RESEARCH ARTICLE OPEN ACCESS Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis MAGNIFY-MS Nicola de Stefano, MD, PhD, Frederik Barkhof, MD, Xavier Montalban, MD, PhD, Anat Achiron, MD, PhD, FAAN, Correspondence Dr. de Stefano Tobias Derfuss, MD, Andrew Chan, MD, Suzanne Hodgkinson, MBBS, PhD, Alexandre Prat, MD, PhD, FRCPC, destefano@unisi.it Letizia Leocani, MD, PhD, Klaus Schmierer, MD, PhD, Finn Sellebjerg, MD, PhD, DMSc, Patrick Vermersch, MD, PhD, Heinz Wiendl, MD, PhD, Birgit Keller, Dipl-Stat, and Sanjeev Roy, MBBS, MD, MAGNIFY-MS Study Group Neurol Neuroimmunol Neuroinflamm 2022;9:e1187. doi:10.1212/NXI.0000000000001187 Abstract MORE ONLINE Background and Objectives Class of Evidence The onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an im- Criteria for rating portant parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine therapeutic and diagnostic studies tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS. NPub.org/coe Methods MRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium- enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed. Results Included in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (−1.193 between month 1 and month 6, −1.500 between month 2 and month 6, and −1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (−0.857 at month 2, −1.355 at month 3, and −1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6. Discussion Findings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time. Trial Registration Information NCT03364036; Date registered: December 06, 2017. From the Department of Medicine (N.S.), Surgery and Neuroscience, University of Siena, Siena, Italy; Department of Radiology (F.B.), VU University Medical Center, Amsterdam, The Netherlands; UCL Institute of Neurology (F.B.), London, UK; Department of Neurology-Neuroimmunology (X.M.), Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d’Hebron, Universitat Autonoma de Barcelona, Spain; Multiple Sclerosis Center (A.A.), Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (T.D.), University Hospital Basel, Switzerland; Department of Neurology (A.C.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Ingham Institute for Applied Medical Research (S.H.), University of New South Wales Medicine, Sydney, Australia; Department of Neurosciences (A.P.), Université de Montréal, QC, Canada; Experimental Neurophysiology Unit (L.L.), Vita-Salute San Raffaele University, Milan, Italy; The Blizard Institute (K.S.), Centre for Neuroscience, Surgery & Trauma, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, UK and; Clinical Board Medicine (Neuroscience) (K.S.), The Royal London Hospital, Barts Health NHS Trust, UK; Danish MS Center (F.S.), Department of Neurology, Copenhagen University Hospital–Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine (F.S.), University of Copenhagen, Denmark; Univ. Lille (P.V.), Inserm U1172 LilNCog, CHU Lille, FHU Precise, France; Department of Neurology (H.W.), Institute of Translational Neurology, University of Münster, Germany; the healthcare business of Merck KGaA (B.K.), Darmstadt, Germany; and Ares Trading S.A. (S.R.), Eysins, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany). Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by Merck Healthcare KGaA (Darmstadt, Germany). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary CUA = combined unique active; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; MS = multiple sclerosis; TEAE = treatment-emergent adverse event. Classification of Evidence Using frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time. Multiple sclerosis (MS) is a chronic, inflammatory, and neu- receive cladribine tablets 10 mg (MAVENCLAD, Merck B.V., rodegenerative disease of the CNS. A key tool used in the Amsterdam, The Netherlands; 3.5 mg/kg cumulative dose diagnosis and monitoring of MS is MRI, in which T1 over 2 years) with 2 weeks of active treatment per annual gadolinium-enhancing (Gd+) lesions and new or enlarging course. Patients included in the present analysis were planned T2 lesions are routinely evaluated. MRI is also a useful tool in to receive the first week of treatment starting at baseline, and determining the onset of action of disease-modifying thera- the second week of treatment during week 5 (month 1). The pies (DMTs), a parameter that is considered important for interim analysis presented here included