Drug Safety (2020) 43:635–643 https://doi.org/10.1007/s40264-020-00948-x ORIGINAL RESEARCH ARTICLE Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety Gavin Giovannoni1 · Andrew Galazka2 · Regina Schick3 · Thomas Leist4 · Giancarlo Comi5 · Xavier Montalban6,7 · Doris Damian8 · Fernando Dangond8 · Stuart Cook9 Published online: 23 May 2020 © The Author(s) 2020 Abstract Introduction Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur. Objective This analysis reports on pregnancy outcomes in the cladribine clinical development program. Methods Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the ‘at-risk’ period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group. Results In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (clad- ribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the ‘at-risk’ period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Correspond- ing findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the ‘at-risk’ period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the ‘at-risk’ period for cladribine. Conclusions While limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject. Clinical Trial Registration CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350. Extended author information available on the last page of the article Vol.:(0123456789) 636 G. Giovannoni et al. phosphorylation to its 2-chlorodeoxyadenosine triphosphate Key Points metabolite. Intracellular phosphorylation of cladribine is specifically mediated by the enzyme deoxycytidine kinase In ten clinical studies of cladribine, used to treat mul- and de-phosphorylation occurs due to 5ʹ-nucleotidase [5]. tiple sclerosis (MS), study subjects were asked to use The phosphorylated form preferentially accumulates in lym- contraception to avoid getting pregnant. However, some phocytes owing to their unique constitutively high deoxycy- women did become pregnant, as did the female partners tidine kinase levels and low 5ʹ-nucleotidase levels compared of some men with MS who took part in the studies. We with other cells in the body. Following activation of the drug report the outcomes for these pregnancies as part of a in lymphocytes, 2-chlorodeoxyadenosine triphosphate may large safety analysis. be incorporated into the DNA strands resulting in breaks and There were 70 pregnancies in total; 49 in the cladribine interference with DNA synthesis, leading to their selective group and 21 in the placebo group. The outcomes for apoptosis. In other cell-types, 5ʹ-nucleotidases balance the these pregnancies (including abortions and live births) activity of deoxycytidine kinase and prevent 2-chlorodeoxy- were very similar for the two groups. adenosine triphosphate accumulation. In reproductive toxicology studies performed in animals These findings are what we would expect for women in (unpublished observations, Merck KGaA), cladribine did not the general population, as well as women with MS who show effects on female fertility or on peri-postnatal devel- become pregnant. A new study is being conducted to opment of the offspring. Cladribine was found to be terato- obtain more information on pregnancies when women genic in mice and rabbits when given intravenously. In mice, are treated with cladribine for MS. cladribine did not show effects on male fertility; however, it did show depletion of germ cells, spermatids, and sperma- tozoa. No effects on male reproductive performance were seen as assessed after the completion of one spermatogenic cycle without cladribine treatment, and no testicular histo- 1 Introduction pathological changes were seen after this one spermatogenic cycle, together demonstrating a complete recovery. Multiple sclerosis (MS) is most commonly diagnosed in indi- Cladribine has a short half-life in humans (< 24 h) and viduals aged 20–40 years. Three quarters of newly diagnosed after administration is rapidly eliminated from the body [6]. cases are in women, often of childbearing age [1]. Conse- However, in view of its teratogenicity in mice and rabbits at quently, reproductive considerations are important for female doses higher than those used in humans, and the short-term patients with MS receiving treatment with disease-modifying effects on male germ cells noted above, caution should be drugs (DMDs) that have pregnancy-related warnings. exercised with respect to conception during and after clad- The majority of pharmacological agents for MS require ribine dosing. Bearing in mind physiological development of regular dosing and presence of the agent to maintain the reproductive tissues, 3 months after exposure to cladribine is clinical effect. This may represent a challenge to disease adequate time for a follicular or spermatogenic development management in patients who wish to become pregnant, cycle to complete. At the time of development of prescrib- but do not wish to be at risk for MS disease activity. More ing information concerning the use of parenteral cladribine recently, some treatment approaches approved or consid- in hematological malignancies, 3 additional months were ered for MS, including autologous bone marrow transplant, added as a precaution; thus, a 6-month period was proposed alemtuzumab, ocrelizumab, and cladribine tablets, harbor during which female and male patients should not conceive the promise of longer term remission of MS disease activ- to avoid risk of exposure of a