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Safety and Efficacy of Delayed-Release Dimethyl Fumarate in Pediatric Patients With Relapsing Multiple Sclerosis (FOCUS)
ARTICLE IN PRESS Pediatric Neurology ■■ (2018) ■■–■■
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Pediatric Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n u
Original Article
Safety and Efficacy of Delayed-Release Dimethyl Fumarate in Pediatric Patients With Relapsing Multiple Sclerosis (FOCUS) Raed Alroughani a, Rajiv Das b, Natasha Penner b, Joe Pultz b, Catherine Taylor b, Satish Eraly b,* a b
Dasman Diabetes Institute, Dasman, Kuwait and Amiri Hospital, Sharq, Kuwait Biogen, Cambridge, Massachusetts
A R T I C L E
I N F O
Article history: Received 15 March 2018 Accepted 18 March 2018 Keywords: Relapsing-remitting multiple sclerosis Dimethyl fumarate Safety Efficacy Pediatric Pharmacokinetics
A B S T R A C T
Background: No therapies have been formally approved by the Food and Drug Administration for use in pediatric multiple sclerosis, a rare disease. Objective: We evaluated the safety, efficacy, and pharmacokinetics of dimethyl fumarate in pediatric patients with multiple sclerosis. Methods: FOCUS, a phase 2, multicenter study of patients aged 10 to 17 years with relapsing-remitting multiple sclerosis, comprised an eight-week baseline and 24-week treatment period; during treatment, patients received dimethyl fumarate (120 mg twice daily on days one to seven; 240 mg twice a day thereafter). Magnetic resonance imaging scans were obtained at week −8, day 0, week 16, and week 24. The primary end point was the change in T2 hyperintense lesion incidence from the baseline period to the final 8 weeks of treatment. Secondary end points were pharmacokinetic parameters and adverse event incidence. Results: Twenty of 22 enrolled patients completed the study. There was a significant reduction in T2 hyperintense lesion incidence from baseline to the final eight weeks of treatment (P = 0.009). Adverse events (most commonly gastrointestinal events and flushing) and pharmacokinetic parameters were consistent with adult findings. No serious adverse events were considered dimethyl fumarate related. Conclusions: Dimethyl fumarate treatment was associated with a reduction in magnetic resonance imaging activity in pediatric patients; pharmacokinetic and safety profiles were consistent with those in adults. Dimethyl fumarate is a potential treatment for pediatric multiple sclerosis. © 2018 Elsevier Inc. All rights reserved.
Introduction Pediatric multiple sclerosis (MS) is a rare disease. Although approximately 2% to 5% of all MS cases are estimated to have an onset before the age of 18 years,1 the proportion of persons younger than 18 years old among patients with MS is expected to be substantially lower, because at any given point in time the great majority of patients with pediatric onset of disease would be adults. In fact, the worldwide pooled prevalence of pediatric MS in countries where data are available is 0.57 per 100,000, compared with 72.3 per 100,000 for adult MS.2 The degree to which adult and pediatric MS are pathophysiologically similar has been debated given age-related differences in the extent of inflammation and demyelination. Notably,
Trial registration: ClinicalTrials.gov, NCT02410200. https://clinicaltrials.gov/ ct2/show/NCT02410200. * Corresponding author. E-mail address: [email protected] (S. Eraly) https://doi.org/10.1016/j.pediatrneurol.2018.03.007 0887-8994/© 2018 Elsevier Inc. All rights reserved.
pediatric MS almost invariably presents with a relapsing-remitting course characterized by a high relapse rate, rather than with a progressive course.1,3-5 However, inflammation and demyelination are components of the disease regardless of age and are present even in patients in the later progressive phase.5 Thus, the totality of evidence suggests that although quantitative differences may exist, adult and pediatric MS share the same basic disease mechanisms of inflammation, demyelination, and neurodegeneration.5,6 Further support for this view would be provided by demonstration that therapies effective for adult MS also are effective for pediatric MS. No disease-modifying therapies have yet been approved by the Food and Drug Administration or extensively studied in interventional, prospective clinical trials for use in pediatric patients with MS. The efficacy and safety of interferon beta (IFN-β) and glatiramer acetate, the most commonly used agents in pediatric MS, have been almost exclusively assessed in observational studies (the European Medicines agency has granted limited approval for the use of IFN-β in patients ≥12 years of age).4,7,8 Most recently, the PARADIGMS study has published final results showing that children and adolescents with MS had an 82% lower relapse
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rate with fingolimod versus IFN-β1a, but as yet fingolimod is not approved for the treatment of pediatric MS. Current recommendations regarding the use of these agents in pediatric patients, including dosing, are based on adaptation of adult treatment guidelines and expert opinion. In adult patients with relapsing-remitting MS (RRMS), delayedrelease dimethyl fumarate (DMF; also known as gastro-resistant DMF) has demonstrated strong efficacy and a favorable benefitrisk profile in two phase 3 studies (DEFINE and CONFIRM)9,10 and an associated long-term extension study (ENDORSE).11 Currently, there are few published data available on use of DMF to treat children or adolescents with MS.12 The objective of FOCUS was to evaluate the efficacy, pharmacokinetics (PK), and safety of DMF in pediatric patients with MS. Patients and Methods
were obtained from each patient and his or her parent or legal guardian. FOCUS was registered at ClinicalTrials.gov (NCT02410200). Eligible patients included males and females aged 10 to 17 years at the time of enrollment, with body weight ≥30 kg and a diagnosis of RRMS according to both the McDonald13 and the International Pediatric Multiple Sclerosis Study Group criteria for pediatric MS.14 Included patients also had to be ambulatory, with an Expanded Disability Status Scale score of ≤5.0, and had to have experienced at least one relapse in the 12 months or two relapses in the 24 months before screening. The main exclusion criteria were progressive MS, disorders mimicking MS, or a history of clinically significant comorbid disorders or conditions. Patients were also excluded if they received prior medications such as DMF (at any time); fingolimod, teriflunomide, or natalizumab (within 6 months before week −8 MRI); or glatiramer acetate, IFN-β, or corticosteroids (within 28 days before week −8 MRI).
