whichever occurred first. No investigational product or placebo (CIs) on Adj-AE per 100 PY, estimated by the Miettinen and Nurminen was administered during the PREMIERE registry period. method unless otherwise specified (Miettinen and Nurminen, 1985). The Monotherapy Oral cohort represents the primary cohort that Data are also presented for the system organ class ‘skin and sub­ evaluated the safety of cladribine tablets 3.5 mg/kg as monotherapy cutaneous tissue disorders’ and for the preferred term ‘rash, general­ with long-term follow-up data, and was used for all safety analyses ized’, as part of the AESI evaluation. described in this report. Patients from the ONWARD study were ex­ cluded from the Monotherapy Oral cohort, because patients received 3. Results IFN-beta treatment in addition to cladribine tablets. 3.1. Patient characteristics 2.2. Analysis of adverse events and serious adverse events This final integrated safety analysis for the Monotherapy Oral co­ All safety analyses were performed using the ‘as treated principle’, hort included 923 patients who received cladribine tablets 3.5 mg/kg as described in a prior safety publication (Cook et al., 2019), with pa­ and 641 patients who received placebo. Patient characteristics were tients who switched from placebo to cladribine tablets 3.5 mg/kg generally balanced between the two groups (Table 1). Approximately having their time on placebo censored at the time of switch. Patients two-thirds of patients were women and the mean age was similar be­ who were treated with cladribine tablets 3.5 mg/kg in CLARITY and tween those receiving placebo and those receiving cladribine tablets were re-exposed in a subsequent study/period (i.e. in CLARITY Exten­ 3.5 mg/kg. The number of patients exposed to cladribine tablets sion) had their time on cladribine tablets 3.5 mg/kg censored at the 3.5 mg/kg was larger and they had a longer average time period of time of re-exposure. All integrated analyses were performed using SAS® follow up compared to those who received placebo, reflective of the fact Software version 9.2 or later. that placebo-treated patients from CLARITY may have received cla­ Adverse events (AEs) and Medical Histories in all studies were re­ dribine tablets 3.5 mg/kg in CLARITY Extension. coded using the Medical Dictionary of Regulatory Activities (MedDRA) v20.0. As previously described (Cook et al., 2019), treatment emergent 3.2. Serious TEAEs AEs (TEAEs) were defined as AEs absent prior to treatment that oc­ curred on or after day 1 during the treatment and observation period. The incidence of serious TEAEs is summarized in Table 2. Overall Assessments of AEs mainly used observation-adjusted incidence rates the reported number of serious TEAEs was higher in the cladribine ta­ (Adj-AE). Adjusted AE incidence per 100 patient-years (Adj-AE per 100 blets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 ser­ PY) were calculated as the time-adjusted AE incidence rate; this can be ious TEAE) versus the placebo group (68/641 [10.6%] patients with at interpreted as the average number of events expected to occur in 100 least 1 serious TEAE). The corresponding incidence of serious TEAEs patient-years, calculated as 100*(number of patients with at least one was 3.80 and 3.05 per 100 PY, respectively. There were no cases of Table 1 Characteristics of patients included in the Monotherapy Oral cohort from the cladribine tablets clinical development program. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) Patient-yearsa 2421.5 3936.7 Time on study, years;a mean (SD) 3.79 (2.67) 4.28 (2.54) Time on study, ≥96 weeks (~2 years), n (%) 493 (76.9) 784 (84.9) Time on study, ≥192 weeks (~4 years), n (%) 204 (31.8) 431 (46.7) Time on study, ≥432 weeks (~9 years), n (%) 18 (2.8) 26 (2.8) Age, years;b mean (SD) Median Range 37.15 (9.83) 36.53 18.1–64.2 37.84 (10.48) 37.62 18.2–66.1 Age ≤40 years,b n (%) 396 (61.8) 540 (58.5) Age >40 years,b n (%) 245 (38.2) 383 (41.5) Female, n (%) 424 (66.1) 612 (66.3) Prior treatment with DMD, n (%) 131 (20.4) 184 (19.9) DMD, disease-modifying drug; SD, standard deviation. a Cumulative to October 2018. b As reported at first dosing date. 3 T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 progressive multifocal leukoencephalopathy in the cladribine clinical infections occurred more frequently in the cladribine tablets 3.5 mg/kg development program for MS. group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Herpes zoster occurred more frequently during periods 3.3. Serious adverse events of special interest of Grade 3 or 4 lymphopenia (<0.5 × 109 cells/L) with an Adj-AE of 4.15 versus 0.64 per 100 PY. There were no cases of serious dis­ 3.3.1. Lymphopenia seminated herpes zoster attributed to treatment with cladribine tablets. In the cladribine tablets 3.5 mg/kg group, 4/923 patients had The incidence of pneumonia was similar in both groups, with an Adj-AE lymphopenia classified as a serious TEAE, resulting in an Adj-AE of 0.10 of 0.15 per 100 PY for cladribine tablets 3.5 mg/kg versus 0.12 per 100 per 100 PY (Table 3). There were no serious lymphopenia events in the PY for placebo. placebo group. 3.3.3. Malignancy 3.3.2. Infections Overall, there was a numerical imbalance in malignancy incidence The overall incidence of infection and infestations is shown in between cladribine tablets 3.5 mg/kg and placebo with an Adj-AE of Table 3. The rate of serious infections and infestations was 2.5% (23/ 0.26 and 0.12 per 100 PY, respectively (difference not statistically 923 patients) in the cladribine tablets 3.5 mg/kg group and 1.6% (10/ significant); this was based on 10 cases of malignant tumors in the 641 patients) in the placebo group, resulting in an Adj-AE of 0.60 and cladribine tablets 3.5 mg/kg group with an exposure of 3918.9 patient 0.42 per 100 PY, respectively. years, versus 3 cases in the placebo group with an exposure of 2414.8 In the cladribine tablets 3.5 mg/kg group, 2/923 patients (0.2%) patient years (Table 5). There was no clustering of malignancies of any experienced serious herpes zoster, resulting in an Adj-AE of 0.05 per type i.e. different cancer types were only reported once in cladribine 100 PY. There were no cases of serious herpes zoster in the placebo tablets 3.5 mg/kg patients (with the exception of malignant melanoma, group. There was one case each of tuberculosis and pulmonary tu­ which was reported in two patients). Timing of diagnosis of malignancy berculosis in the cladribine tablets 3.5 mg/kg group classified as ser­ versus start of study drug ranged from 169 to 1853 days (Table 5). No ious. There was no obvious pattern of increase in other serious re­ increase in malignancies commonly associated with immunosuppres­ spiratory infections. Incidence of AESI severe infections, AESI sion was observed. opportunistic infections, and AESI herpetic infections for the Compared to the matched GLOBOCAN reference population (GLO­ Monotherapy Oral cohort are summarized in Table 4. BOCAN, 2012), the rate of malignancies observed with cladribine ta­ The incidence of severe infections was low in both the cladribine blets 3.5 mg/kg in the final integrated safety analysis was not different tablets 3.5 mg/kg group (Adj-AE of 0.76 per 100 PY) and the placebo from the expected rate in the matched reference population (SIR, 0.88; group (Adj-AE of 0.81 per 100 PY). The incidence of opportunistic in­ 95% CI, 0.44–1.69; Fig. 2). The corresponding SIR for placebo was 0.42 fections was an Adj-AE of 0.31 per 100 PY for cladribine tablets 3.5 mg/ (95% CI, 0.12–1.33). The GLOBOCAN database does not include data kg and 0.17 per 100 PY for placebo; the difference was driven primarily on non-melanoma skin cancers (NMSCs); however, there was no in­ by fungal infections. Fungal infections were mainly mucocutaneous and crease in NMSCs compared with placebo and no increase compared there were no systemic infections such as candida sepsis. AESI herpetic with key epidemiological data from Denmark (Norgaard et al., 2019). Table 2 Frequently reported serious* TEAEs (Adj-AE per 100 PY of ≥0.10; excluding TEAEs of special interest) in the Monotherapy Oral cohort from the cladribine tablets clinical development program. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) System organ class Preferred term n Total PY Adj-AE per 100 PY n Total PY Adj-AE per 100 PY At least 1 serious TEAE 68 2226.2 3.05 133 3498.1 3.80 Cardiac disorders 6 2410.4 0.25 7 3917.4 0.18 Endocrine disorders 4 2411.2 0.17 3 3929.3 0.08 Thyroid mass 3 2412.2 0.12 1 3934.5 0.03 Eye disorders 3 2418.2 0.12 3 3927.8 0.08 Gastrointestinal disorders 3 2403.0 0.12 11 3895.9 0.28 General disorders and administration site conditions 3 2413.0 0.12 6 3930.4 0.15 Hepatobiliary disorders 3 2413.0 0.12 6 3930.1 0.15 Injury, poisoning and procedural complications 5 2397.6 0.21 17 3885.1 0.44 Investigations 6 2402.7 0.25 14 3883.7 0.36 Blood creatine phosphokinase increased 4 2418.1 0.17 7 3908.0 0.18 Musculoskeletal and connective tissue disorders 3 2415.7 0.12 6 3919.2 0.15 Nervous system disorders 6 2411.7 0.25 12 3896.1 0.31 Pregnancy, puerperium and perinatal conditions 7 2407.1 0.29 9 3901.8 0.23 Abortion spontaneous† 3 2416.6 0.12 2 3935.1 0.05 Pregnancy 3 2413.5 0.12 1 3930.5 0.03 Psychiatric disorders 5 2411.7 0.21 4 3929.5 0.10 Renal and urinary disorders 3 2414.1 0.12 3 3927.0 0.08 Reproductive system and breast disorders 3 2411.6 0.12 8 3897.1 0.21 Respiratory, thoracic and mediastinal disorders 4 2410.3 0.17 8 3903.6 0.20 Surgical and medical procedures 3 2408.4 0.12 6 3915.6 0.15 *Serious was defined as resultant in death, life-threatening, required inpatient hospitalization, congenital anomaly or birth defect, or was otherwise considered as medically important. † Spontaneous miscarriage. The Medical Dictionary for Regulatory Activities (MedDRA) v20.0 was used for adverse event coding. Adj-AE per 100 PY, adjusted adverse events incidences per 100 patient-years; AESI, adverse events of special interest; PY, patient-years; TEAE, treatment emergent adverse events. 4 T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 Table 3 Table 4 Serious* TEAEs of special interest in the Monotherapy Oral cohort from the Summary of AESI infections and infestations (severe infection, opportunistic cladribine tablets clinical development program. For AESI malignancies, see infection, and herpetic infection; Adj-AE of ≥0.05 in any group) for the Table 5. Monotherapy Oral cohort from the cladribine tablets clinical development program. Placebo (N = 641) Cladribine tablets 3.5 mg/kg (N = 923) Placebo (N = 641) Cladribine tablets 3.5 mg/kg System organ class n Total PY Adj-AE n Total PY Adj-AE (N = 923) Preferred term per per 100 n Total PY Adj-AE n Total PY Adj-AE 100 PY PY per 100 per 100 PY PY Blood and lymphatic 0 2421.5 0 10 3912.7 0.26 system disorders Severe infection 19 2358.8 0.81 29 3829.1 0.76 Lymphopenia 0 2421.5 0 4 3925.4 0.10 Appendicitis 2 2419.0 0.08 1 3930.8 0.03 Infections and 10 2395.8 0.42 23 3857.2 0.60 Gastroenteritis 0 2421.5 0 2 3925.3 0.05 infestations Herpes zoster 1 2415.6 0.04 3 3928.1 0.08 Anal abscess 0 2421.5 0 1 3932.5 0.03 Pneumonia 4 2412.6 0.17 6 3907.4 0.15 Appendicitis 2 2419.0 0.08 1 3930.8 0.03 Pyelonephritis 0 2421.5 0 2 3927.2 0.05 Breast abscess 0 2421.5 0 1 3933.2 0.03 Sinusitis 0 2421.5 0 2 3935.0 0.05 Chronic hepatitis C 1 2414.9 0.04 0 3936.7 0 Urinary tract 2 2418.9 0.08 4 3923.4 0.10 Chronic sinusitis 1 2419.6 0.04 0 3936.7 0 infection Diverticulitis 0 2421.5 0 1 3936.5 0.03 Opportunistic 4 2411.0 0.17 12 3874.8 0.31 Erysipelas 1 2414.5 0.04 0 3936.7 0 infection Gastroenteritis 0 2421.5 0 1 3933.2 0.03 Fungal infection 2 2418.9 0.08 9 3891.0 0.23 Herpes zoster 0 2421.5 0 2 3929.7 0.05 Herpetic infection 19 2343.1 0.81 60 3737.0 1.61 Infection 0 2421.5 0 1 3936.6 0.03 Herpes simplex 2 2412.2 0.08 5 3916.9 0.13 Influenza 0 2421.5 0 1 3935.2 0.03 Herpes virus 1 2416.1 0.04 4 3920.9 