all data reported up highly effective DMTs. to the 6-month study assessment; the cutoff date for the last patient was on January 23, 2020. Cladribine tablets have been approved in the European Union for the treatment of highly active relapsing MS. This dis- The screening visit of MAGNIFY-MS, at which patients ease course typically manifests with rapid and early onset provided informed consent and undertook a clinical MRI of disability often with high relapse rates and early motor, assessment, was planned to be conducted 3 months before the cerebellar, and/or cognitive dysfunction.1,2 Approximately baseline visit that was conducted within 7 days of the sched- 4%–32% of clinical trial populations are thought to experience uled start date. A minimum gap of 4 weeks was required this highly active disease course,1-6 although it should be between MRI assessment at the screening visit and the next noted that these studies used different definitions as to what assessment at the baseline visit. Further visits at months 1 constitutes highly active MS. The early initiation of highly (day 30), 2 (day 60), 3 (day 90), and 6 (day 180) after effective DMT is particularly important in this group of pa- initiating treatment with cladribine tablets had a time window tients to prevent disability accrual.7-9 of ±7 days from the scheduled date of visit (Figure 2). The placebo-controlled CLARITY study demonstrated high Patients were planned to be included if they were aged ≥18 efficacy of cladribine tablets on clinical and MRI outcomes years, with a diagnosis of highly active relapsing MS and an over 96 weeks,10,11 and indicated an early clinical effect within Expanded Disability Status Scale (EDSS) score of ≤5. En- the first 6 months.12 Because the first MRI assessment in rollment occurred at 50 centers in 14 countries between May CLARITY was conducted 6 months after the initiation of 28, 2018, and April 23, 2019. In this study, highly active treatment, the question of whether the treatment effect of relapsing MS was defined as one relapse in the previous year cladribine tablets starts earlier remained unanswered. and at least one T1 Gd+ lesion, or 9 or more T2 lesions while on therapy with other DMTs; or 2 or more relapses in the Using frequent MRI assessments of the brain over the first 6 previous year whether on DMT or not. Exclusion criteria months of the MAGNIFY-MS study (NCT03364036), our included: a lymphocyte count not within normal laboratory primary research question concerned the onset of action of limits; presence of signs of progressive multifocal leu- cladribine tablets 3.5 mg/kg in patients with highly active koencephalopathy; positive tests for HIV, hepatitis B or C, or relapsing MS. We also report a subgroup analysis of patients active/latent tuberculosis; active malignancy; allergy or hy- with high relapse activity, prior DMT use, or combined persensitivity to Gd and/or any other contraindication to unique active (CUA) lesion counts >0 at baseline. perform MRI; and previous exposure to alemtuzumab, fin- golimod, mitoxantrone, natalizumab, or ocrelizumab. Methods Efficacy End Points Study Design and Participants The MRI-based end point of the primary analysis was the MAGNIFY-MS was a 2-year, phase IV, open-label, single-arm difference in CUA lesion counts during postbaseline periods study (Figure 1), in which eligible patients were scheduled to (period 1: month 1 visit–month 6 visit, period 2: month 2 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 Neurology.org/NN Figure 1 Study Design Second treatment course may be delayed for some patients, according to the lymphocyte count. *Highly active relapsing MS was defined as one relapse in the previous year and at least one T1 Gd+ lesion, or 9 or more T2 lesions while on therapy with other DMTs; or 2 or more relapses in the previous year whether on DMT or not. 9HPT = 9-hole peg test; CUA = combined unique active; EDSS = Expanded Disability Status Scale; KFS = Kurtzke Functional System; MS = multiple sclerosis; SDMT = Symbol Digit Modalities Test; T25FW = timed 25-foot walk; TB = tuberculosis. visit–month 6 visit, and period 3: month 3 visit–month 6 visit) report occurrences of treatment-emergent adverse events compared with the baseline period (Screening Visit–Baseline (TEAEs), defined as all adverse events with an onset date after Visit). CUA lesions were defined as the