Study design and participants Procedures This study, entitled “Open-Label, multicenter, multiple-dose study of the effect of DMF on MRI Lesions and PK in pediatric subjects with RRMS aged 10 to 17 years” (FOCUS) was a phase 2, singlearm, multicenter, open-label study in pediatric patients with RRMS conducted between June 2015 and September 2016 at 12 sites across ten countries: Poland (n = 5), Kuwait (n = 3), Germany (n = 3), Bulgaria (n = 3), Turkey (n = 2), Lebanon (n = 2), Latvia (n = 1), Belgium (n = 1), Czech Republic (n = 1), and the United States (n = 1). The study comprised a four-week screening period, an eight-week offtreatment baseline period, and a 24-week treatment period (Fig 1). A safety follow-up visit was conducted four weeks after the last dose of study treatment. During the eight-week baseline period, all patients were off MS treatment and underwent baseline brain magnetic resonance imaging (MRI) scans at week −8 and day 0. During the treatment period, clinic visits were conducted on day 1, day 8, and weeks 4, 8, 12, 16, and 24, with follow-up brain MRIs at weeks 16 and 24. Eligible patients had the opportunity to continue to receive DMF for up to an additional two years (extension study; ClinicalTrials.gov, NCT02555215; data not shown). The study was conducted in accordance with relevant US federal regulations, the Declaration of Helsinki, and the International Council on Harmonisation Guideline for Good Clinical Practice. Approvals were granted by relevant institutional ethics committees for study protocol and amendments, and written assent and consent forms
During the 24-week open-label treatment period, all patients received DMF 120 mg twice a day (BID) for the first week (day one to day seven), and DMF 240 mg BID, the approved dosage for adult patients, thereafter.15,16 DMF was temporarily or permanently discontinued if any laboratory values, including lymphocyte count, met predefined thresholds.15 Assessments continued during the periods of treatment discontinuation, and resumption of treatment was considered on an individual basis depending on normalization of laboratory values. Compliance with study treatment dosing was monitored and recorded by study site staff. Protocol-defined relapses (onset of new or recurrent neurologic symptoms not associated with fever or infection, of duration ≥24 hours, and accompanied by new objective neurologic findings) were treated at the discretion of the study investigator using the protocol-approved treatment for relapse (either three days or five days of intravenous methylprednisolone 1000 mg/d). Outcomes MRI scans were read by an independent central MRI center using advanced image analysis to limit variance. The eight-week interval between MRI scans at baseline and follow-up was chosen as the minimum period to allow a statistically reliable determination of incidence of new or newly enlarging T2 hyperintense lesions, con-
FIGURE 1. Design of the FOCUS study. BID, twice a day; DMF, delayed-release dimethyl fumarate; MRI, magnetic resonance imaging.
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sidering the practical need to conduct an efficient study that minimized burden on enrolled patients. The primary end point was change in the number of new or newly enlarging T2 hyperintense lesions during the last eight weeks of the on-treatment period (weeks 16 to 24) compared with the number of new or newly enlarging T2 hyperintense lesions during the eight-week baseline period. The primary end point population was defined as patients who received at least one dose of DMF and had new or newly enlarging T2 hyperintense lesions during the baseline period. A sensitivity analysis was performed and included patients in the primary analysis, as well as patients who did not have new or newly enlarging T2 hyperintense lesions during the baseline period. In addition to the assessment of radiological efficacy, the incidence of protocoldefined relapses was used for exploratory analysis. Secondary pharmacokinetic end points included maximum observed plasma concentration (Cmax), time to reach Cmax, and area under the concentration-time curve from time 0 to hour 12 (AUC0–12h). Pharmacokinetic sampling was conducted at ten time points on day eight (predose through ten hours post dose) to evaluate drug exposure. Because orally administered DMF is rapidly and completely metabolized to monomethyl fumarate (MMF), all pharmacokinetic analyses were performed using plasma MMF concentrations. The pharmacokinetic analysis population was defined as patients who received at least one dose of DMF and had at least one pharmacokinetic parameter available. Secondary safety end points included incidence of adverse events (AEs), serious AEs, and treatment discontinuations owing to AEs. All AEs were coded using the Medical Dictionary for Regulatory Activities (version 19.0) and classified by the investigator by relationship to study treatment and severity (mild, moderate, severe). Treatmentemergent AEs (TEAEs) were defined as AEs occurring or worsening after the beginning of study treatment. Physical examination and vital sign measurements (including body temperature, pulse rate, systolic and diastolic blood pressure, and respiratory rate) as well as 12-lead electrocardiogram readings and laboratory assessments were also performed. Laboratory assessments included measurement of lymphocyte counts, serum alanine aminotransferase (ALT), and serum aspartate aminotransferase (AST) at week −4 or baseline, day one, day eight (+3 days), week four (±7 days), week eight (±7 days), week 12 (±7 days), week 16 (±7 days), week 24 (±7 days) or early withdrawal, week 28 (±7 days), and unscheduled relapse assessment visits. The safety analysis population was defined as those patients who received at least one dose of DMF. Analysis of MMF Determination of plasma concentrations of MMF was conducted by inVentiv Health Clinical Lab, Inc (Princeton, NJ) using a validated liquid chromatography-tandem mass spectrometry method that followed US Food and Drug Administration guidelines.17 Further details on the MMF analysis methodology are described in the Supplementary Methods. Statistical analysis The sample size of the primary end point population (n = 15) was determined based on providing at least 80% probability that the median change from baseline in T2 hyperintense lesion incidence would be below 0, and 65% probability that the upper limit of the 90% Hodges-Lehmann confidence interval (CI) would be ≤0, assuming a 45% true reduction in lesion incidence. Additionally, the calculated sample size was sufficient to obtain 90% CIs of geometric means for Cmax and AUC within ranges of 0.81 to 1.24 and 0.86 to 1.16, respectively, and to observe an AE with an underlying occurrence rate of 10% or higher. Twenty-two patients were enrolled to accommodate the potential early withdrawal of up to seven pa-
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tients. Patients without new or newly enlarging T2 hyperintense lesions during the baseline period were excluded from the primary end point analysis, but were included in sensitivity analyses. Summary statistics were presented for the primary end point data, pharmacokinetic parameters, and incidence of AEs. The 90% Hodges-Lehmann CI was determined for the median change in the number of new or newly enlarging T2 hyperintense lesions (primary end point), and within-patient comparisons were made using the Wilcoxon signed rank test to calculate P values for determination of statistical significance. All summaries and statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results In total, 22 patients were enrolled; 20 completed the study and 15 were included in the primary end point analysis population. Five patients without new or newly enlarging T2 hyperintense lesions during the baseline period were excluded from the primary end point analysis based on the prespecified statistical plan intended to restrict analysis to patients with evidence of disease activity at baseline. These patients were included in the sensitivity analysis described below. Twenty-one patients were included in the pharmacokinetic analysis population, and 22 in the safety population. Patient baseline demographic and disease characteristics are shown in Table 1. Before this study, 12 (55%) patients had received MS therapy; most commonly IFN-β1a (n = 7, 32%). Median (range) time on DMF treatment was 172 (11 to 182) days. Overall there was a high patient compliance rate (median compliance >95%). For the primary end point population (n = 15 completers), mean (standard error) change in number of new or newly enlarging T2 hyperintense lesions was −7.9 (4.2), and median (90% CI) change was −2.0 (−8.0 to −1.5, P = 0.009). For the sensitivity analysis, which included those patients without MRI activity at baseline (n = 20), mean (standard error) change in number of new or newly enlarging T2 hyperintense lesions was −5.9 (3.2), and median (90% CI) change was −1.0 (−5.0 to −0.5, P = 0.009). There was an approximately threefold reduction in new or newly T2 hyperintense lesion formation at 24 weeks of treatment compared with the baseline period (Fig 2). The total number of relapses retrospectively reported in the study cohort (n = 22) that occurred during the year before study entry was 33, and the number of relapses reported during the 24-week on-treatment period was eight. The unadjusted annualized relapse rate was 1.5 for the year before study entry and 0.8 for the 24week treatment period. Most (15 of 22, 68%) patients experienced
TABLE 1. Patient Baseline Demographic and Disease Characteristics in FOCUS Characteristic
All Patients (N = 22)
Age in years, mean (range) Female, n (%) Weight in kg, mean (range) Time since first MS symptoms in years, median (range) Time since MS diagnosis in years, median (range) Relapses in prior year, mean (range) Relapses in prior 2 years, mean (range) Any prior MS treatment, n (%) EDSS score, mean (range) Baseline number of new/newly enlarging T2 hyperintense lesions,* mean (SE)
15.8 (13-17) 14 (64) 66.2 (46.0-91.2) 2 (1-9) 1 (0-6) 1.5 (0-4) 2.1 (1-5) 12 (55) 1.2 (0-3.5) 7.6 (3.3)
Abbreviations: EDSS = Expanded Disability Status Scale (performed by investigators after undergoing standardized training). MS = Multiple sclerosis. Values are given as mean (minimum, maximum) unless otherwise specified. * Mean number of new or newly enlarging T2 hyperintense lesions observed in the eight-week baseline pretreatment period (weeks −8 to 0).