0.10 Myocarditis bacterial 1 2419.7 0.04 0 3936.7 0 infection Peritonitis 0 2421.5 0 1 3929.8 0.03 Herpes zoster 4 2397.1 0.17 28 3855.8 0.73 Pilonidal cyst 0 2421.5 0 1 3929.0 0.03 Oral herpes 10 2387.5 0.42 20 3868.4 0.52 Pneumonia 3 2415.2 0.12 6 3907.4 0.15 Varicella 2 2416.1 0.08 3 3926.7 0.08 Pulmonary tuberculosis 0 2421.5 0 1 3933.6 0.03 Pyelonephritis 0 2421.5 0 2 3927.2 0.05 Adj-AE per 100 PY, adjusted adverse events incidences per 100 patient-years; Salpingo-oophoritis 0 2421.5 0 1 3934.6 0.03 AESI, adverse events of special interest. Subcutaneous abscess 0 2421.5 0 1 3936.4 0.03 AESI Severe infection is a custom grouping defined by any serious or severe Tuberculosis 0 2421.5 0 1 3936.7 0.03 event belonging to the MedDRA system organ class Infections and infestations. Urethral abscess 1 2421.4 0.04 0 3936.7 0 Urinary tract infection 1 2419.9 0.04 4 3923.4 0.10 AESI Opportunistic infection is based on respective lists available in the context of HIV infections. It includes MedDRA preferred terms associated to viral, fungal, protozoal and bacterial Skin and subcutaneous 1 2420.5 0.04 3 3934.5 0.08 infections which is different from the data presented in the previous manuscript tissue disorders by Cook et al. 2019.14 Rash generalized 0 2421.5 0 1 3936.6 0.03 AESI Herpetic infection is defined by any events from MedDRA HLT = Herpes viral infections. The Medical Dictionary for Regulatory Activities (MedDRA) v20.0 was used for adverse event coding. Adj-AE per 100 PY, adjusted adverse events incidences per 100 patient-years; confirm the low level of serious TEAEs associated with cladribine ta­ AESI, adverse events of special interest; PY, patient-years; TEAE, treatment blets 3.5 mg/kg in patients with RRMS. The results of this updated emergent adverse events. analysis are therefore consistent with those from previously published *Serious was defined as resultant in death, life-threatening, required inpatient analyses, cumulative to February 2015 and May 2017, respectively hospitalization, congenital anomaly or birth defect, or was otherwise con­ (Cook et al., 2019; Cook et al., 2018). sidered as medically important. The current summary focuses on the Monotherapy Oral cohort, as this is in line with the approved dose of cladribine tablets (3.5 mg/kg). There was no increase in the risk of malignancy over time with This analysis does not present in detail data from the previously re­ cladribine tablets 3.5 kg/mg (Fig. 3). The malignancy rate for cla­ ported ‘All Exposed’ cohort of patients from the clinical development dribine tablets 3.5 kg/mg during years 1–4 was an Adj-AE of 0.29 per program because that cohort includes data for other cladribine for­ 100 PY and from year 5 onwards was 0.17 per 100 PY. In contrast, the mulations and dosing regimens (Cook et al., 2019). The final results malignancy rate in the placebo group during years 1–4 was an Adj-AE from the All Exposed cohort are, however, in line with the earlier re­ of 0.06 per 100 PY, but higher from year 5 onwards at 0.29 per 100 PY; port, and at the final cut-off included 1976 patients who received cla­ however, the overall number of events was small. dribine with an exposure of 9854.7 patient years and 802 who received placebo with an exposure of 2781.8 patient years. 3.3.4. Skin and subcutaneous tissue disorders As for previous reports, the safety data analyzed here are presented In the cladribine tablets 3.5 mg/kg group, 1/923 patients had as observation-adjusted incidence rates per 100 patient years of ex­ generalized rash classified as a serious TEAE, resulting in an Adj-AE of posure and follow-up time to account for different follow-up times in 0.03 per 100 PY (Table 3). There were no reports of serious generalized the treatment arms (Cook et al., 2019; Cook et al., 2018). This is re­ rash in the placebo group. levant for this long-term update because the observation time for the placebo group is only about one third that of the cladribine tablets 3.5 