combination of the T1 the initiation of treatment with cladribine tablets. Gd+ lesions and new or enlarging active T2 lesions (without T1 Gd+) for the respective period and were standardized to Statistical Analysis one scan (for T1 Gd+) or 1 month (for active T2). As per the All statistical analyses were performed on the full analysis set, MRI protocol, new or enlarging active T2 lesions without T1 which was defined as all patients who received ≥1 dose of cla- Gd+ activity were determined from a comparison of the prior dribine tablets (full analysis set/safety set). This approach follows T2-weighted sequence with reference to the T1 Gd-enhanced the intent-to-treat principle. All patients who were intended to be sequence. As part of the analysis, colocalizing 3-dimensional treated actually received at least one dose of cladribine tablets. lesions were counted as one lesion. If a new or enlarging T2 hyperintense lesion on a T2-weighted sequence had a corre- The 3 hypotheses to determine whether CUA lesion counts sponding T1 hyperintense signal on a T1-Gd enhanced se- were reduced after treatment with cladribine tablets were tested quence at the same time point, the lesion would be counted as separately for each of the 3 predefined postbaseline periods a T1 Gd+ hyperintense lesion without also counting it as a (Figure 2). Type I error inflation due to multiple testing was new or enlarging T2 lesion. controlled using a sequential testing procedure starting the test procedure with the test for period 3, followed by period 2, and The statistical analysis also investigated the components of finally period 1. The hypothesis for each period was rejected at the CUA lesion count (i.e., the standardized T1 Gd+ lesion a significance level of 0.025 (one sided) if the previous hy- count calculated as the mean across all scans of a period to pothesis could also be rejected. The change in CUA lesion account for a different number of scans during a period and count was analyzed by applying a mixed-effects linear model the active T2 lesion count standardized to 1 month to account accounting for within pooled center correlation and adjusted for different period lengths) and the lesion count at each visit. for CUA lesion count during the baseline period, age, and In addition, the proportion of patients CUA lesion free by baseline EDSS score (≤3, >3). The primary analysis was eval- period and T1 Gd+ lesion free by visit is presented. uated for robustness by applying a wide range of alternative statistical methods, including nonparametric tests and gener- Assessment of Relapses and Safety alized linear models assuming negative binomial distribution. During the study, qualifying relapses were defined as a neuro- logic abnormality (either newly appearing or reappearing) sep- Other MRI parameters were analyzed in an explorative way arated by at least 30 days from onset of a preceding clinical event similar to that for the primary end point. For MRI parameters and lasting for at least 24 hours; absence of fever (>37.5°C/ analyzed by visit, a model for repeated measures was applied 99.5°F) or known infection; and objective neurologic impair- taking into account within-patient correlations. ment, correlating with the patient’s reported symptoms, defined as either an increase in at least one of the functional system To evaluate consistency of results across special patient scores of the EDSS or an increase of the total EDSS score. We populations, the following subgroups were defined: patients Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 3 Figure 2 Definition of Periods Used for Analysis in the MAGNIFY-MS Study The baseline period was defined as screening to baseline and had a median duration of 35.0 days. with high relapse activity (defined as 2 or more relapses in the Darmstadt, Germany. All requests should be submitted in previous year) vs those without, prior DMT use (yes/no), and writing to the data-sharing portal for the healthcare business of a subset of patients with CUA lesion count >0 during the Merck KGaA, Darmstadt, Germany merckgroup.com/en/re- baseline period. search/our-approach-to-research-and-development/healthcare/ clinical-trials/commitment-responsible-data-sharing.html. When For each patient, the cutoff date for this interim analysis was the healthcare business of Merck KGaA, Darmstadt, Germany defined by that individual