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TABLE 3. Most Common TEAEs
FIGURE 2. Mean (SE) number of new or newly enlarging T2 hyperintense lesions during the baseline period versus the on-treatment period. SE, standard error.
no relapses during the on-treatment period, compared with two (of 22, 9%) patients during the year before study entry. The mean and coefficient of variation values for the indicated pharmacokinetic parameters on day 8 are shown in Table 2. For seven patients, elimination half-life, AUC from time 0 to infinity (AUC0–∞), and AUC0–12h could not be calculated owing to an insufficient number of time points in the terminal phase. For 10 patients with 10-hour plasma concentration at the lower limit of quantitation, AUC0–∞ could be approximated as AUC0–10h; therefore, for these patients, apparent clearance was estimated as dose/AUC0–10h. With 21 patients in this study providing PK data, it was possible to robustly estimate key PK parameters with reasonable confidence. The PK of DMF in the patients in the study (C max : 2.00 ± 1.29 mg/L; AUC 0-12h : 3.62 ± 1.16 h·mg/L, which corresponds to an overall daily AUC of 7.24 h·mg/L) was consistent with that previously observed in adult patients (mean Cmax: 1.87 mg/L and daily AUC: 8.21 h·mg/L in adult patients with MS). Most (20 of 22, 91%) patients experienced a TEAE; 16 (73%) experienced a TEAE considered related to DMF. The most common TEAEs were gastrointestinal events (mainly abdominal pain, nausea,
TABLE 2. Mean Pharmacokinetic Parameters for Monomethyl Fumarate at Day 8 in Pediatric Patients With RRMS Parameter
n
Value (Coefficient of Variation %)
AUC0–10h, h·μg/mL AUC0–12h, h·μg/mL AUC0–∞, h·μg/mL Cmax, μg/mL Tmax, h Vz/F, L CL/F, L/h
21 14 14 21 21 14 17
3.6 (43) 3.6 (32)* 3.6 (32) 2.0 (64) † 4.2 (37) 98.2 (93) 74.5 (41)
Abbreviations: AUC0–∞ = Area under the concentration-time curve from time 0 to infinity. AUC0–10h = Area under the concentration-time curve from time 0 to hour 10. AUC0–12h = Area under the concentration-time curve from time 0 to hour 12. CL/F = Apparent clearance. Cmax = Maximum observed plasma concentration. RRMS = Relapsing-remitting multiple sclerosis. Tmax = Time to maximum observed plasma concentration. Vz/F = Apparent volume of distribution. Orally administered delayed-release dimethyl fumarate is rapidly and completely metabolized to monomethyl fumarate; the pharmacokinetic analyses were performed with plasma monomethyl fumarate concentrations. * 90% confidence interval = 3.1 to 4.2. † 90% confidence interval = 1.5 to 2.5.
Event
Patients, n (%) (N = 22)
Any AE* Gastrointestinal disorders† Flushing MS relapse Headache Cough Fatigue Vertigo Upper respiratory tract infection Viral upper respiratory infection Alopecia Dysmenorrhea Lymphocyte count decreased Nasopharyngitis Oropharyngeal pain
20 (91) 12 (55) 10 (45) 7 (32) 4 (18) 3 (14) 3 (14) 3 (14) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9)
Abbreviations: AE = Adverse event. MS = Multiple sclerosis. TEAE = Treatment-emergent adverse event. AEs coded using Medical Dictionary for Regulatory Activities System Organ Class (SOC) and Preferred Term (PT). * A patient was counted only once within each SOC or PT. † Group of PTs.
and vomiting), flushing, and MS relapse, occurring in 12 (55%), 10 (45%), and 7 (32%) patients, respectively (Table 3). Eight relapses were experienced by the seven patients who had TEAEs of relapse; these eight relapses occurred on days 3, 5, 25, 49, 67, 97, 108, and 113. Headache was noted in four (18%) patients. AEs were transient and resolved either with symptomatic treatment or spontaneously. Two patients discontinued treatment owing to AEs before 24 weeks (one because of MS relapse and one because of urticaria). Six serious AEs were reported (five MS relapses and one case of vertigo) in five patients; none of these were considered to be related to study treatment by the investigators. No serious infections or opportunistic infections were reported in any patients. Regarding laboratory abnormalities of interest, lymphocyte count reductions below the lower limit of normal, ALT elevation, and AST elevation occurred in five (23%), three (15%), and two (10%) patients, respectively (Table 4). Of the five patients with a lymphocyte count less than the lower limit of normal, three had a count <0.8 × 10 9 /L and one had a count <0.5 × 10 9 /L, which had in-
TABLE 4. Laboratory Abnormalities of Interest at Any Time Abnormality Lymphocytes ALC
Patients, n (%) 5 (23) 2 (10) 2 (10) 1 (5) 3 (15) 2 (10) 2 (10)
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creased to >0.5 × 109/L when the next measurement was taken 6 weeks later. No patients met the criteria for study drug discontinuation on the basis of severe prolonged lymphopenia (defined as lymphocyte count <0.5 × 109/L for >6 months). Mean lymphocyte counts decreased from 1.95 × 109/L at baseline to 1.58 × 109/L at 24 weeks of DMF exposure, representing a reduction of ~18%. The ALT and AST elevations were isolated; two of the events (one ALT and one AST elevation) were reported as AEs, and occurred in the same patient within the first 30 days of treatment. Both were reported as moderate in severity and resolved spontaneously. They were not considered related to DMF treatment by the investigators. Discussion This study of pediatric MS demonstrated that treatment with DMF was associated with a significant decrease in the number of new or newly enlarging T2 hyperintense lesions (median [90% CI] change for the primary end point population was −2.0 [−8.0 to −1.5], P = 0.009). The sensitivity analysis for all enrolled and completer patients was designed to limit the bias of excluding patients without new or newly enlarging T2 hyperintense lesions during the baseline period; the results were similar to those reported for the primary analysis population (median [90% CI] change in the number of new or newly enlarging T2 hyperintense lesions was −1.0 [−5.0 to −0.5], P = 0.009). The values of individual pharmacokinetic parameters of MMF in pediatric patients in this study were broadly similar to those previously reported for adult patients (Biogen data on file), and the safety profile of DMF in this study was consistent with the observed profile in adult patients.9,10 Currently, IFN-β and glatiramer acetate are the most commonly used first-line disease-modifying agents for the treatment of naive pediatric patients with MS.4,7 In patients treated with IFN-β, several observational studies have shown a reduction in relapse rate during treatment compared with pretreatment periods, despite the high treatment failure or discontinuation rates observed (up to 64% in one long-term study over 60 months).4,18 Outcomes for patients treated with glatiramer acetate in observational studies appear favorable but are limited in terms of the small number of patients assessed.4 Natalizumab has been assessed in a large Italian study involving 101 children (mean age at onset 12.9 