mg/kg group, and the comparison would not be meaningful if 4. Discussion presented as percentages. The adjusted incidence rates of serious TEAEs decreased with the This analysis marks the final update to the safety data from the longer follow-up in this report. In addition, no new major safety find­ clinical development program for the approved dose of cladribine ta­ ings were identified, and there were no new/significant adverse events blets 3.5 mg/kg and includes the finalized data from the end of the emerging during long-term follow-up after treatment with cladribine PREMIERE registry (cumulative to October 2018). Overall, results 5 T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 Table 5 cladribine tablets has minimal deleterious impact on long-term immune Number of AESI malignancies, timing of events, incidence rates, risk difference, function (Giovannoni, 2017; Baker et al., 2017; Comi et al., 2019; and risk ratio for the Monotherapy Oral cohort from the cladribine tablets Leist and Weissert, 2009; Stuve et al., 2019; Wiendl, 2017). clinical development program. There was no increased risk for infections with the exception of Placebo Cladribine tablets 3.5 mg/kg serious herpes zoster, which showed an increased incidence among N = 641) (N = 923) cladribine tablets 3.5 mg/kg recipients versus placebo (Adj-AE of 0.05 n Days at n Days at per 100 PY in the cladribine tablets 3.5 mg/kg group versus no cases in onset* onset* the placebo group). Previous analyses have shown that frequency of Neoplasms benign, malignant and infections is related to occurrences of severe lymphopenia unspecified (incl cysts and (<0.5 × 109 cells/L) (Giovannoni et al., 2010; Giovannoni et al., 2018; polyps) Cook et al., 2019). In patients treated with cladribine tablets 3.5 mg/kg, Basal cell carcinoma 1 1972 1 1317 Grade 4 lymphopenia (<0.2 × 109 cells/L) occurred in <1% of pa­ Bile duct adenocarcinoma 0 0 1 926 Bowen's disease 0 0 1 465 tients, but the nature of their infections was not different to that ob­ Breast cancer 0 0 1 1711 served in the overall patient group (Giovannoni et al., 2010; Cervical carcinoma stage 0 2 1871, 993 0 0 Giovannoni et al., 2018; Cook et al., 2019). It was clear, however, that Malignant melanoma 0 0 2 1204, 419 herpes zoster occurred more frequently during periods of severe lym­ Ovarian cancer 0 0 1 169 Pancreatic carcinoma metastatic 0 0 1 509 phopenia than in periods without severe lymphopenia. A time-to-event Papillary thyroid cancer 0 0 1 582 analysis reported from the February 2015 cut off suggested that the risk Rectal cancer 0 0 1 1853 of herpes zoster or herpetic infections may be temporally linked to the n Total PY N Total PY dosing period with cladribine tablets 3.5 mg/kg in years 1 and 2, but n/PY at risk 3 2414.8 10 3918.9 the low number of overall events did not allow definitive conclusions to Incidence per 100 PY 0.12 0.26 Risk difference per 100 PY 0.1309 be drawn (Cook et al., 2019). Known risk factors for herpes zoster in­ 95% CI of risk difference per 100 −0.1304, clude family history, being female, white, and, of particular relevance PY† 0.3645 to patients taking cladribine tablets, immunosuppression (Kawai and Risk ratio 2.0540 Yawn, 2017). There was one case each of tuberculosis and pulmonary 95% CI of risk ratio‡ 0.5653, 7.4632 tuberculosis in the cladribine tablets 3.5 mg/kg group classified as serious. However, these cases were seen in patients who received their AESI, adverse events of special interest; CI, confidence interval; PY, patient- first doses of cladribine tablets 3.5 mg/kg prior to the implementation years. of mandatory tuberculosis screening. There was no obvious pattern of *(Imputed AE onset date - first study drug date)+1. increase in other serious respiratory infections. †CI computed using the Miettinen and Nurminen method. The incidence rate of serious or severe infections was low in the ‡CI computed with the Wald method for the number of patients with events cladribine