conceptus [7]. Following dis- ity beyond presence of the DMD. While the practice sur- cussions with regulatory authorities at the time of approval rounding DMDs and pregnancy is evolving, more evidence of cladribine tablets in MS, it was decided to apply the same is needed, especially for newer agents [2]. precautionary 6-month period. As per the prescribing infor- In patients with relapsing MS who received cladribine mation, pregnancy has to be excluded prior to starting clad- tablets 10 mg (3.5-mg/kg cumulative dose over 2 years, ribine tablets, and both female and male patients must use administered as one treatment course of 1.75 mg/kg per year, effective contraception during treatment and for 6 months with each treatment course consisting of up to 10 treatment after the last dose of cladribine to avoid pregnancy (and days), attenuation of disease activity was observed [3] and partner pregnancy) during this time [5]. We report on preg- sustained for many patients in years 3 and 4 without further nancy outcomes in female patients with MS and the partners treatment [4]. Cladribine is a prodrug that enters the cell of male patients with MS who became pregnant during the via nucleoside transporter proteins and becomes active upon cladribine clinical development program. Pregnancy Outcomes During the Clinical Development of Cladribine for MS 637 2 Methods initially treated with placebo and subsequently with cladrib- ine, the first 2 years of their data were analyzed as part of the 2.1 Study Population placebo group and if/when they switched to cladribine, all of their subsequent data were attributed to the cladribine group. Pregnancy outcomes were evaluated as part of an integrated If a patient received cladribine followed by placebo, all of safety analysis of ten studies, including nine clinical tri- their data were attributed to the cladribine group; these data als and a long-term safety registry (Table 1). The analysis were not included in the placebo group analysis. included patients who participated in the cladribine tablet clinical trial program in patients with a first clinical demyeli- 2.2 Pregnancy Outcomes and Data Analysis nating event (i.e., CLARITY [3], CLARITY Extension [4] in patients with relapsing–remitting MS, and ORACLE-MS This analysis is based on data collected through pregnancy [9]), and the phase II ONWARD study [10], which assessed report forms and parent child/fetus adverse event report the effects of treatment with cladribine tablets plus interferon forms used in the clinical trials that comprised the cladribine (IFN)-β in patients with relapsing MS. The long-term safety clinical development program. We first evaluated pregnancy registry (PREMIERE) followed patients from the cladribine outcomes for pregnant women with MS who were exposed tablet studies to provide insight into the medium-to-longer to cladribine or placebo, i.e., direct pregnancies for the all- term safety of treatment with cladribine tablets in patients exposed cohort. Thereafter, we evaluated direct pregnan- with relapsing MS or a first clinical demyelinating event. cies among female patients in the ‘at-risk’ cohort, i.e., the Patient safety data collected by the registry up to the comple- subgroup of patients who became pregnant either during tion date of 25 October, 2018 were included in this analysis. cladribine administration or within 6 months (183 days) of Patients with MS who participated in five earlier clinical the last dose (this precautionary period is specified in the studies that assessed the efficacy and safety of parenteral prescribing information to avoid any possible embryofetal cladribine were also included in the analysis. The integra- exposure to cladribine). Data were also described for partner tion of safety data from all ten of these studies comprised a pregnancies (i.e., those that occurred in female partners of population of 2778 patients (cladribine, n = 1976; placebo, male study participants with MS), using the same definitions n = 802) recruited from over 35 countries worldwide, and of exposure outlined above. represented data from the complete clinical development Pregnancy outcomes were separated into the following program for cladribine in MS. This population is referred to categories: live birth, elective termination (i.e., pregnancy as the all-exposed cohort throughout this article [8]. terminated according to the patient’s decision), spontaneous For ethical reasons, some trials used a switch design to abortion, therapeutic termination (i.e., medically indicated prevent patients initially randomized to placebo from spend- termination) with reasons, and unknown outcome. Any con- ing prolonged periods without active treatment. In patients genital malformations were also to be reported. According Table 1  Summary of clinical Study Design Formulation Phase Numbera studies using cladribine tablets or parenteral cladribine used in CLARITY [3] R, DB CT III 1326 the integrated safety analysis CLARITY Extension [4] R, DB CT IIIb 806 ORACLE-MS [9] R, DB CT III 617 ONWARD [10] R, DB CT IIb 172 PREMIEREb Extension CT Observational 1170 Scripps-A OL iv II 7 Scripps-B R, DB sc II 11 Scripps-C R, DB sc II 52 MS-Scripps R, DB iv II 49 MS-001 R, DB sc III 159 CT cladribine tablets, DB double-blind, iv intravenous, MS multiple sclerosis, OL open-label, R rand- omized, sc subcutaneous a Number of patients