years) with highly active disease and a suboptimal response to first-line therapies.19 The mean treatment duration was 34.2 ± 18.3 months; during natalizumab treatment, 15 relapses were recorded in nine patients. The mean annualized relapse rate (SD) was 2.3 ± 1.0 in the year before natalizumab treatment and decreased to 0.1 ± 0.3 (P < 0.001) at the last natalizumab infusion. There was also a decrease in the proportion of patients with new T2 hyperintense or gadolinium-enhancing lesions (4.8% at 30 months versus 11.0% at six months).19 With regard to fingolimod, the first oral immunomodulating agent approved for adult MS, a large phase 3 study comparing fingolimod with IFN-β in pediatric patients with MS has been completed, and the full results were recently presented.8 Treatment with fingolimod resulted in an 82% reduction in annualized relapse rate over a period of up to two years, compared with IFN-β (P < 0.001), and a significant reduction in the number of new or newly enlarging T2 and gadolinium-enhancing T1 lesions in the brain. A retrospective review of 13 children (aged ≤18 years) treated with DMF over a median of 15.0 months (range 1 to 25) found that most (77%) children tolerated dose escalation to the usual adult dose of 240 mg BID.12 Further, eight of nine (89%) patients who had ≥12 months of follow-up on treatment showed stabilized or reduced relapse rates and disability scores on treatment. The most common AEs reported were facial flushing, gastrointestinal discomfort, rash, and malaise. The results of the present interventional trial confirm these initial observational findings and add further detail related to the extent of improvement in radiological and clinical mea-
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sures of disease activity. Our results also provide pharmacokinetic data showing a similar overall profile to that of adult patients. A phase 3 study (ClinicalTrials.gov, NCT02283853) of DMF versus IFN-β in pediatric MS is currently ongoing. Expected enrollment is ~140 patients aged 10 to 17 years. This trial will provide information about the efficacy and safety of DMF compared with IFN-β. The main strengths of the current study were the high proportion of patients completing the study and the high patient compliance rate with study treatment (>95%). Limitations are the lack of a control group and the small number of patients (the latter is mainly because of the rarity of the population analyzed and, therefore, the inherent challenges associated with enrolling a larger study). Furthermore, because this is a single-arm study, a “regression-to-the-mean effect” cannot be excluded. However, a significant reduction in MRI activity is observed whether or not patients with baseline MRI activity are included, attenuating the likelihood of a regression-to-themean effect substantially biasing the results. Despite these potential limitations, the results of this phase 2 interventional trial provide evidence that the efficacy, PK, and safety profiles of DMF in pediatric patients with RRMS are consistent with those observed in adult patients, providing support for the pathophysiological similarity of adult and pediatric MS. In conclusion, DMF showed radiological efficacy in pediatric patients with MS and similar pharmacokinetic and safety characteristics to those noted in adults. These results provide indirect support for an overlap between pediatric and adult MS in pathophysiology and disease-modifying therapy response. This study suggests DMF may prove to be a well-tolerated treatment option for pediatric patients with RRMS. Further clinical controlled studies are warranted. Contributors R.A., investigator, was involved in data collection and interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. R.D. was involved in data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. N.P. was involved in pharmacokinetic analysis, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. J.P. was involved in statistical analysis, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. C.T. was involved in communication of data, and in the drafting, critical revision, and approval of the final version of the manuscript. S.E. was involved in study design, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.A. reports speaker and scientific advisory board honoraria from Bayer HealthCare, Biogen, GlaxoSmithKline, Merck, Novartis, and Sanofi-Genzyme, and research support from Biogen, Merck, and Novartis for the establishment of regional MS registries and conduct of clinical trials. N.P., C.T., and S.E. are employees of and hold stock/stock options in Biogen. R.D. and J.P. are contractors for Biogen. Funding Biogen funded the study design, data collection and analysis, and medical writing support in the development of the manuscript. The
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corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Acknowledgments The authors would like to thank all the study participants. Principle investigators were Andrew Kornberg (Royal Children’s Hospital, Melbourne, Australia); Veneta Bojinova-Tchamova (MHATNP Sv. Naum, EAD Clinic of Neurology, Sofia, Bulgaria); Martin Valis (Fakultni nemocnice Hradec Kralove, Czech Republic); Peter Huppke (Universitaetsmedizin Goettingen, Niedersachsen, Germany); Janbernd Kirschner (Universitaetsklinikum Freiburg, Baden Wuerttemberg, Germany); Astrid Blaschek (Klinikum der Universitaet Muenchen, Bayern, Germany); Guntis Rozentals (Children’s Clinical University Hospital, Riga, Latvia); Gabriela Klodowska-Duda (Neuro-Care Site Management Organization, Katowice, Poland); Barbara Steinborn (Oddział Kliniczny Neurologii Dzieci i Młodziez˙y, Poznan, Poland); Maria Mazurkiewicz-Beldzinska (Uniwersyteckie Centrum Kliniczne Gdansk, Poland); Bulent Kara (Kocaeli University Medical Faculty, Kocaeli, Turkey); Banu Anlar (Hacettepe University Medical Faculty, Ankara, Turkey); Gulsen Akman Demir (Istanbul Bilim University Medical Facility, Istanbul, Turkey); Murat Terzi (Ondokuz Mayis University Medical Facility, Samsun, Turkey); Gregory Aaen (Loma Linda University Children’s Hospital, California, United States); Helene Verhelst (Universitair Ziekenhuis Gent, Gent, Belgium); Raed Alroughani (Dasman Diabetes Institute, Kuwait City, Kuwait); and Bassem Yamout (American University of Beirut Medical Center, Beirut, Lebanon). Biogen provided funding for medical writing support in the development of this paper. The named authors of the paper were the principal contributors to the clinical study report (CSR) of the FOCUS study. This CSR formed the basis of an initial draft of the manuscript prepared by Mark Snape, MBBS, and Ana Antaloae, PhD, from Excel Scientific Solutions. Monica Dodge from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper and provided their final approval of all content. Supplementary data Supplementary data related to this article can be found at https:// doi.org/10.1016/j.pediatrneurol.2018.03.007.