patient’s month 6 visit date. The has a coresearch, codevelopment, or comarketing or cop- redacted study protocol and statistical analysis plan for romotion agreement or when the product has been out-licensed, MAGNIFY-MS have been published on clinicaltrials.gov the responsibility for disclosure might be dependent on the (NCT03364036).13 agreement between parties. Under these circumstances, the healthcare business of Merck KGaA, Darmstadt, Germany will Sample Size and Statistical endeavor to gain agreement to share data in response to requests. Power Considerations Based on the CLARITY trial, the estimated treatment effect concerning the number of CUA lesions at month 6 was ap- Results proximately 1.3 vs placebo. As the primary end point for the MAGNIFY-MS trial is comparison of CUA lesions between A total of 313 patients were screened for enrollment into the the baseline and postbaseline periods, but with a single-arm MAGNIFY-MS study, and 270 of these patients initiated design, a more conservative treatment effect of 0.8 lesions treatment with cladribine tablets 3.5 mg/kg (43 patients were (and SD of 4.0) was assumed for the sample size calculation in screening failures). A mean (SD) age of 37.7 (±9.75) years the absence of a comparator group. A normal approximation and a median EDSS score of 2.0 at baseline were observed, to the distribution of the primary end point was also assumed. and patients were predominantly female (66.7%). Patient On the basis of such assumptions, a sample size of 265 pa- demographics and characteristics are shown in Table 1. tients was required to achieve 90% power for a paired t-test with a type I error rate of 0.05. During the baseline period, 52.2% (141/270) of patients had CUA lesions present on their MRI scans; 52.2% (141/270) Standard Protocol Approvals, Registrations, had T1 Gd+ lesions present, and 17.8% (48/270) had active and Patient Consents T2 lesions without the presence of T1 Gd+ lesions (eFigure 1, Ethical approval for the MAGNIFY-MS study was obtained links.lww.com/NXI/A723). After treatment initiation, sig- from independent ethics committees at each local trial site, nificant reductions in the mean CUA lesion count were ob- and the study was performed in line with the principles of the served from month 1 onward compared with the baseline Declaration of Helsinki. All participants provided written in- period: −1.193 between month 1 and month 6; −1.500 be- formed consent before participation in the study. tween month 2 and month 6, and −1.692 between month 3 and month 6; all p < 0.0001 (Figure 3). Results from the Data Availability primary analysis were confirmed by nonparametric methods, Any requests for data by qualified scientific and medical re- as well as methods assuming negative binomial distribution, searchers for legitimate research purposes will be subject to the and are thus considered robust to potential deviations from Data Sharing Policy of the healthcare business of Merck KGaA, the normal distribution. 4 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 Neurology.org/NN Table 1 Patient Demographics and Characteristics Table 1 Patient Demographics and Characteristics (continued) Total patients, Total n = 270 patients, n = 270 Female, n (%) 180 (66.7) Median (range) 0.0 (0–50) Age in y, mean (±SD) 37.7 ± 9.75 T1 Gd+ lesion count at baseline visit, n (%) 258 (95.6) Time since onset of MS in mo, mean (±SD) 84.9 ± 85.46 Patients with ≥1 lesion, n (%) 107 (39.6) Time since first relapse in mo, mean (±SD) 54.4 ± 72.57 Mean (±SD) 1.6 ± 4.06 No. of relapses within 12 mo before baseline, n (%) Median (range) 0 (0–41) 0 3 (1.1) 1 103 (38.1) Abbreviations: CUA = combined unique active; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium en- 2 133 (49.3) hancing; MS = multiple sclerosis. Missing data were due to MRIs not performed at site, not evaluable, or excluded because of steroid treatment. >2 31 (11.5) a Parameters are standardized to one scan (for T1 Gd+) or 1 month (for CUA and active T2). EDSS score, n (%) b Denotes the mean number across all scans during a period. ≤3 204 (75.6) >3 66 (24.4) Likewise, standardized T1 Gd+ and total active T2 lesion counts Median (range) 2.0 (0–5) were reduced during all 3 periods. Results also showed that T1 No. of previous DMTs, n (%) Gd+ and total active T2 lesion counts were reduced between month 2 and month 6 after treatment initiation (Figure 4, 0 117 (43.3) A and B). The proportion of patients without any CUA lesions 1 88 (32.6) increased from 52.0% during period 1 to 80.5% during period 3 2 50 (18.5) (eFigure 2a, links.lww.com/NXI/A723), and the proportion of patients without any T1 Gd+ lesions increased to 91.4% by >2 15 (5.6) month 6 (eFigure 2b, links.lww.com/NXI/A723). a Standardized CUA lesion count during the baseline 256 (94.8) period, n (%) Subgroup analyses of patients with and without high relapse Patients with ≥1 lesion, n (%) 141 (52.2) activity, with and without prior DMT use, and a subset with Mean (±SD) 1.9 ± 4.90 CUA lesion count >0 during the baseline period, found sig- Median (range) 0.5 (0–51.4) nificant reductions in CUA lesion counts in all subgroups/ subsets and for all periods (eTable 1, links.lww.com/NXI/ Standardizedb T1 Gd+ lesion count during the baseline 258 (95.6) period, n (%) A723). Prior DMTs are listed in eTable 2, links.lww.com/ Patients with ≥1 lesion, n (%) 141 (52.2) NXI/A723. Mean (±SD) 1.6 ± 4.27 After initiating treatment, a total of 13 patients experienced at Median (range) 0.5 (0–45.5) least one qualifying relapse during the 6-month study period; Standardized total active T2 lesion count during the 256 (94.8) all were treated with steroids, and 2 patients were hospitalized. baseline period, n (%) For all reported relapses (qualifying and nonqualifying), 21 Patients with ≥1 lesion, n (%) 107 (39.6) patients experienced at least one relapse; 18 patients were Mean (±SD) 1.5 ± 3.71 treated with steroids, and 3 patients were hospitalized. Median (range) 0 (0–39.3) In all, 70.7% (191/270) of patients experienced a TEAE Standardizeda total active T2 lesion count (without T1 256 (94.8) Gd+) during the baseline period, n (%) (eTable 3, links.lww.com/NXI/A723), with 47.4% (128/ Patients with ≥1 lesion, n (%) 48 (17.8) 270) of patients having encountered mild events. Treatment- related TEAEs were experienced by 33.0% (89/270) of pa- Mean (±SD) 0.3 ± 0.95 tients, with 23.3% (63/270) of patients having encountered Median (range) 0 (0–5.9) mild events. No new safety findings were observed. T1 Gd+ lesion count at screening visit, n (%) 254 (94.1) Classification of Evidence Patients with ≥1 lesion, n (%) 108 (40.0) Using frequent MRI assessments of the brain over the first 6 Mean (±SD) 1.6 ± 4.80 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 5 Figure 3 Change in MRI Lesion Counts From the Baseline/Baseline Period *Postbaseline periods are compared with the baseline period, and postbaseline visits are compared with the baseline visit. Period 1 (month 1 visit–month 6 visit); period 2 (month 2 visit–month 6 visit); period 3 (month 3 visit–month 6 visit). Models by period: mixed-effects linear model fitted for each period separately. Models by visit: mixed linear model for repeated measures taking within-subject correlation into account. †Parameters are standardized to 1 month. ‡Data are for means within a period. CI = confidence interval; CUA = combined unique active; Gd+ = gadolinium enhancing. 3.5 mg/kg in adult patients with highly active relapsing MS. treatment initiation with a more pronounced effect apparent This study provides Class IV evidence that, in such patients, during subsequent months. Using active T2 lesions, the onset treatment with cladribine tablets is associated with an early of disease-modifying activity was detectable from month 2 (day onset of action with reductions in active MRI lesion counts 60) after treatment initiation. It is well established that T1 Gd+ from month 2 (day 60) onward, with an increasing reduction lesions are the most sensitive conventional MRI index of dis- in such lesions over time. ease activity, and therefore, it is not surprising that the readouts on T2-weighted scans were also significant from month 2 after treatment initiation.17 Discussion The data presented here suggest an early treatment effect of Our results corroborate and supersede a recently published cladribine tablets on MRI-detectable disease activity that can post hoc analysis of the ORACLE-MS study of cladribine be observed from 1 month after treatment initiation. Reduc- tablets in patients with a first episode of demyelination tions in CUA lesion counts increased over time, irrespective of (clinically isolated syndrome).18 In that study, significant ef- patients’ baseline relapse activity or prior DMT use. fects on MRI lesion counts were detected at week 13 and, thus, significantly earlier than in CLARITY, where the first MRI is an essential tool in the diagnosis and monitoring of MS, follow-up scans were scheduled at 6 months.12 However, which led to its incorporation into the McDonald criteria in detection of yet earlier effects was precluded by the study 2001 and its subsequent revisions.14 It is well established that design of ORACLE-MS where follow-up MRI was scheduled MRI is a more sensitive technique to measure disease activity no earlier than week 13. compared with other disease-related indices, such as relapse rates.15 T1 Gd+ and active T2 lesions are the most commonly The onset of action of cladribine tablets reported here maps used MRI parameters to assess disease activity.15,16 onto key elements of the adaptive immune cell response in the peripheral blood, where CD19+ B cells are reduced by ap- The previously reported MRI results from the CLARITY study proximately 90% within 4–8 weeks after initiation of treat- underpinned the clinical benefits of treatment with cladribine ment.19 Although the recovery of the overall CD19+ B-cell pool tablets in patients with relapsing MS and showed a significant is driven by naive and activated phenotypes, levels of memory reduction in the presence of lesions during the 96-week B cells can remain reduced for at least 12 months.20,21 In trial.10,11 The MRI findings from our preplanned analysis of the contrast to the rapid reduction of B cells, cladribine tablets MAGNIFY-MS study therefore provide key information about have a slower and more moderate effect on the reduction of the onset of the disease-modifying activity of cladribine tablets. CD4+ and CD8+ T cells, whereby nadir is reached at 3–6 Based on CUA or T1 Gd+ lesions, a significant reduction in months after treatment initiation.21 These findings underpin, lesion activity was observed from month 1 (day 30) after at least in part, the long-term effect of cladribine tablets on 6 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 Neurology.org/NN Figure 4 (A) T1 Gd+ Lesion Count and (B) Active T2 Lesion Count* by Visit Values indicate the mean +SD for each visit. *Active T2 lesion count (by visit), i.e., the new or enlarging T2 lesions compared with the previous visit. Be- cause of the way in which the data were derived for the active T2 lesions, it was not possible to provide month 1 data. Gd+, gadolinium enhancing. disease control in patients with highly active relapsing MS. An generally the case in the aforementioned studies. As a re- ongoing analysis of immune cell subset dynamics in the sult, regression to mean may contribute to the reduction in MAGNIFY-MS population will further explore the potential active MRI lesions after initiation of treatment. It should mechanistic basis of the early onset of action of cladribine also be noted that direct comparisons of MRI efficacy tablets.21 outcomes across studies should be made with caution be- cause of differing assessment schedules and baseline patient Previous studies determining the effect on T1 Gd+ and active characteristics. T2 lesions for current DMTs (including cladribine tablets, fingolimod, and natalizumab) have been comparable, showing In conclusion, this 6-month primary analysis of the MAGNIFY- reductions in T1 Gd+ lesion counts of between 85% and 92% MS study indicates that treatment with cladribine tablets 3.5 over 2-year study periods.10,11,22-25 Results for T2 lesion re- mg/kg is associated with an early onset of action detected on duction in these articles are more varied, with reductions of MRI. Significant reductions were observed in CUA lesion 51% observed with fingolimod22 compared with 83% with counts from month 1 (day 30) after initiation of treatment and natalizumab23,24 and 61%–73% with cladribine tablets.10,11 irrespective of patients’ baseline relapse activity or prior DMT However, in most of the abovementioned studies, the first use. No new safety findings were observed. An additional MRI scans were conducted at 6 months or later after the start follow-up analysis for the MAGNIFY-MS study is planned at 2 of treatment, with the exception of natalizumab25 and further years, when all patients will have completed the study. studies investigating fingolimod26 and ocrelizumab27 where MRI was conducted before 6 months. This current lack of Acknowledgment literature underlines the importance of the MAGNIFY-MS The authors thank patients and their families, investigators, study in which MRI findings from the first 6 months after coinvestigators, and the study teams at each of the participating treatment were evaluated. The main limitation of MAGNIFY- centers and at the healthcare business of Merck KGaA, MS is that this is a single-arm study without a control Darmstadt, Germany. Medical writing assistance, in terms of a group. Therefore, results for each period were compared contribution to drafting the manuscript and peer review with the baseline period rather than a placebo group, as was responses through the collation of information and relevant Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 7 documentation under the full guidance of the listed authors and Germany), Novartis, Roche, and Sanofi. She has received harmonizing author comments via an online collaboration tool, money for travel and speaker honoraria from Bayer, Biogen, was provided by Claire Mwape of inScience Communications, the healthcare business of Merck KGaA (Darmstadt, Ger- Springer Healthcare Ltd, UK, and supported by the healthcare many), Novartis, Roche, and Sanofi. AP has received hono- business of Merck KGaA, Darmstadt, Germany. raria and operating grants from pharmaceutical companies. LL has received honoraria for consulting services or speaking Study Funding activities from Biogen, the healthcare business of Merck This study was supported by the healthcare business of Merck KGaA (Darmstadt, Germany), Novartis, and Roche and re- KGaA, Darmstadt, Germany (CrossRef Funder ID: search support from Biogen, the healthcare business of Merck 10.13039/100009945). KGaA (Darmstadt, Germany), and Novartis. KS has received research support from Biogen, the healthcare business of Disclosure Merck KGaA (Darmstadt, Germany), and Novartis; speaking NDS is a consultant for Bayer, Biogen, the healthcare business honoraria from, and/or served in an advisory role for, Amgen- of Merck KGaA (Darmstadt, Germany), Novartis, Roche, Gensenta, Biogen, EMD Serono, the healthcare business of Sanofi, and Teva; has grants or grants pending from FISM and Merck KGaA (Darmstadt, Germany), Novartis, Roche, Novartis; is on the speakers’ bureaus of Biogen, the healthcare Sanofi, and Teva; and remuneration for teaching activities business of Merck KGaA (Darmstadt, Germany), Novartis, from AcadeMe, Medscape, and the Neurology Academy. FS Roche, Sanofi, and Teva; and has received travel funds from has served on scientific advisory boards, been on the steering the healthcare business of Merck KGaA (Darmstadt, Ger- committees of clinical trials, served as a consultant, received many), Novartis, Roche, Sanofi, and Teva. FB is supported by support for congress participation, received speaker hono- the NIHR Biomedical Research Centre at UCLH and is a raria, or received research support for his laboratory from consultant to Biogen, Combinostics, IXICO, the healthcare Biogen, Celgene (BMS), EMD Serono, the healthcare busi- business of Merck KGaA (Darmstadt, Germany), and Roche. ness of Merck KGaA (Darmstadt, Germany), Novartis, XM has received speaking honoraria and travel expenses for Roche, Sanofi, and Teva. PV has received honoraria or con- participation in scientific meetings and has been a steering sulting fees from AB Science, Biogen, Celgene (BMS), committee member of clinical trials or participated in advisory Imcyse, the healthcare business of Merck KGaA (Darmstadt, boards of clinical trials in the past years with AbbVie, Actelion Germany), Novartis, Roche, Sanofi, and Teva and research (Janssen/J&J), Alexion, Bayer, Biogen, Celgene (BMS), support from Novartis, Roche, and Sanofi. HW is member of EMD Serono, Immunic, Janssen Pharmaceuticals, MedDay, scientific advisory boards/steering committees for Bayer, the healthcare business of Merck KGaA (Darmstadt, Ger- Biogen, the healthcare business of Merck KGaA (Darmstadt, many), Mylan, NervGen, Novartis, Roche, Sanofi, and Teva. Germany), Novartis, Roche, Sanofi, and Teva. He received AA has received honoraria or consulting fees from Bayer, speaker honoraria and travel support from Bayer, Biogen, Biogen, Celgene (BMS), the healthcare business of Merck CSL Behring, EMD Serono, Fresenius Medical Care, the KGaA (Darmstadt, Germany), Novartis, Roche, and Sanofi healthcare business of Merck KGaA (Darmstadt, Germany), and research support from Bayer, Biogen, the healthcare OmniaMed, Novartis, Sanofi, and Teva. He received com- business of Merck KGaA (Darmstadt, Germany), Roche, and pensation as a consultant from Biogen, the healthcare busi- Sanofi. TD serves on scientific advisory boards for Bayer, ness of Merck KGaA (Darmstadt, Germany), Novartis, Actelion (Janssen/J&J), Biogen, Celgene (BMS), GeNeuro, OmniaMed, Roche, and Sanofi. He has received research MedDay, the healthcare business of Merck KGaA (Darm- support from Bayer, Biogen, the healthcare business of Merck stadt, Germany), Mitsubishi Pharma, Novartis Pharmaceuti- KGaA (Darmstadt, Germany), Novartis, Sanofi, and Teva, as cals, Roche, and Sanofi; has received funding for travel and/or well as German Ministry for Education and Research (BMBF), speaker honoraria from Bayer, Biogen, the healthcare business German Research Foundation (DFG), Else Kröner Fresenius of Merck KGaA (Darmstadt, Germany), Novartis, Roche, Foundation, Fresenius Foundation, Hertie Foundation, the and Sanofi; and receives research support from Biogen, the healthcare business of Merck KGaA (Darmstadt, Germany), European Union, Novartis Pharma, Roche, the Swiss Novartis, NRW Ministry of Education and Research, In- MS Society, and the Swiss National Foundation. AC has re- terdisciplinary Center for Clinical Studies (IZKF) Münster, ceived speakers’/board honoraria from Actelion (Janssen/ and RE Children’s Foundation. BK is an employee of the J&J), Almirall, Bayer, Biogen, Celgene (BMS), the healthcare healthcare business of Merck KGaA, Darmstadt, Germany. SR business of Merck KGaA (Darmstadt, Germany), Novartis, is an employee of Ares Trading S.A., Eysins, Switzerland (an Roche, Sanofi, and Teva, all for hospital research funds. He affiliate of Merck KGaA, Darmstadt, Germany). Go to Neu- received research support from Biogen, Sanofi, and UCB, the rology.org/NN for full disclosures. European Union, and the Swiss National Foundation. He serves as associate editor of the European Journal of Neurology, Publication History on the editorial board for Clinical and Translational Neuro- Received by Neurology: Neuroimmunology & Neuroinflammation science, and as topic editor for the Journal of International December 1, 2021. Accepted in final form April 19, 2022. Submitted Medical Research. SH serves on advisory boards for Bayer, and externally peer reviewed. The handling editor was Scott S. Zamvil, Biogen, the healthcare business of Merck KGaA (Darmstadt, MD, PhD, FAAN. 8 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 Neurology.org/NN Appendix Authors Appendix (continued) Name Location Contribution Name Location Contribution Nicola de Department of Medicine, Study concept or design and Heinz Department of Neurology, Study concept or design and Stefano, MD, Surgery and Neuroscience, analysis or interpretation of Wiendl, MD, Institute of Translational analysis or interpretation of PhD University of Siena, Siena, data PhD Neurology, University of data Italy Münster, Münster, Germany Frederik Department of Radiology, Study concept or design and Birgit Keller, The healthcare business of Study concept or design and Barkhof, MD VU University Medical analysis or interpretation of Dipl-Stat Merck KGaA, Darmstadt, analysis or interpretation of Center, Amsterdam, The data Germany data Netherlands; UCL Institute of Neurology, London, UK Sanjeev Roy, Ares Trading S.A., Eysins, Major role in the acquisition MBBS, MD Switzerland (an affiliate of of data; study concept or Xavier Department of Neurology- Study concept or design and Merck KGaA, Darmstadt, design; and analysis or Montalban, Neuroimmunology, Centre analysis or interpretation of Germany) interpretation of data MD, PhD d’Esclerosi Múltiple de data Catalunya (Cemcat), Hospital Universitario Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain References 1. 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N Engl J Med. 2006;355(11):1124-1140. 24. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of 27. Barkhof F, Kappos L, Wolinsky JS, et al. Onset of clinical and MRI efficacy of natalizumab in relapsing MS. Neurology. 2007;68(17):1390-1401. ocrelizumab in relapsing multiple sclerosis. Neurology. 2019;93(19):e1778–e1786. 10 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 4 | July 2022 Neurology.org/NN