randomized to double-blind treatment or enrolled into the study b The PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Trials) registry was a prospective, observational, long-term safety study of patients with MS that commenced in 2009 and completed in 2018. It was open to patients who had participated in one of the clinical studies of cladribine tablets (CLARITY, CLARITY Extension, ORACLE-MS, or ONWARD) in which patients continued to be followed up for long-term monitoring 638 G. Giovannoni et al. to routine processes, live births were not followed beyond dose of 3.87-mg/kg cladribine tablets in the CLARITY trial. delivery. Follow-up was only conducted for cases with a In 14 of 49 (28.6%) pregnancies, elective termination was pending pregnancy outcome, unknown pregnancy outcome, selected, and in 11 of 49 (22.4%) pregnancies, spontane- or in the case of an abnormality at birth (such as congenital ous abortions occurred. A total of five therapeutic termina- anomalies or other serious health conditions) until confirma- tions of pregnancy were performed in four patients who had tion of the abnormality or until 1 year after birth. Descriptive received cladribine treatment (two terminations for ectopic statistics, including number of outcomes (n) and propor- pregnancies in one patient, a termination for choriocarci- tions, were calculated for each pregnancy outcome. noma in one patient, and two terminations due to fetal death in PREMIERE patients who had the last dose of cladribine approximately 3 years prior to pregnancy). 3 Results In female patients who had received placebo (n = 535), there were 21 direct pregnancies in 19 patients; nine of 21 3.1 Patient Characteristics (42.9%) pregnancies led to live births, four (19.0%) ended in elective terminations, and five (23.8%) resulted in spontane- The all-exposed cohort consisted of 1976 patients (Table 2) ous abortions. Therapeutic terminations were performed for who had been treated with cladribine, with a total exposure two placebo recipients, including one patient after an ultra- time of 9855 patient-years (1306 women, 66.1%), and 802 sound scan revealed a Dandy–Walker congenital malforma- patients who had received placebo for 2782 patient-years of tion and progressive placental abruption, which occurred exposure (535 women, 66.7%). The patient-years of expo- approximately 2 years and 1 month after the last administra- sure to cladribine in the all-exposed cohort was higher than tion of placebo. The other was in a placebo recipient who for placebo because the majority of clinical studies involved experienced rupture of the amniotic sac and fetal death in randomization of patients to treatment in a 2:1 ratio (active the 17th week of gestation. The outcome of pregnancy in treatment:placebo), the possibility of switching to cladribine one placebo recipient was unknown. tablets during CLARITY Extension, and also because of the attribution policy (see also the earlier section on study 3.3 Direct Pregnancies During Cladribine Dosing population for details). or Within 6 Months After the Last Dose (‘At‑Risk’ Cohort) 3.2 Direct Pregnancies in Female Study Participants A total of 16 direct pregnancies in 16 female patients In total, 70 direct pregnancies occurred among 62 female (Table 3) occurred during the period of cladribine dosing patients in the all-exposed cohort (including repeat preg- or within 6 months after the last dose; three of 16 (18.8%) nancies during the observational registry study) (Table 3). pregnancies were live births, ten (62.5%) pregnancies ended In female patients who had been exposed to cladribine in elective terminations, and two (12.5%) ended with spon- (n = 1306), 49 pregnancies occurred in 43 patients. Of taneous abortions. Therapeutic termination for an ectopic these, 19 of 49 (38.8%) pregnancies resulted in live births. pregnancy occurred in one patient. There were no pregnan- A pregnancy that occurred 2 years and 3 months after the cies with congenital anomalies or with unknown outcomes. last dose of cladribine tablets resulted in the birth of twins. In female patients receiving placebo, 11 pregnancies A congenital malformation (omphalocele) was reported occurred of which five (45.5%) resulted in live births. Of in one of the twins. The patient had received a cumulative the 11 pregnancies, there were three (27.3%) spontaneous Table 2  Demographics and Patient characteristics Placebo (n = 802) Cladribine (n = 1976) characteristics of patients included in the all-exposed Female, n (%) 535 (66.7) 1306 (66.1) cohort Time on study in weeks, mean (SD) 180.99 (135.03) 260.23 (139.20) Patient-years of exposure 2782 9855 Age at clinical study baseline (years), mean (SD) 37.6 (9.8) 37.7 (10.1) Median 37.0 38.0 Minimum; maximum 18; 64 18; 65 Age ≤ 40 years, n (%) 485 (60.5) 1162 (58.8) Prior treatment with DMD, n (%) 188 (23.4) 505 (25.6) Disease duration in years, mean (SD) 9.50 (7.44) 8.91 (7.21) DMD disease-modifying drug, SD standard deviation Pregnancy Outcomes During the Clinical Development of Cladribine for MS 639 Table 3  Pregnancy outcomes in Pregnancy outcomes, n (%) All-exposed cohort At-risk ­cohorta the cladribine multiple sclerosis clinical program (direct Cladribine Placebo Cladribine Placebo pregnancies only) pregnancies pregnancies pregnancies pregnancies (N = 49) (N = 21) (N = 16) (N = 11) Live birth 19 (38.8) 9 (42.9) 3 (18.8) 5 (45.5) Elective termination 14 (28.6) 4 (19.0) 10 (62.5) 2 (18.2) Spontaneous abortion 11 (22.4) 5 (23.8) 2 (12.5) 3 (27.3) Therapeutic termination 5 (10.2) 2 (9.5) 1 (6.2) 0 (0) Congenital abnormalities n = 1b n = 1c 0 0 Unknown 0 (0) 1 (4.8) 0 (0) 1 (9.1) Please refer to the main text for a description of outcomes for partner pregnancies (i.e., pregnancies that occurred in female partners of male study participants) a Pregnancies categorized as starting during cladribine or placebo treatment or within 6 months since the most recent dose, and are a subset of the total number of pregnancies that occurred in cladribine- or pla- cebo-treated patients b One case of omphalocele reported in one twin from a pregnancy that occurred approximately 2 years and 3 months after the last dose of cladribine tablets c An ultrasound scan revealed a Dandy–Walker malformation in a pregnancy that occurred approximately 2 years and 1 month after the last dose of placebo abortions and two (18.2%) elective terminations. There was embryofetal risks of cladribine exposure with recommenda- one (9.1%) pregnancy with an unknown outcome. tions and measures to avoid pregnancy. There were two reports of congenital malformations in 3.4 Outcome of Partner Pregnancies the present analysis, one in a twin from a pregnancy aris- ing > 2 years after the last dose of cladribine tablets (ompha- For the all-exposed cohort, nine pregnancies occurred in the locele) and one from a pregnancy arising > 2 years after the female partners of nine cladribine-treated male patients with last dose of placebo (Dandy–Walker malformation). The MS who participated in the clinical trial program; each of omphalocele case could not be plausibly related to cladribine these pregnancies resulted in live births, with one fetal dis- treatment because it occurred so long after the last dose that tress recorded due to nuchal cord. There were two pregnan- there was no embryofetal exposure to the drug. cies among the female partners of two placebo-treated male The most relevant information from the present analysis patients with MS, and the outcomes of these were unknown. concerns the pregnancy outcomes of the 16 female patients Pregnancies occurred in two female partners of male who were exposed to cladribine during the ‘at-risk’ period patients treated with cladribine during the ‘at-risk’ period (i.e., the time window of cladribine treatment and up to of treatment or within 6 months after the most recent dose. 6 months after the last dose). Approximately one tenth of Both of these pregnancies resulted in live births. such pregnancies resulted in spontaneous abortions. There were no reports of congenital malformations during the ‘at- risk’ period. Of the three live births from these 16 pregnan- 4 Discussion cies, one pregnancy occurred 2 weeks after the last dose of cladribine and two pregnancies occurred 5–6 months after Despite the guidance to study participants about the need the last dose. Another two live births resulted from partner for contraception in each of the clinical trials, a number of pregnancies that occurred in women whose male partners pregnancies occurred in the cladribine clinical program in had received treatment with cladribine (within 6 months of MS. Of the 70 pregnancies that occurred in the all-exposed the last dose). All five of these live births resulted in other- cohort, 40% resulted in live births, 26% in elective termina- wise healthy newborns. tions, 23% in spontaneous abortions, and 10% in therapeu- While the findings of the current analysis are limited tic terminations (1% had an unknown outcome). Compared by the small sample size (which is unsurprising given that with placebo recipients, there was a higher proportion of patients were advised to avoid pregnancy by using effective termination among cladribine-treated patients. This was as contraception while in the clinical trials [5]), the observa- expected because patients received cladribine in an open- tions are generally consistent with epidemiological data on label manner in several studies and extension periods, and pregnancy outcomes for the general population or women the study protocols made specific reference to the potential with MS. For example, in the all-exposed and ‘at-risk’ 640 G. Giovannoni et al. cohorts, respectively, 22.4% and 12.5% of pregnancies in monoclonal antibodies natalizumab, alemtuzumab, and patients who were treated with cladribine ended with spon- ocrelizumab, there is evidence of reproductive toxicity in taneous abortions. This is comparable to the findings of animals; however, limited data are available on outcomes for a meta-analysis that reported on pregnancy outcomes for pregnant women [23, 25–28, 38–42]. The European Public 13,144 women with MS, and found that the combined rate Assessment Report for Ocrelizumab detailed 6/48 cases of of spontaneous abortion and therapeutic termination was abnormal findings (including structural malformation, infec- 27.9% (95% confidence interval 23.6–32.7%) [14]. Sponta- tion, and low birth weight) in live births from female sub- neous abortions occurred in 23.8% of the placebo cohort, a jects who participated in clinical studies, where conception proportion that is consistent with epidemiological data for occurred from approximately 3 months up to 3 years after the MS untreated population [15, 16]. the last administered dose [43]. Our