References 1. Chou I-J, Wang H-S, Whitehouse WP, Constantinescu CS. Paediatric multiple sclerosis: update on diagnostic criteria, imaging, histopathology and treatment choices. Curr Neurol Neurosci Rep. 2016;16:68. 2. Multiple Sclerosis International Federation (MSIF). Atlas of MS 2013: Mapping Multiple Sclerosis Around the World. Available at http://www.msif.org/wpcontent/uploads/2014/09/Atlas-of-MS.pdf. Accessed November 16, 2017. 3. Chitnis T. Pediatric multiple sclerosis. Neurologist. 2006;12:299–310. 4. Ghezzi A, Amato MP, Makhani N, Shreiner T, Gartner J, Tenembaum S. Pediatric multiple sclerosis: conventional first-line treatment and general management. Neurology. 2016;87(9 suppl 2):S97–S102. 5. Waldman A, O’Connor E, Tennekoon G. Childhood multiple sclerosis: a review. Ment Retard Dev Disabil Res Rev. 2006;12:147–156. 6. Bar-Or A, Hintzen RQ, Dale RC, Rostasy K, Bruck W, Chitnis T. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases. Neurology. 2016;87(9 suppl 2):S12–S19. 7. Simone M, Chitnis T. Use of disease-modifying therapies in pediatric MS. Curr Treat Options Neurol. 2016;18:36. 8. Chitnis TAD, Arnold DL, Banwell B, et al. PARADIGMS: a randomised doubleblind study of fingolimod versus interferon β-1a in paediatric multiple sclerosis. Paris, France: 2017. the 7th Joint ECTRIMS-ACTRIMS meeting on October 28, 2017. 9. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087– 1097. 10. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–1107. 11. Gold R, Arnold DL, Bar-Or A, et al. Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: interim analysis of ENDORSE, a randomized extension study. Mult Scler. 2017;23:253–265. 12. Makhani N, Schreiner T. Oral dimethyl fumarate in children with multiple sclerosis: a dual-center study. Pediatr Neurol. 2016;57:101–104. 13. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302. 14. Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19:1261–1267. 15. Biogen. Tecfidera [prescribing information. 2017. Available at https:// www.tecfidera.com/content/dam/commercial/multiple-sclerosis/tecfidera/pat/ en_us/pdf/full-prescribing-info.pdf. Accessed May 8, 2017. 16. European Medicines Agency. Tecfidera 120 mg gastro-resistant hard capsules [summary of product characteristics]. Available at http://www.ema.europa.eu/ docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/ WC500162069.pdf. Accessed May 5, 2017. 17. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM). Guidance for industry. Bioanalytical method validation. 2001. Available at http://www.fda.gov/downloads/Drugs/GuidanceCompilance RegulatoryInformation/Guidances/ucm070107.pdf. Accessed July 10, 2017. 18. Ghezzi A, Amato MP, Annovazzi P, et al. Long-term results of immunomodulatory treatment in children and adolescents with multiple sclerosis: the Italian experience. Neurol Sci. 2009;30:193–199. 19. Ghezzi A, Moiola L, Pozzilli C, et al. Natalizumab in the pediatric MS population: results of the Italian registry. BMC Neurol. 2015;15:174.
Contents lists available at ScienceDirect
Pediatric Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n u
Original Article
Safety and Efficacy of Delayed-Release Dimethyl Fumarate in Pediatric Patients With Relapsing Multiple Sclerosis (FOCUS) Raed Alroughani a, Rajiv Das b, Natasha Penner b, Joe Pultz b, Catherine Taylor b, Satish Eraly b,* a b
Dasman Diabetes Institute, Dasman, Kuwait and Amiri Hospital, Sharq, Kuwait Biogen, Cambridge, Massachusetts
A R T I C L E
I N F O
Article history: Received 15 March 2018 Accepted 18 March 2018 Keywords: Relapsing-remitting multiple sclerosis Dimethyl fumarate Safety Efficacy Pediatric Pharmacokinetics
A B S T R A C T
Background: No therapies have been formally approved by the Food and Drug Administration for use in pediatric multiple sclerosis, a rare disease. Objective: We evaluated the safety, efficacy, and pharmacokinetics of dimethyl fumarate in pediatric patients with multiple sclerosis. Methods: FOCUS, a phase 2, multicenter study of patients aged 10 to 17 years with relapsing-remitting multiple sclerosis, comprised an eight-week baseline and 24-week treatment period; during treatment, patients received dimethyl fumarate (120 mg twice daily on days one to seven; 240 mg twice a day thereafter). Magnetic resonance imaging scans were obtained at week −8, day 0, week 16, and week 24. The primary end point was the change in T2 hyperintense lesion incidence from the baseline period to the final 8 weeks of treatment. Secondary end points were pharmacokinetic parameters and adverse event incidence. Results: Twenty of 22 enrolled patients completed the study. There was a significant reduction in T2 hyperintense lesion incidence from baseline to the final eight weeks of treatment (P = 0.009). Adverse events (most commonly gastrointestinal events and flushing) and pharmacokinetic parameters were consistent with adult findings. No serious adverse events were considered dimethyl fumarate related. Conclusions: Dimethyl fumarate treatment was associated with a reduction in magnetic resonance imaging activity in pediatric patients; pharmacokinetic and safety profiles were consistent with those in adults. Dimethyl fumarate is a potential treatment for pediatric multiple sclerosis. © 2018 Elsevier Inc. All rights reserved.
Introduction Pediatric multiple sclerosis (MS) is a rare disease. Although approximately 2% to 5% of all MS cases are estimated to have an onset before the age of 18 years,1 the proportion of persons younger than 18 years old among patients with MS is expected to be substantially lower, because at any given point in time the great majority of patients with pediatric onset of disease would be adults. In fact, the worldwide pooled prevalence of pediatric MS in countries where data are available is 0.57 per 100,000, compared with 72.3 per 100,000 for adult MS.2 The degree to which adult and pediatric MS are pathophysiologically similar has been debated given age-related differences in the extent of inflammation and demyelination. Notably,
Trial registration: ClinicalTrials.gov, NCT02410200. https://clinicaltrials.gov/ ct2/show/NCT02410200. * Corresponding author. E-mail address: [email protected] (S. Eraly) https://doi.org/10.1016/j.pediatrneurol.2018.03.007 0887-8994/© 2018 Elsevier Inc. All rights reserved.
pediatric MS almost invariably presents with a relapsing-remitting course characterized by a high relapse rate, rather than with a progressive course.1,3-5 However, inflammation and demyelination are components of the disease regardless of age and are present even in patients in the later progressive phase.5 Thus, the totality of evidence suggests that although quantitative differences may exist, adult and pediatric MS share the same basic disease mechanisms of inflammation, demyelination, and neurodegeneration.5,6 Further support for this view would be provided by demonstration that therapies effective for adult MS also are effective for pediatric MS. No disease-modifying therapies have yet been approved by the Food and Drug Administration or extensively studied in interventional, prospective clinical trials for use in pediatric patients with MS. The efficacy and safety of interferon beta (IFN-β) and glatiramer acetate, the most commonly used agents in pediatric MS, have been almost exclusively assessed in observational studies (the European Medicines agency has granted limited approval for the use of IFN-β in patients ≥12 years of age).4,7,8 Most recently, the PARADIGMS study has published final results showing that children and adolescents with MS had an 82% lower relapse
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rate with fingolimod versus IFN-β1a, but as yet fingolimod is not approved for the treatment of pediatric MS. Current recommendations regarding the use of these agents in pediatric patients, including dosing, are based on adaptation of adult treatment guidelines and expert opinion. In adult patients with relapsing-remitting MS (RRMS), delayedrelease dimethyl fumarate (DMF; also known as gastro-resistant DMF) has demonstrated strong efficacy and a favorable benefitrisk profile in two phase 3 studies (DEFINE and CONFIRM)9,10 and an associated long-term extension study (ENDORSE).11 Currently, there are few published data available on use of DMF to treat children or adolescents with MS.12 The objective of FOCUS was to evaluate the efficacy, pharmacokinetics (PK), and safety of DMF in pediatric patients with MS. Patients and Methods
were obtained from each patient and his or her parent or legal guardian. FOCUS was registered at ClinicalTrials.gov (NCT02410200). Eligible patients included males and females aged 10 to 17 years at the time of enrollment, with body weight ≥30 kg and a diagnosis of RRMS according to both the McDonald13 and the International Pediatric Multiple Sclerosis Study Group criteria for pediatric MS.14 Included patients also had to be ambulatory, with an Expanded Disability Status Scale score of ≤5.0, and had to have experienced at least one relapse in the 12 months or two relapses in the 24 months before screening. The main exclusion criteria were progressive MS, disorders mimicking MS, or a history of clinically significant comorbid disorders or conditions. Patients were also excluded if they received prior medications such as DMF (at any time); fingolimod, teriflunomide, or natalizumab (within 6 months before week −8 MRI); or glatiramer acetate, IFN-β, or corticosteroids (within 28 days before week −8 MRI).