tablets 3.5 mg/kg group and no relevant differences versus using a Poisson regression model with fixed effect for treatment group and with placebo were observed at the preferred term level. This reflects infec­ log of time at risk as an offset. When the observed rate is zero, the lower limit is tion screening requirements in the clinical program, which are also set to zero and the exact formula is used for the upper limit. reflected in the prescribing information for cladribine tablets (Groves et al., 2013). A numerical imbalance in the incidence of malignancy was noted between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however, the difference was not statistically significant. The duration from first intake of study drug until a malignancy diagnosis was highly variable and there was no in­ crease in the incidence of malignancies over time. The incidence of malignancies was higher during the first 4 years of the program than for the subsequent 4 years, for cladribine tablets 3.5 mg/kg. Surprisingly, the incidence of malignancies in the placebo group was lower than expected during the first 4 years of the program and higher than ex­ pected in the subsequent 4 years. To determine the effect of dose on malignancy, an analysis using data from the All Exposed and Monotherapy Oral cohorts for the 3.5 mg/kg and 5.25 mg/kg groups was previously undertaken (Cook et al., 2011). This analysis showed that, overall, there was no clear evidence of a dose effect of cladribine on malignancy risk in patients with MS based on more than 9500 pa­ tient years of cladribine exposure (Cook et al., 2011). The observation-adjusted incidence of malignancies is lower than the previous reports (Cook et al., 2019; Cook et al., 2018), and is ex­ Fig. 2. Malignancy incidence for cladribine tablets 3.5 mg/kg compared with a plained by the number of cases not changing in this update and there matched GLOBOCAN reference population. being a longer follow up. Similarly, when compared to the reference CI, confidence interval; PY, patient-years; SIR, standardized incidence ratio (calculated against the matched GLOBOCAN reference population, excluding GLOBOCAN population, the SIR for cladribine tablets 3.5 mg/kg in this non-melanoma skin cancer due to inconsistent reporting). final analysis (0.88) was lower than in the previous publication (0.97) (Cook et al., 2019). In both GLOBOCAN population analyses, the rate of malignancies with cladribine tablets 3.5 mg/kg was similar to the ex­ tablets 3.5 mg/kg. It is also worth noting that despite the risk of sec­ pected rate from the matched reference population and the rate of ondary autoimmune disorders with some MS treatments malignancies with placebo was lower than expected overall. (Genzyme Therapeutics Ltd. 2018), there were no secondary auto­ In summary, this final report consolidates over 8 years of safety data immune disorders reported in the Monotherapy Oral cohort. This from the clinical development program of cladribine tablets and iden­ finding provides further evidence that the mechanism of action of tified no new major safety findings. These integrated analyses 6 T. Leist, et al. Multiple Sclerosis and Related Disorders 46 (2020) 102572 Fig. 3. Risk of malignancy over time for cladribine tablets 3.5 mg/kg and placebo. demonstrate the favorable AE profile and safety for cladribine tablets TL has received consultancy fees or clinical research grants from 3.5 mg/kg monotherapy in patients with RRMS, which are now well Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, characterized over long-term use. It is unique for a disease-modifying and Teva Neuroscience. drug to have such long-term safety data available soon after approval. SC has received honoraria for lectures/consultations from Actinobac Furthermore, there are two on-going post-approval safety studies Biomed Inc., Bayer HealthCare, Biogen, Merck KGaA (Darmstadt, (CLARION [EU PAS Register number, EUPAS24484] and CLEAR [EU Germany), Neurology Reviews, Sanofi-Aventis, and Teva PAS Register number, EUPAS25027]) that are looking at the long-term Pharmaceuticals; has served on advisory boards for Actinobac Biomed overall safety of patients exposed to prescribed cladribine tablets as Inc., Bayer HealthCare, Biogen, Merck KGaA (Darmstadt, Germany), well as pregnancy outcomes. Results from these studies will be reported and Teva Pharmaceuticals; and has received grant support from Bayer periodically. HealthCare. GC has received consulting fees from Bayer Schering, Biogen, Author statement Genentech/Roche, Merck KGaA (Darmstadt, Germany), Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd; lec­ We confirm that all authors made substantial contributions to the ture fees from Bayer Schering, Biogen, Merck KGaA (Darmstadt, concept and design, or analysis and interpretation of data, and to the Germany), Novartis, Sanofi-Aventis, Serono Symposia International drafting of the manuscript or revising it critically for important in­ Foundation, and Teva Pharmaceutical Industries Ltd; and trial grant tellectual content. In addition, all authors provided final approval of the support from Bayer Schering, Biogen, Genentech/Roche, Merck KGaA manuscript. (Darmstadt, Germany), Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd. Funding XM has received speaking honoraria and travel expenses for scien­ tific meetings, has been a steering committee member of clinical trials Merck KGaA, Darmstadt, Germany provided financial support for or participated in advisory boards of clinical trials in the past 3 years the conduct of the research and preparation of the article. Merck KGaA, with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Darmstadt, Germany, in collaboration with all authors, was involved in EXCEMED, Genzyme, MedDay, Merck KGaA (Darmstadt, Germany) the study design; in the collection, analysis and interpretation of data; MSIF, Nervgen, NMSS, Novartis, Roche, Sanofi-Genzyme, Teva in the writing of the report; and in the decision to submit the article. Pharmaceutical, and TG Therapeutics. GG has received speaker honoraria and consulting fees from AbbVie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen, Data availability statement Celgene, FivePrime, GlaxoSmithKline, GW Pharma, Ironwood, Merck & Co., Merck KGaA (Darmstadt, Germany), Novartis, Pfizer Inc., Protein Any requests for data by qualified scientific and medical researchers Discovery Laboratories, Roche, Sanofi-Genzyme, Teva Pharmaceutical for legitimate research purposes will be subject to Merck KGaA's Data Industries Ltd, UCB, and Vertex Pharmaceuticals; and has received re­ Sharing Policy. All requests should be submitted in writing to Merck search support unrelated to this study from Biogen, Ironwood, Merck & KGaA's data sharing portal https://www.merckgroup.com/en/ Co., Novartis and Takeda. research/our-approach-to-research-and-development/healthcare/ AN is an employee of Merck KGaA, Darmstadt, Germany. clinical-trials/commitment-responsible-data-sharing.html. When Merck DD is an employee of EMD Serono Research & Development KGaA has a co-research, co-development, or co-marketing or co-pro­ Institute, Inc., Billerica, USA, a business of Merck KGaA, Darmstadt, motion agreement, or when the product has been out-licensed, the re­ Germany. sponsibility for disclosure might be dependent on the agreement be­ SS is a former employee of EMD Serono Research & Development tween parties. Under these circumstances, Merck KGaA will endeavor to Institute, Inc., Billerica, USA, a business of Merck KGaA, Darmstadt, gain agreement to share data in response to requests. Germany. AG is an employee of Merck, Aubonne, Switzerland, a division of Declaration of Competing Interest Merck KGaA, Darmstadt, Germany. The authors declare the following financial interests/personal re­ lationships which may be considered as potential competing interests: 7 T. Leist, et al. 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