results for partner pregnancies support previously A key factor that differentiates cladribine tablets from published pregnancy data for female partners of male most of the other DMD treatments is the pulsed nature of patients treated for MS. Reporting prospective observational administration of the drug compared with the long-term data from the Italian Pregnancy Dataset, for example, Pecori administration of maintenance therapies. Cladribine has a et al. reported no association between DMD exposure of short half-life and is therefore eliminated from plasma and fathers at the time of conception and the risk of spontane- tissues less than 1 week after completion of each annual ous abortion, adverse fetal outcomes, and congenital mal- administration [6]. While there are currently no data to formations; the study summarized outcomes for 78 pregnan- evaluate the interaction between cladribine and oral contra- cies fathered by patients with MS, 45 (58%) of whom were ceptives, the potential for drug–drug interactions is, in prin- receiving DMDs at the time of conception (predominantly ciple, reduced by the short treatment schedule and exposure. β-interferons [n = 39] and glatiramer acetate [n = 6]) [11]. However, this remains a topic of interest and a drug–drug Although available data are limited, it has also been reported interaction study between cladribine tablets and ethinyl that MS and MS-related clinical factors, including DMD use estradiol plus levonorgestrel is ongoing (NCT03745144). in fathers, are not associated with adverse birth outcomes As per product labeling, women of childbearing potential, [12, 13]. using systemically acting hormonal contraceptives, should As with cladribine tablets, the majority of DMDs (dime- add a barrier method during cladribine treatment and up to thyl fumarate, teriflunomide, fingolimod, alemtuzumab, 4 weeks after the last dose because of the unknown effects natalizumab, and ocrelizumab) carry a prescribing infor- on hormonal birth control [5]. mation warning that exposure during pregnancy may cause The effect of cladribine on human fertility is unknown fetal harm or spontaneous abortion, based on results from [5]. In mice, there were no effects on fertility in either female animal studies [17–28]. The precise nature of the concern or male mice; however, testicular effects were observed in varies between agents. No evidence of reproductive toxicity mice and monkeys. Similar to female patients, as per pre- or malformations was observed in pregnant women exposed scribing information, male patients must take precautions to glatiramer acetate [22, 29]. Recent data on pregnancy and to prevent pregnancy of their partner during treatment with infant outcomes from the European IFN-β Pregnancy Reg- cladribine tablets and for at least 6 months after the last istry and population-based registers in Finland and Sweden dose [5]. showed no evidence that IFN-β exposure before concep- The findings of the current analysis are limited by the tion and/or during pregnancy adversely affected pregnancy small number of exposed pregnancies although the findings or infant outcomes [30]. Indeed, these findings are now represent the totality of experience from the clinical devel- reflected in the current labeling for IFN-β, which also states opment program for cladribine in MS, and will therefore that IFN-β may be considered during pregnancy if clinically provide relevant information for patients and healthcare pro- needed [31–35]. For dimethyl fumarate, fingolimod, and ter- viders alike. It is also important to consider that the present iflunomide, there is evidence of reproductive toxicity in ani- analysis was not a formal pregnancy exposure study; rather, mals with higher dose exposures but no clear signal, based the analysis utilized data collected through pregnancy report on limited clinical experience, in human pregnancy. A small forms and parent child/fetus adverse event report forms used study of leflunomide (the parent compound of teriflunomide, in the clinical trials. Consequently, further information rel- marketed in the USA since 1998 for treatment of rheumatoid evant to pregnancy outcomes, such as dose response, tim- arthritis), for example, noted no substantially increased risk ing of pregnancy, and confounders, was limited. For exam- of adverse pregnancy outcomes due to leflunomide exposure ple, there was no information on specific patient behaviors [36]. An analysis of the global pharmacovigilance database related to risk management that may have confounded the did not indicate any teratogenic signals in patients treated results, such as smoking, alcohol consumption, and drug with teriflunomide [37], and prospective data are being abuse during pregnancy. The present study was also limited captured worldwide in the post-marketing setting. For the in terms of systematic follow-up after birth, considering that Pregnancy Outcomes During the Clinical Development of Cladribine for MS 641 some congenital anomalies may not be evident at the time Acknowledgements The authors thank patients and their families; of birth and only diagnosed at a later date. Further study is investigators; co-investigators; the study teams at each of the participat- ing centers and at Merck KGaA, Darmstadt, Germany; and Magnhild clearly warranted to provide additional information on preg- Sandberg Wollheim for an