Study design and participants Procedures This study, entitled “Open-Label, multicenter, multiple-dose study of the effect of DMF on MRI Lesions and PK in pediatric subjects with RRMS aged 10 to 17 years” (FOCUS) was a phase 2, singlearm, multicenter, open-label study in pediatric patients with RRMS conducted between June 2015 and September 2016 at 12 sites across ten countries: Poland (n = 5), Kuwait (n = 3), Germany (n = 3), Bulgaria (n = 3), Turkey (n = 2), Lebanon (n = 2), Latvia (n = 1), Belgium (n = 1), Czech Republic (n = 1), and the United States (n = 1). The study comprised a four-week screening period, an eight-week offtreatment baseline period, and a 24-week treatment period (Fig 1). A safety follow-up visit was conducted four weeks after the last dose of study treatment. During the eight-week baseline period, all patients were off MS treatment and underwent baseline brain magnetic resonance imaging (MRI) scans at week −8 and day 0. During the treatment period, clinic visits were conducted on day 1, day 8, and weeks 4, 8, 12, 16, and 24, with follow-up brain MRIs at weeks 16 and 24. Eligible patients had the opportunity to continue to receive DMF for up to an additional two years (extension study; ClinicalTrials.gov, NCT02555215; data not shown). The study was conducted in accordance with relevant US federal regulations, the Declaration of Helsinki, and the International Council on Harmonisation Guideline for Good Clinical Practice. Approvals were granted by relevant institutional ethics committees for study protocol and amendments, and written assent and consent forms
During the 24-week open-label treatment period, all patients received DMF 120 mg twice a day (BID) for the first week (day one to day seven), and DMF 240 mg BID, the approved dosage for adult patients, thereafter.15,16 DMF was temporarily or permanently discontinued if any laboratory values, including lymphocyte count, met predefined thresholds.15 Assessments continued during the periods of treatment discontinuation, and resumption of treatment was considered on an individual basis depending on normalization of laboratory values. Compliance with study treatment dosing was monitored and recorded by study site staff. Protocol-defined relapses (onset of new or recurrent neurologic symptoms not associated with fever or infection, of duration ≥24 hours, and accompanied by new objective neurologic findings) were treated at the discretion of the study investigator using the protocol-approved treatment for relapse (either three days or five days of intravenous methylprednisolone 1000 mg/d). Outcomes MRI scans were read by an independent central MRI center using advanced image analysis to limit variance. The eight-week interval between MRI scans at baseline and follow-up was chosen as the minimum period to allow a statistically reliable determination of incidence of new or newly enlarging T2 hyperintense lesions, con-
FIGURE 1. Design of the FOCUS study. BID, twice a day; DMF, delayed-release dimethyl fumarate; MRI, magnetic resonance imaging.
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sidering the practical need to conduct an efficient study that minimized burden on enrolled patients. The primary end point was change in the number of new or newly enlarging T2 hyperintense lesions during the last eight weeks of the on-treatment period (weeks 16 to 24) compared with the number of new or newly enlarging T2 hyperintense lesions during the eight-week baseline period. The primary end point population was defined as patients who received at least one dose of DMF and had new or newly enlarging T2 hyperintense lesions during the baseline period. A sensitivity analysis was performed and included patients in the primary analysis, as well as patients who did not have new or newly enlarging T2 hyperintense lesions during the baseline period. In addition to the assessment of radiological efficacy, the incidence of protocoldefined relapses was used for exploratory analysis. Secondary pharmacokinetic end points included maximum observed plasma concentration (Cmax), time to reach Cmax, and area under the concentration-time curve from time 0 to hour 12 (AUC0–12h). Pharmacokinetic sampling was conducted at ten time points on day eight (predose through ten hours post dose) to evaluate drug exposure. Because orally administered DMF is rapidly and completely metabolized to monomethyl fumarate (MMF), all pharmacokinetic analyses were performed using plasma MMF concentrations. The pharmacokinetic analysis population was defined as patients who received at least one dose of DMF and had at least one pharmacokinetic parameter available. Secondary safety end points included incidence of adverse events (AEs), serious AEs, and treatment discontinuations owing to AEs. All AEs were coded using the Medical Dictionary for Regulatory Activities (version 19.0) and classified by the investigator by relationship to study treatment and severity (mild, moderate, severe). Treatmentemergent AEs (TEAEs) were defined as AEs occurring or worsening after the beginning of study treatment. Physical examination and vital sign measurements (including body temperature, pulse rate, systolic and diastolic blood pressure, and respiratory rate) as well as 12-lead electrocardiogram readings and laboratory assessments were also performed. Laboratory assessments included measurement of lymphocyte counts, serum alanine aminotransferase (ALT), and serum aspartate aminotransferase (AST) at week −4 or baseline, day one, day eight (+3 days), week four (±7 days), week eight (±7 days), week 12 (±7 days), week 16 (±7 days), week 24 (±7 days) or early withdrawal, week 28 (±7 days), and unscheduled relapse assessment visits. The safety analysis population was defined as those patients who received at least one dose of DMF. Analysis of MMF Determination of plasma concentrations of MMF was conducted by inVentiv Health Clinical Lab, Inc (Princeton, NJ) using a validated liquid chromatography-tandem mass spectrometry method that followed US Food and Drug Administration guidelines.17 Further details on the MMF analysis methodology are described in the Supplementary Methods. Statistical analysis The sample size of the primary end point population (n = 15) was determined based on providing at least 80% probability that the median change from baseline in T2 hyperintense lesion incidence would be below 0, and 65% probability that the upper limit of the 90% Hodges-Lehmann confidence interval (CI) would be ≤0, assuming a 45% true reduction in lesion incidence. Additionally, the calculated sample size was sufficient to obtain 90% CIs of geometric means for Cmax and AUC within ranges of 0.81 to 1.24 and 0.86 to 1.16, respectively, and to observe an AE with an underlying occurrence rate of 10% or higher. Twenty-two patients were enrolled to accommodate the potential early withdrawal of up to seven pa-
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tients. Patients without new or newly enlarging T2 hyperintense lesions during the baseline period were excluded from the primary end point analysis, but were included in sensitivity analyses. Summary statistics were presented for the primary end point data, pharmacokinetic parameters, and incidence of AEs. The 90% Hodges-Lehmann CI was determined for the median change in the number of new or newly enlarging T2 hyperintense lesions (primary end point), and within-patient comparisons were made using the Wilcoxon signed rank test to calculate P values for determination of statistical significance. All summaries and statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results In total, 22 patients were enrolled; 20 completed the study and 15 were included in the primary end point analysis population. Five patients without new or newly enlarging T2 hyperintense lesions during the baseline period were excluded from the primary end point analysis based on the prespecified statistical plan intended to restrict analysis to patients with evidence of disease activity at baseline. These patients were included in the sensitivity analysis described below. Twenty-one patients were included in the pharmacokinetic analysis population, and 22 in the safety population. Patient baseline demographic and disease characteristics are shown in Table 1. Before this study, 12 (55%) patients had received MS therapy; most commonly IFN-β1a (n = 7, 32%). Median (range) time on DMF treatment was 172 (11 to 182) days. Overall there was a high patient compliance rate (median compliance >95%). For the primary end point population (n = 15 completers), mean (standard error) change in number of new or newly enlarging T2 hyperintense lesions was −7.9 (4.2), and median (90% CI) change was −2.0 (−8.0 to −1.5, P = 0.009). For the sensitivity analysis, which included those patients without MRI activity at baseline (n = 20), mean (standard error) change in number of new or newly enlarging T2 hyperintense lesions was −5.9 (3.2), and median (90% CI) change was −1.0 (−5.0 to −0.5, P = 0.009). There was an approximately threefold reduction in new or newly T2 hyperintense lesion formation at 24 weeks of treatment compared with the baseline period (Fig 2). The total number of relapses retrospectively reported in the study cohort (n = 22) that occurred during the year before study entry was 33, and the number of relapses reported during the 24-week on-treatment period was eight. The unadjusted annualized relapse rate was 1.5 for the year before study entry and 0.8 for the 24week treatment period. Most (15 of 22, 68%) patients experienced
TABLE 1. Patient Baseline Demographic and Disease Characteristics in FOCUS Characteristic
All Patients (N = 22)
Age in years, mean (range) Female, n (%) Weight in kg, mean (range) Time since first MS symptoms in years, median (range) Time since MS diagnosis in years, median (range) Relapses in prior year, mean (range) Relapses in prior 2 years, mean (range) Any prior MS treatment, n (%) EDSS score, mean (range) Baseline number of new/newly enlarging T2 hyperintense lesions,* mean (SE)
15.8 (13-17) 14 (64) 66.2 (46.0-91.2) 2 (1-9) 1 (0-6) 1.5 (0-4) 2.1 (1-5) 12 (55) 1.2 (0-3.5) 7.6 (3.3)
Abbreviations: EDSS = Expanded Disability Status Scale (performed by investigators after undergoing standardized training). MS = Multiple sclerosis. Values are given as mean (minimum, maximum) unless otherwise specified. * Mean number of new or newly enlarging T2 hyperintense lesions observed in the eight-week baseline pretreatment period (weeks −8 to 0).
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TABLE 3. Most Common TEAEs
FIGURE 2. Mean (SE) number of new or newly enlarging T2 hyperintense lesions during the baseline period versus the on-treatment period. SE, standard error.
no relapses during the on-treatment period, compared with two (of 22, 9%) patients during the year before study entry. The mean and coefficient of variation values for the indicated pharmacokinetic parameters on day 8 are shown in Table 2. For seven patients, elimination half-life, AUC from time 0 to infinity (AUC0–∞), and AUC0–12h could not be calculated owing to an insufficient number of time points in the terminal phase. For 10 patients with 10-hour plasma concentration at the lower limit of quantitation, AUC0–∞ could be approximated as AUC0–10h; therefore, for these patients, apparent clearance was estimated as dose/AUC0–10h. With 21 patients in this study providing PK data, it was possible to robustly estimate key PK parameters with reasonable confidence. The PK of DMF in the patients in the study (C max : 2.00 ± 1.29 mg/L; AUC 0-12h : 3.62 ± 1.16 h·mg/L, which corresponds to an overall daily AUC of 7.24 h·mg/L) was consistent with that previously observed in adult patients (mean Cmax: 1.87 mg/L and daily AUC: 8.21 h·mg/L in adult patients with MS). Most (20 of 22, 91%) patients experienced a TEAE; 16 (73%) experienced a TEAE considered related to DMF. The most common TEAEs were gastrointestinal events (mainly abdominal pain, nausea,
TABLE 2. Mean Pharmacokinetic Parameters for Monomethyl Fumarate at Day 8 in Pediatric Patients With RRMS Parameter
n
Value (Coefficient of Variation %)
AUC0–10h, h·μg/mL AUC0–12h, h·μg/mL AUC0–∞, h·μg/mL Cmax, μg/mL Tmax, h Vz/F, L CL/F, L/h
21 14 14 21 21 14 17
3.6 (43) 3.6 (32)* 3.6 (32) 2.0 (64) † 4.2 (37) 98.2 (93) 74.5 (41)
Abbreviations: AUC0–∞ = Area under the concentration-time curve from time 0 to infinity. AUC0–10h = Area under the concentration-time curve from time 0 to hour 10. AUC0–12h = Area under the concentration-time curve from time 0 to hour 12. CL/F = Apparent clearance. Cmax = Maximum observed plasma concentration. RRMS = Relapsing-remitting multiple sclerosis. Tmax = Time to maximum observed plasma concentration. Vz/F = Apparent volume of distribution. Orally administered delayed-release dimethyl fumarate is rapidly and completely metabolized to monomethyl fumarate; the pharmacokinetic analyses were performed with plasma monomethyl fumarate concentrations. * 90% confidence interval = 3.1 to 4.2. † 90% confidence interval = 1.5 to 2.5.
Event
Patients, n (%) (N = 22)
Any AE* Gastrointestinal disorders† Flushing MS relapse Headache Cough Fatigue Vertigo Upper respiratory tract infection Viral upper respiratory infection Alopecia Dysmenorrhea Lymphocyte count decreased Nasopharyngitis Oropharyngeal pain
20 (91) 12 (55) 10 (45) 7 (32) 4 (18) 3 (14) 3 (14) 3 (14) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9) 2 (9)
Abbreviations: AE = Adverse event. MS = Multiple sclerosis. TEAE = Treatment-emergent adverse event. AEs coded using Medical Dictionary for Regulatory Activities System Organ Class (SOC) and Preferred Term (PT). * A patient was counted only once within each SOC or PT. † Group of PTs.
and vomiting), flushing, and MS relapse, occurring in 12 (55%), 10 (45%), and 7 (32%) patients, respectively (Table 3). Eight relapses were experienced by the seven patients who had TEAEs of relapse; these eight relapses occurred on days 3, 5, 25, 49, 67, 97, 108, and 113. Headache was noted in four (18%) patients. AEs were transient and resolved either with symptomatic treatment or spontaneously. Two patients discontinued treatment owing to AEs before 24 weeks (one because of MS relapse and one because of urticaria). Six serious AEs were reported (five MS relapses and one case of vertigo) in five patients; none of these were considered to be related to study treatment by the investigators. No serious infections or opportunistic infections were reported in any patients. Regarding laboratory abnormalities of interest, lymphocyte count reductions below the lower limit of normal, ALT elevation, and AST elevation occurred in five (23%), three (15%), and two (10%) patients, respectively (Table 4). Of the five patients with a lymphocyte count less than the lower limit of normal, three had a count <0.8 × 10 9 /L and one had a count <0.5 × 10 9 /L, which had in-
TABLE 4. Laboratory Abnormalities of Interest at Any Time Abnormality Lymphocytes ALC
Patients, n (%) 5 (23) 2 (10) 2 (10) 1 (5) 3 (15) 2 (10) 2 (10)
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creased to >0.5 × 109/L when the next measurement was taken 6 weeks later. No patients met the criteria for study drug discontinuation on the basis of severe prolonged lymphopenia (defined as lymphocyte count <0.5 × 109/L for >6 months). Mean lymphocyte counts decreased from 1.95 × 109/L at baseline to 1.58 × 109/L at 24 weeks of DMF exposure, representing a reduction of ~18%. The ALT and AST elevations were isolated; two of the events (one ALT and one AST elevation) were reported as AEs, and occurred in the same patient within the first 30 days of treatment. Both were reported as moderate in severity and resolved spontaneously. They were not considered related to DMF treatment by the investigators. Discussion This study of pediatric MS demonstrated that treatment with DMF was associated with a significant decrease in the number of new or newly enlarging T2 hyperintense lesions (median [90% CI] change for the primary end point population was −2.0 [−8.0 to −1.5], P = 0.009). The sensitivity analysis for all enrolled and completer patients was designed to limit the bias of excluding patients without new or newly enlarging T2 hyperintense lesions during the baseline period; the results were similar to those reported for the primary analysis population (median [90% CI] change in the number of new or newly enlarging T2 hyperintense lesions was −1.0 [−5.0 to −0.5], P = 0.009). The values of individual pharmacokinetic parameters of MMF in pediatric patients in this study were broadly similar to those previously reported for adult patients (Biogen data on file), and the safety profile of DMF in this study was consistent with the observed profile in adult patients.9,10 Currently, IFN-β and glatiramer acetate are the most commonly used first-line disease-modifying agents for the treatment of naive pediatric patients with MS.4,7 In patients treated with IFN-β, several observational studies have shown a reduction in relapse rate during treatment compared with pretreatment periods, despite the high treatment failure or discontinuation rates observed (up to 64% in one long-term study over 60 months).4,18 Outcomes for patients treated with glatiramer acetate in observational studies appear favorable but are limited in terms of the small number of patients assessed.4 Natalizumab has been assessed in a large Italian study involving 101 children (mean age at onset 12.9 years) with highly active disease and a suboptimal response to first-line therapies.19 The mean treatment duration was 34.2 ± 18.3 months; during natalizumab treatment, 15 relapses were recorded in nine patients. The mean annualized relapse rate (SD) was 2.3 ± 1.0 in the year before natalizumab treatment and decreased to 0.1 ± 0.3 (P < 0.001) at the last natalizumab infusion. There was also a decrease in the proportion of patients with new T2 hyperintense or gadolinium-enhancing lesions (4.8% at 30 months versus 11.0% at six months).19 With regard to fingolimod, the first oral immunomodulating agent approved for adult MS, a large phase 3 study comparing fingolimod with IFN-β in pediatric patients with MS has been completed, and the full results were recently presented.8 Treatment with fingolimod resulted in an 82% reduction in annualized relapse rate over a period of up to two years, compared with IFN-β (P < 0.001), and a significant reduction in the number of new or newly enlarging T2 and gadolinium-enhancing T1 lesions in the brain. A retrospective review of 13 children (aged ≤18 years) treated with DMF over a median of 15.0 months (range 1 to 25) found that most (77%) children tolerated dose escalation to the usual adult dose of 240 mg BID.12 Further, eight of nine (89%) patients who had ≥12 months of follow-up on treatment showed stabilized or reduced relapse rates and disability scores on treatment. The most common AEs reported were facial flushing, gastrointestinal discomfort, rash, and malaise. The results of the present interventional trial confirm these initial observational findings and add further detail related to the extent of improvement in radiological and clinical mea-
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sures of disease activity. Our results also provide pharmacokinetic data showing a similar overall profile to that of adult patients. A phase 3 study (ClinicalTrials.gov, NCT02283853) of DMF versus IFN-β in pediatric MS is currently ongoing. Expected enrollment is ~140 patients aged 10 to 17 years. This trial will provide information about the efficacy and safety of DMF compared with IFN-β. The main strengths of the current study were the high proportion of patients completing the study and the high patient compliance rate with study treatment (>95%). Limitations are the lack of a control group and the small number of patients (the latter is mainly because of the rarity of the population analyzed and, therefore, the inherent challenges associated with enrolling a larger study). Furthermore, because this is a single-arm study, a “regression-to-the-mean effect” cannot be excluded. However, a significant reduction in MRI activity is observed whether or not patients with baseline MRI activity are included, attenuating the likelihood of a regression-to-themean effect substantially biasing the results. Despite these potential limitations, the results of this phase 2 interventional trial provide evidence that the efficacy, PK, and safety profiles of DMF in pediatric patients with RRMS are consistent with those observed in adult patients, providing support for the pathophysiological similarity of adult and pediatric MS. In conclusion, DMF showed radiological efficacy in pediatric patients with MS and similar pharmacokinetic and safety characteristics to those noted in adults. These results provide indirect support for an overlap between pediatric and adult MS in pathophysiology and disease-modifying therapy response. This study suggests DMF may prove to be a well-tolerated treatment option for pediatric patients with RRMS. Further clinical controlled studies are warranted. Contributors R.A., investigator, was involved in data collection and interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. R.D. was involved in data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. N.P. was involved in pharmacokinetic analysis, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. J.P. was involved in statistical analysis, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. C.T. was involved in communication of data, and in the drafting, critical revision, and approval of the final version of the manuscript. S.E. was involved in study design, data interpretation, and in the drafting, critical revision, and approval of the final version of the manuscript. All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.A. reports speaker and scientific advisory board honoraria from Bayer HealthCare, Biogen, GlaxoSmithKline, Merck, Novartis, and Sanofi-Genzyme, and research support from Biogen, Merck, and Novartis for the establishment of regional MS registries and conduct of clinical trials. N.P., C.T., and S.E. are employees of and hold stock/stock options in Biogen. R.D. and J.P. are contractors for Biogen. Funding Biogen funded the study design, data collection and analysis, and medical writing support in the development of the manuscript. The
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corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Acknowledgments The authors would like to thank all the study participants. Principle investigators were Andrew Kornberg (Royal Children’s Hospital, Melbourne, Australia); Veneta Bojinova-Tchamova (MHATNP Sv. Naum, EAD Clinic of Neurology, Sofia, Bulgaria); Martin Valis (Fakultni nemocnice Hradec Kralove, Czech Republic); Peter Huppke (Universitaetsmedizin Goettingen, Niedersachsen, Germany); Janbernd Kirschner (Universitaetsklinikum Freiburg, Baden Wuerttemberg, Germany); Astrid Blaschek (Klinikum der Universitaet Muenchen, Bayern, Germany); Guntis Rozentals (Children’s Clinical University Hospital, Riga, Latvia); Gabriela Klodowska-Duda (Neuro-Care Site Management Organization, Katowice, Poland); Barbara Steinborn (Oddział Kliniczny Neurologii Dzieci i Młodziez˙y, Poznan, Poland); Maria Mazurkiewicz-Beldzinska (Uniwersyteckie Centrum Kliniczne Gdansk, Poland); Bulent Kara (Kocaeli University Medical Faculty, Kocaeli, Turkey); Banu Anlar (Hacettepe University Medical Faculty, Ankara, Turkey); Gulsen Akman Demir (Istanbul Bilim University Medical Facility, Istanbul, Turkey); Murat Terzi (Ondokuz Mayis University Medical Facility, Samsun, Turkey); Gregory Aaen (Loma Linda University Children’s Hospital, California, United States); Helene Verhelst (Universitair Ziekenhuis Gent, Gent, Belgium); Raed Alroughani (Dasman Diabetes Institute, Kuwait City, Kuwait); and Bassem Yamout (American University of Beirut Medical Center, Beirut, Lebanon). Biogen provided funding for medical writing support in the development of this paper. The named authors of the paper were the principal contributors to the clinical study report (CSR) of the FOCUS study. This CSR formed the basis of an initial draft of the manuscript prepared by Mark Snape, MBBS, and Ana Antaloae, PhD, from Excel Scientific Solutions. Monica Dodge from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper and provided their final approval of all content. Supplementary data Supplementary data related to this article can be found at https:// doi.org/10.1016/j.pediatrneurol.2018.03.007.
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