insightful review of the draft manuscript. nancy outcomes among cladribine-treated patients. Medical writing assistance was provided by Sarah Wetherill and Steve The clinical and radiological efficacy of cladribine 3.5- Winter of inScience Communications, Springer Healthcare Ltd, Ches- mg/kg tablets persists in many patients for 4 years or pos- ter, UK, and was funded by Merck KGaA, Darmstadt, Germany. sibly longer [4]. This may potentially represent a window of Author Contributions GG, AG, RS, TL, GC, XM, DD, FD, and SC all opportunity for patients who want to have a child and who made substantial contributions to the concept and design, or analysis are willing to delay pregnancy for at least 6 months after and interpretation of data, and to the drafting of the manuscript or completion of the second-year treatment course (ensuring revising it critically for important intellectual content. In addition, all they receive the full recommended dose for cladribine tab- authors provided final approval of the manuscript. lets). However, for all therapies used in MS, large and well- Data Availability For all new products or new indications approved in powered studies with adequate numbers of exposed preg- both the European Union and the USA after 1 January, 2014, Merck nancies are required to provide patients desiring pregnancy KGaA will share patient- and study-level data after deidentification, as with better information on which to make their treatment well as redacted study protocols and clinical study reports from clini- decisions. In the case of cladribine tablets, CLEAR (EU cal trials in patients. These data will be shared with qualified scientific and medical researchers, upon a researcher’s request, as necessary for PAS Register number EUPAS25027) is a non-interventional conducting legitimate research. Such requests must be submitted in post-authorization safety study based on secondary use of writing to the company’s data sharing portal and will be internally data from various automated healthcare databases and reg- reviewed regarding criteria for researcher qualifications and legitimacy istries. This is ongoing in several countries to obtain data on of the research purpose. the effect of oral cladribine exposure, in a cohort of preg- nant women with MS and in a cohort of pregnant women Compliance with Ethical Standards whose pregnancy is fathered by men with MS exposed to Funding The design of this study and the collection and analysis of oral cladribine. Exposed cohorts will be compared to unex- data, and medical writing and editorial support in development of this posed cohorts. manuscript were sponsored by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany (rest of the world). 5 Conclusions Conflict of interest Gavin Giovannoni has received speaker honoraria As MS is most commonly diagnosed in women, many of and consulting fees from AbbVie, Actelion, Atara Bio, Almirall, Bayer whom may be of childbearing age, reproductive planning Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW with respect to MS treatment requires careful consideration, Pharma, Ironwood, Merck & Co., Merck KGaA, Novartis, Pfizer Inc., especially because the continuation of many DMDs is not Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, and Vertex Pharmaceuticals; and has received advised during pregnancy. It is therefore important to col- research support unrelated to this study from Biogen Idec, Ironwood, lect and report data on pregnancy outcomes in women who Merck & Co., and Novartis. Andrew Galazka is an employee of Merck, have been taking DMDs or who are the partners of men with Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Ger- MS who have received such treatment. While limited by the many. Regina Schick is an employee of Merck KGaA, Darmstadt, Ger- many. Thomas Leist has received consultancy fees or clinical research small number of pregnancies and related data, highlighting grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, the need for further study, the observations in this integrated ONO, Pfizer, and Teva Neuroscience. Giancarlo Comi has received safety analysis of the clinical development program of clad- consulting fees from Bayer Schering, Biogen Idec, Genentech-Roche, ribine were consistent with epidemiological data on preg- Merck, Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd; lecture fees from Bayer Schering, Biogen Dompè, Mer- nancy outcomes for the general population or women with ck, Novartis, Sanofi-Aventis, Serono Symposia International Founda- MS. No congenital malformations were observed with clad- tion, and Teva Pharmaceutical Industries Ltd; and trial grant support ribine during the ‘at-risk’ period. It should be noted that the from Bayer Schering, Biogen Dompè, Biogen Idec, Genentech-Roche, period of therapeutic effectiveness that patients might expect Merck, Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd. Xavier Montalban has received speaking honoraria following treatment with cladribine tablets is substantially and travel expenses for scientific meetings, has been a steering com- longer than the period during which recommended contra- mittee member of clinical trials or participated in advisory boards of ception should be practiced. However, the data currently clinical trials in the past years with Actelion, Bayer, Biogen, Celgene, available for pregnancy and cladribine in MS are limited, Excemed, Genzyme, Merck, MSIF, NMSS, Novartis, Roche, Sanofi- Genzyme, and Teva Pharmaceuticals. Doris Damian and Fernando and as recommended by regulatory authorities, additional Dangond are employees of EMD Serono Research & Development In- studies are needed, and a post-authorization safety study is stitute, Inc., a business of Merck KGaA, Darmstadt, Germany. Stuart therefore ongoing. Cook has received honoraria for lectures/consultations from Actinobac Biomed, Inc., Bayer HealthCare, Biogen Idec, Merck KGaA, Neurol- 642 G. Giovannoni et al. ogy Reviews, Sanofi-Aventis, and Teva Pharmaceuticals; has served Lancet Neurol. 2014;13(3):257–67. https:​ //doi.org/10.1016/s1474​ on advisory boards for Actinobac Biomed, Inc., Bayer HealthCare, -4422(14)70005​-5. Biogen Idec, Merck KGaA, and Teva Pharmaceuticals; and received 10. Montalban X, Leist TP, Cohen BA, Moses H, Campbell J, Hicking grant support from Bayer HealthCare. C, et al. Cladribine tablets added to IFN-beta in active relapsing MS: the ONWARD study. Neurol Neuroimmunol Neuroinflamm. Ethics approval No formal ethics approval was required in this analy- 2018;5(5):e477. https​://doi.org/10.1212/nxi.00000​00000​00047​7. sis: for each clinical trial included in this integrated analysis, approval 11. Pecori C, Giannini M, Portaccio E, Ghezzi A, Hakiki B, Pasto was granted by an independent ethics committee. L, et al. Paternal therapy with disease modifying drugs in mul- tiple sclerosis and pregnancy outcomes: a prospective observa- Consent to participate All patients provided written informed consent tional multicentric study. BMC Neurol. 2014;14:114. https​://doi. prior to enrollment in the clinical trial. org/10.1186/1471-2377-14-114. 12. Hellwig K, Haghikia A, Gold R. Parenthood and immu- nomodulation in patients with multiple sclerosis. J Neurol. Open Access This article is licensed under a Creative Commons Attri- 2010;257(4):580–3. https​://doi.org/10.1007/s0041​5-009-5376-z. bution-NonCommercial 4.0 International License, which permits any 13. Lu E, Zhu F, Zhao Y, van der Kop M, Sadovnick AD, Synnes non-commercial use, sharing, adaptation, distribution and reproduction A, et al. Birth outcomes of pregnancies fathered by men with in any medium or format, as long as you give appropriate credit to the multiple sclerosis. Mult Scler. 2014;20(9):1260–4. https​://doi. original author(s) and the source, provide a link to the Creative Com- org/10.1177/13524​58514​52130​8. mons licence, and indicate if changes were made. The images or other 14. Finkelsztejn A, Brooks JB, Paschoal FM Jr, Fragoso YD. What third party material in this article are included in the article’s Creative can we really tell women with multiple sclerosis regarding preg- Commons licence, unless indicated otherwise in a credit line to the nancy? A systematic review and meta-analysis of the literature. material. If material is not included in the article’s Creative Commons Br J Obstet Gynaecol. 2011;118(7):790–7. https​://doi.org/10.111 licence and your intended use is not permitted by statutory regula- 1/j.1471-0528.2011.02931​.x. tion or exceeds the permitted use, you will need to obtain permission 15. Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The repro- directly from the copyright holder. To view a copy of this licence, visit ductive effects of beta interferon therapy in pregnancy: a lon- http://creat​iveco​mmons​.org/licen​ses/by-nc/4.0/. gitudinal cohort. Neurology. 2005;65(6):807–11. https​://doi. org/10.1212/01.wnl.00001​80575​.77021​.c4. 16. Ebrahimi N, Herbstritt S, Gold R, Amezcua L, Koren G, Hellwig K. Pregnancy and fetal outcomes following natalizumab exposure References in pregnancy: a prospective, controlled observational study. Mult Scler. 2015;21(2):198–205. https​://doi.org/10.1177/13524​58514​ 1. Kamm CP, Uitdehaag BM, Polman CH. Multiple sclerosis: current 54679​0. knowledge and future outlook. Eur Neurol. 2014;72(3–4):132–41. 17. EMD Serono, Inc. Rebif 22 μg, 44 μg FDA approved label. 2019. 2. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato Available from: www.fda.gov. Accessed 29 Oct 2019. MP, Chandraratna D, et al. ECTRIMS/EAN guideline on the phar- 18. Biogen Idec Inc. Avonex 30 μg FDA approved label. 2019. Avail- macological treatment of people with multiple sclerosis. Eur J able from: www.fda.gov. Accessed 29 Oct 2019. Neurol. 2018;25(2):215–37. https​://doi.org/10.1111/ene.13536​. 19. Bayer HealthCare Pharmaceuticals Inc. Betaseron 0.25 mg FDA 3. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann approved label. 2019. Available from: www.fda.gov. Accessed 29 P, Soelberg Sorensen P, et al. A placebo-controlled trial of Oct 2019. oral cladribine for relapsing multiple sclerosis. N Engl J Med. 20. Novartis Pharmaceutical Corporation. Extavia 0.25 mg FDA 2010;362(5):416–26. https​://doi.org/10.1056/NEJMo​a0902​533. approved label. 2016. Available from: www.fda.gov. Accessed 4. Giovannoni G, Soelberg Sorensen P, Cook S, Rammohan K, 11 Sep 2018. Rieckmann P, Comi G, et al. Safety and efficacy of cladribine tab- 21. Biogen Idec Inc. Plegridy 125 μg FDA approved label. 2019. lets in patients with relapsing-remitting multiple sclerosis: Results Available from: www.fda.gov. Accessed 29 Oct 2019. from the randomized extension trial of the CLARITY study. Mult 22. Teva Neuroscience, Inc. Copaxone 20 mg, 40 mg FDA approved Scler. 2018;24(12):1594–604. https​://doi.org/10.1177/13524​ label. Available from: www.fda.gov. Accessed 11 Sep 2018. 58517​72760​3. 23. Biogen Inc. Tecfidera 240 mg FDA approved label. 2017. Avail- 5. Merck Europe B.V. Mavenclad 10 mg summary of product char- able from: www.fda.gov. Accessed 11 Sep 2018. acteristics. 2020. Available from: www.ema.europ​a.eu. Accessed 24. Genzyme Corporation. Aubagio 7 mg, 14 mg FDA approved label. 13 Jan 2020. 2016. Available from: www.fda.gov. Accessed 11 Sep 2018. 6. Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson 25. Novartis AG. Gilenya 0.5 mg FDA approved label. 2018. Avail- MO. Population pharmacokinetics of cladribine in patients with able from: www.fda.gov. Accessed 11 Sep 2018. multiple sclerosis. Clin Pharmacokinet. 2017;56(10):1245–53. 26. Biogen Inc. Tysabri 300 mg FDA approved label. 2018. Available https​://doi.org/10.1007/s4026​2-017-0516-6. from: www.fda.gov. Accessed 11 Sep 2018. 7. Hartung HP, Aktas O, Kieseier B, Giancarlo Comi GC. Develop- 27. Genzyme Corporation. Lemtrada 12 mg FDA approved label. ment of oral cladribine for the treatment of multiple sclerosis. 2017. Available from: www.fda.gov. Accessed 11 Sep 2018. J Neurol. 2010;257(2):163–70. https​://doi.org/10.1007/s0041​ 28. Genentech, Inc. Ocrevus 30 mg/mL FDA approved label. 2017. 5-009-5359-0. Available from: www.fda.gov. Accessed 11 Sep 2018. 8. Cook S, Leist T, Comi G, Montalban X, Giovannoni G, Nolting A, 29. Teva Pharmaceuticals Ltd. Copaxone 20 mg/mL summary of et al. Safety of cladribine tablets in the treatment of patients with product characteristics. 2017. Available from: www.medic​ines. multiple sclerosis: an integrated analysis. Mult Scler Relat Disord. org.uk. Accessed 11 Sep 2018. 2019;29:157–67. https​://doi.org/10.1016/j.msard​.2018.11.021. 30. Hellwig K, Duarte Caron F, Wicklein E-M, Bhatti A, Adamo A. 9. Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Har- Pregnancy outcomes from the global pharmacovigilance database tung HP, et al. Effect of oral cladribine on time to conversion on interferon beta-1b exposure. Ther Adv Neurol Disord. 2020;13. to clinically definite multiple sclerosis in patients with a first https​://doi.org/10.1177/17562​86420​91031​0. demyelinating event (ORACLE MS): a phase 3 randomised trial. Pregnancy Outcomes During the Clinical Development of Cladribine for MS 643 31. Biogen Idec Ltd. Avonex 30 μg summary of product characteris- treatment for relapsing-remitting multiple sclerosis. Neurol Ther. tics. 2019. Available from: www.ema.europa​ .eu. Accessed 29 Oct 2014;3(2):133–8. https​://doi.org/10.1007/s4012​0-014-0020-y. 2019. 38. Biogen Idec Ltd. Tecfidera 240 mg summary of product charac- 32. Bayer AG. Betaferon 250 μg/mL summary of product character- teristics. 2018. Available from: www.ema.europa​ .eu. Accessed 11 istics. 2019. Available from: www.ema.europ​a.eu. Accessed 29 Sep 2018. Oct 2019. 39. Novartis Europharm Limited. Gilenya 0.5 mg summary of prod- 33. Novartis Europharm Ltd. Extavia 250 μg summary of product uct characteristics. 2018. Available from: www.ema.europ​a.eu. characteristics. 2019. Available from: www.ema.europ​a .eu. Accessed 11 Sep 2018. Accessed 29 Oct 2019. 40. Biogen Netherlands B.V. Tysabri 300 mg summary of product 34. Biogen Netherlands B.V. Plegridy 125 μg summary of prod- characteristics. 2018. Available from: www.ema.europ​a .eu. uct characteristics. 2019. Available from: www.ema.europ​a.eu. Accessed 11 Sep 2018. Accessed 29 Oct 2019. 41. Genzyme Therapeutics Ltd. Lemtrada 12 mg summary of prod- 35. Merck Serono Europe Ltd. Rebif 22 μg, 44 μg summary of prod- uct characteristics. 2018. Available from: www.ema.europ​a.eu. uct characteristics. 2019. Available from: www.ema.europ​a.eu. Accessed 11 Sep 2018. Accessed 29 Oct 2019. 42. Roche Registration GmbH. Ocrevus 30 mg/mL summary of prod- 36. Chambers CD, Johnson DL, Robinson LK, Braddock SR, uct characteristics. 2018. Available from: www.ema.europ​a.eu. Xu R, Lopez-Jimenez J, et al. Birth outcomes in women who Accessed 11 Sep 2018. have taken leflunomide during pregnancy. Arthritis Rheum. 43. European Medicines Agency. Ocrevus European public assess- 2010;62(5):1494–503. https​://doi.org/10.1002/art.27358​. ment report. 2017. Available from: www.ema.europa​ .eu. Accessed 37. Kieseier BC, Benamor M. Pregnancy outcomes follow- 31 May 2018. ing maternal and paternal exposure to teriflunomide during Affiliations Gavin Giovannoni1 · Andrew Galazka2 · Regina Schick3 · Thomas Leist4 · Giancarlo Comi5 · Xavier Montalban6,7 · Doris Damian8 · Fernando Dangond8 · Stuart Cook9 6 * Gavin Giovannoni Division of Neurology, St Michael’s Hospital, University g.giovannoni@qmul.ac.uk of Toronto, Toronto, ON, Canada 7 1 Department of Neurology‑Neuroimmunology, Centre Blizard Institute, Barts and the London School of Medicine d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital and Dentistry, Queen Mary University of London, 4 Newark Universitario Vall d’Hebron, Barcelona, Spain Street, London E1 2AT, UK 8 2 EMD Serono Research and Development Institute, Inc., Merck, Aubonne, Switzerland, a division of Merck KGaA, Billerica, MA, USA Darmstadt, Germany 9 3 New Jersey Medical School, Rutgers, The State University Merck KGaA, Darmstadt, Germany of New Jersey, Newark, NJ, USA 4 Comprehensive MS Center, Jefferson University, Philadelphia, PA, USA 5 Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy