Safety,efficacy,and tolerability of alemtuzumab in pediatric patients with active relapsing-remitting multiple sclerosis: The LemKids study

Abstract

Background:

Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients.

Objective:

To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs).

Methods:

LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10–<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment.

Results:

This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset.

Conclusion:

Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months.

Keywords

Multiple sclerosis alemtuzumab monoclonal antibody disease-modifying therapies pediatric brain MRI

Introduction

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, degenerative disease of the central nervous system, affecting over 2.8 million people worldwide.^1,2 Pediatric-onset MS refers to MS diagnosis before age 18.³ This disease is rare in the pediatric population with an incidence of 0.26 to 2.1 cases per 100,000 children.^4,5 Pediatric patients with MS tend to experience more frequent relapses than adults,⁶ which can have a significant long-term impact on physical and cognitive development.⁷ Around 97%-99% of the affected pediatric patients are known to have relapsing-remitting multiple sclerosis (RRMS) as compared with 85%–95% in adults.⁸ Early prevention of relapses in the initial years of clinical onset can significantly reduce worsening of disability.⁹

Historically, clinical evidence based on randomized controlled trials has been lacking for the treatment of pediatric MS and physicians have largely relied on adapting treatment options used in adults with MS.^7,10 Immunomodulatory agents, including interferon beta (IFN-β) and glatiramer acetate (GA), have shown to be well tolerated in the pediatric population with MS.¹¹ However, more than two-thirds of the pediatric patients may not respond to IFN-β and GA, resulting in a switch to an alternative disease-modifying therapy (DMT).^12–14 Three DMTs, fingolimod, teriflunomide, and dimethyl fumarate, have been evaluated in phase 3 controlled trials^15–17 based on which fingolimod is approved in the European Union and the United States, while teriflunomide and dimethyl fumarate are approved in the EU. The PARADIGMS study (NCT01892722, N = 220) conducted in pediatric patients with MS showed that fingolimod was associated with a lower rate of relapses and less accumulation of magnetic resonance imaging (MRI) lesions than IFN-β-1a, but had a higher rate of safety concerns including rare seizures in the fingolimod arm.¹⁸ Another phase 3 clinical trial, TERIKIDS (NCT02201108, N = 166), showed a significant reduction in the number of new or enlarged T2 lesions with teriflunomide versus placebo; however, no significant difference was noted in time to the first confirmed clinical relapse. An increase in pancreatic events was noted in the teriflunomide arm compared with placebo.¹⁹ The CONNECT study (NCT02283853, N = 156) showed reduction in the frequency of relapses and number of new or newly enlarging T2 lesions with dimethyl fumarate versus IFN-β-1a in pediatric patients with MS, though the study was not powered to detect a difference between treatment groups and no adjustments were made for multiplicity.¹⁷

Alemtuzumab (Lemtrada^®; Sanofi) is a humanized monoclonal antibody targeting CD52. It is approved for the treatment of relapsing MS in adults. It is a high-efficacy DMT that requires only limited dosing (two annual courses; additional doses administered only upon continued disease activity).²⁰ Its clinical efficacy in adult patients with MS has been well demonstrated in phase 3 clinical studies—CARE-MS 1 (NCT00530348) and CARE-MS 2 (NCT00548405).^21,22 Based on a meta-analysis, alemtuzumab appears to be among the most effective DMTs for lowering the relapse rates in MS.²³ However, in the United States, its use is generally recommended for patients who have demonstrated an inadequate response to at least two prior-DMTs.²⁴ There are a few safety and tolerability concerns associated with alemtuzumab in MS patients, including infusion-associated reactions, mild-to-moderate infections, and autoimmune adverse events (AEs), like thyroid disorders and immune thrombocytopenia.²⁵ However, alemtuzumab’s safety profile remained consistent with that reported in previous clinical trials, maintaining safety for >13 years in the TOPAZ extension study (NCT02255656, N = 1062) in patients with highly active disease from CARE-MS studies.²⁶ Research has not been conducted so far to establish its efficacy in pediatric patients with MS.

Based on the recommendations by the European Medicines Agency (EMA) and its Pediatric Committee, a superiority study was suggested for the pediatric investigation plan of alemtuzumab. This unique cross-over study (LemKids; NCT03368664) was designed to allow a superiority analysis to be conducted in a small patient population. The objective of this study was to evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with RRMS with disease activity on prior-DMT.

Methods

Study design

LemKids was a multinational, multicenter, phase 3, single-arm, open-label, before-and-after switch study of alemtuzumab in pediatric patients with RRMS. The study consisted of a screening period of 28 days, followed by a prior-DMT phase of 4 months and a treatment phase of approximately 2 years. Safety was monitored for 3 years, while two periods (Period 1: Month (M)-4 to M0 and Period 2: M4 to M8) were defined for efficacy assessments (Figure 1).

The trial was conducted in accordance with the institutional review board or independent ethics committee at each site (Supplemental Table 1), including Good Clinical Practice guidelines, the Declaration of Helsinki, and all applicable laws, rules, and regulations. Each enrolled patient or their legal guardians provided written informed consent before study initiation. The scientific advisory committee and data monitoring committee closely monitored data collection during the study.

Study population

Patients with RRMS from 15 countries, aged 10 to <18 years, as defined by the International Pediatric Multiple Sclerosis Study Group criteria for pediatric MS²⁷ and the criteria of MS based on the McDonald criteria 2010 were included.²⁸ Patients had to have ⩾2 recorded MS relapses and ⩾1 relapse in the past year during treatment with IFN-β or GA after having been on that treatment for ⩾6 months and taking the same at the time of enrollment. Patients had to meet any one of the following three criteria: ⩾1 new or enlarging T2-hyperintense lesion or gadolinium-enhancing lesion while continuing the prior ongoing therapy with IFN-β or GA; or ⩾2 relapses in the past year; or tried ⩾2 DMTs for MS. Patients with Expanded Disability Status Scale (EDSS) score between 0.0 and 5.0 (inclusive) at screening were included.

Patients were excluded from the trial if they had any prior exposure to alemtuzumab; any progressive or non-relapsing forms of MS; or received any treatment with natalizumab, daclizumab, fingolimod, methotrexate, azathioprine, cyclosporine, or mycophenolate mofetil in the previous 6 months or as determined by the treating physician to have residual immune suppression from these or other MS treatment. Patients treated with teriflunomide in the past 12 months except for those who underwent the accelerated elimination procedure as per the local teriflunomide label were excluded. Patients who were previously treated with any cytotoxic therapy or had CD4⁺, CD8⁺, or CD19⁺ absolute cell count in blood at screening below the lower limit of normal (LLN) or had any prior documented history of thrombocytopenia, or platelet count at screening below LLN were not eligible for this study (see Supplemental Table 2 for complete list of exclusion criteria).

Study treatment

Enrolled patients received an intravenous infusion of alemtuzumab for two treatment courses, with a 12-month interval. The first course was administered at M0 for five consecutive days and the second course at M12 for three consecutive days. A dose of 12 mg/day was administered to patients with a bodyweight of ⩾50 kg and that of 0.24 mg/kg/day to patients weighing <50 kg.

Study endpoints and assessments

The primary endpoint was the number of new or enlarging T2 lesions during the prior-DMT period (Period 1: M-4 to M0), compared with a similar period after the first course of alemtuzumab treatment (Period 2: M4 to M8), and was assessed using brain MRI. The secondary endpoints included efficacy, the number of patients with new or enlarging T2 lesions (brain MRI), patient disability (change from baseline in EDSS score), cognition test scores (Brief Visuospatial Memory Test (BVMT) and Symbol Digit Modality Test (SDMT) score), annualized relapse rate (ARR) at Year 2, quality of life (QoL) measured by the Pediatric Quality of Life Inventory (PedsQL™) and pediatric version of the Quality of Life in Neurological Disorders (pediatric Neuro-QoL) questionnaires, pharmacokinetics (PK) parameters (C_max, T_max, AUC, AUC_last, and T_1/2z) assessed using serum concentrations, and pharmacodynamics (PD) by lymphocyte phenotyping. Safety endpoints included AEs, serious AEs (SAEs), treatment-emergent AEs (TEAEs), physical examination, vital signs, and clinical chemistry laboratory tests and were monitored throughout the study.

Statistical analysis

Considering potential screen failures, this trial planned to screen at least 60 pediatric patients, assuming that at least 50 patients would be eligible for evaluation. Considering a potential dropout of 10%, this sample size was anticipated to provide an 85% power to detect a 50% reduction in the number of new or enlarging T2 lesions in Period 2 versus Period 1.

Efficacy endpoints were assessed in the modified intention-to-treat population (i.e. patients who received at least one dose of alemtuzumab and had evaluable data for both Period 1 and Period 2). The safety population consisted of patients who had received at least one dose of alemtuzumab. The PD population comprised of patients who had received at least one dose of alemtuzumab and had evaluable PD data.

The primary statistical objective, superiority of alemtuzumab versus prior-DMT at 5% level of significance, was analyzed using a repeated-measures negative binomial regression model with generalized estimating equations. ARR was estimated using a negative binomial model with robust variance estimation. The secondary endpoint analyses for proportion of patients with new or enlarging T2 lesions during Period 1 and Period 2 were similar to the primary endpoint analyses, except for use of logit link function and the Bernoulli distribution. The change from baseline in cognitive outcomes, PD parameters, EDSS scores, and antibody results were analyzed descriptively. For categorical variables, frequencies and percentages were presented.

Results

This study was terminated prematurely due to inadequate enrollment rates and feasibility concerns (elaborated further in the “Discussion” section). Results, including AEs, are presented based on the limited data collected.

Study disposition and patient baseline characteristics

From October 2017 to April 2019, 46 patients were screened, of whom 16 patients were enrolled in the study. A total of 12 patients completed Period 1 (prior-DMT treatment); however, 1 patient decided not to proceed with Period 2. Of the 11 patients who started Period 2, 7 patients completed the treatment (Figure 2). The follow-up data for 11 patients are provided in the Supplementary Material.

The mean (standard deviation (SD)) age of the enrolled patients was 14.5 (2.2) years, and the majority of patients (12/16, 75%) were 13-18 years of age (Table 1). Three-quarters of the enrolled patients were male (n = 12). The mean (SD) time since the diagnosis of MS was 2.8 (2.07) years.

Table 1.

Patient demographics and baseline characteristics.

	All patients (N = 16)
Age (years), mean (SD)	14.5 (2.2)
Age group (years), n (%)
10-<13	4 (25)
13-<18	12 (75)
Sex, n (%)
Male	12 (75)
Female	4 (25)
Race, n (%)
White	12 (75)
Not reported	4 (25)
Ethnicity, n (%)
Not Hispanic or Latino	12 (75)
Not reported	4 (25)
Weight (kg), mean (SD), n = 11	60.9 (13.6)
BMI group (kg/m²), mean (SD), n = 11	21.5 (4.2)
EDSS score, mean (SD)	1.8 (1.1)
Received prior MS DMTs at baseline, n (%)
Interferons	12 (75)
Interferon Beta-1a	10 (62.5)
Interferon Beta-1b	4 (25.0)
Glatiramer acetate	6 (37.5)
T2-hyperintense lesion volumes (mL), mean (SD)	12.3 (6.3)
T1-hypointense lesion volumes (mL), mean (SD)	2.2 (2.1)
Time (years) since the first MS diagnosis, mean (SD)	2.8 (2.1)
Total number of relapses since the first MS diagnosis, mean (SD)	3.5 (1.2)
Number of relapses within past year, mean (SD)	2.1 (1.3)

BMI: body mass index; DMT: disease-modifying therapy; EDSS: Expanded Disability Status Scale; N: total number of patients; n: number of patients analyzed; MS: multiple sclerosis; SD: standard deviation.

Efficacy

Number of new or enlarging T2 lesions and number of patients with new or enlarging T2 lesions

Alemtuzumab treatment was associated with a lower number of new or enlarging T2 lesions compared with prior-DMT phase (Period 2: 7 vs Period 1: 178). The relative risk for the adjusted number of these lesions per month was 0.04 with a 95% confidence interval (CI) of 0.01-0.14. During Period 2, only 3/11 (27.3%) patients developed new or enlarging T2 lesions versus 10/11 (90.0%) patients during Period 1 (Table 2). Overall, alemtuzumab treatment was associated with lower odds of developing these lesions compared with prior-DMT treatments, with an odds ratio of 0.02 and a 95% CI of 0.00-0.15 (Table 2).

Table 2.

The number of new or enlarging T2 lesions and number of patients with new or enlarging T2 lesions during each period.

	Period 1 (prior-DMT)(N = 11)	Period 2 (alemtuzumab 8 months treatment)(N = 11)
Baseline T2 lesion count, mean (SD)	54.6 (35.6)	72.4 (51.9)
New or enlarging T2 lesions at the end of each period^a
Mean (SD)	3.9 (5.2)	0.2 (0.3)
Total number of new or enlarging T2 lesions	178	7
Follow-up duration, months	58.3	44.5
Unadjusted new or enlarging T2 lesion count per month^b	3.0	0.2
Adjusted number of new or enlarging T2 lesions per month^c
Estimate (95% CI)	3.53 (1.78–7.03)	0.13 (0.03–0.48)
Relative risk (95% CI)	–	0.04 (0.01–0.14)
Number of patients with at least one new or enlarging T2 lesion within each period, N (%)	10 (90.9)	3 (27.3)
Adjusted number of new or enlarging T2 lesion per month^d
Estimate (95% CI)	3.52 (0.55–22.42)	0.05 (0.01–0.38)
Odds ratio (95% CI)	–	0.02 (0.00–0.15)

CI: confidence interval; DMT: disease-modifying therapy; MRI: magnetic resonance imaging; N: number of patients; SD: standard deviation.

Baseline was defined as MRI T2 lesion count collected at the beginning of Period 1 (prior-DMT phase at M-4 visit) and Period 2 (alemtuzumab treatment period at M4 visit); The end of Period 1 was defined at M0 visit while the end of Period 2 was defined at M8 visit.

The number of new and enlarged T2 lesions for each patient divided by the number of follow-up months for that patient.

The total number of new and enlarged T2 lesions that occurred during the study divided by the total number of follow-up months until the end of each period.

Negative binomial regression model with robust variance estimation, with total number of new and enlarged T2 lesions during each period as a response variable, with period indicator, baseline T2 lesion count as covariates and log-transformed number of follow-up months as an offset variable.

Logistic regression model with robust variance estimation, with binary indicator during each period as a response variable (1 for patients with at least one new or enlarging T2 lesion, 0 otherwise), with period indicator and baseline T2 lesion count as covariates and log-transformed number of follow-up months as an offset variable.

Changes in EDSS and ARR

The mean baseline EDSS score was 1.68 (n = 11). After treatment at M4 and M8, the EDSS scores were 1.73 (mean change from baseline was 0.05) and 1.68 (mean change from baseline was 0), respectively (Table 3). The total number of relapses were 4, with an adjusted ARR of 0.18 (95% CI: 0.07-0.46). Overall, four patients (36.4%) experienced at least one relapse (Table 4). However, due to the small dataset, a statistical comparison was not feasible.

Table 3.

EDSS score.

Time point	Mean (SD)	Change from baseline, mean (SD)
Baseline (n = 11)	1.68 (1.33)	-
M4 (n = 11)	1.73 (1.25)	0.05 (0.52)
M8 (n = 11)	1.68 (1.33)	0.00 (0.55)
M24 (n = 6)	1.00 (0.84)	-0.17 (0.61)
M30 (n = 3)	1.50 (0.50)	0.17 (0.58)

EDSS: Expanded Disability Status Scale; M: month; N: number of patients; SD: standard deviation.

Baseline was defined as the last non-missing assessment on or before the first course of alemtuzumab.

Table 4.

Annualized relapse rate.

		N = 11
Number of patients with at least one relapse, n (%)		4 (36.4)
Number of patients who were relapse-free, n (%)		7 (63.6)
Time point	Total number of relapses	Adjusted ARR(95% CI)^a
Overall	4	0.18 (0.07-0.46)
Year 0-1	2	0.19 (0.05-0.68)
Year 1-2	2	0.58 (0.13-2.62)
Year 2-3	0	NC (NC-NC)

ARR: annualized relapse rate; CI: confidence interval; N: total number of patients; n: number of patients; NC: not able to calculate.

Negative binomial regression model with robust variance estimation, with total number of relapses as a response variable, with log-transformed number of follow-up years as an offset variable.

Cognition test scores

No differences were noted in BVMT and SDMT scores between the two treatment periods (Table 5).

Table 5.

Cognition test scores.

	Period 1 (prior-DMT)(N = 11)	Period 2 (alemtuzumab 8 months treatment)(N = 11)
BVMT scores
Baseline (n) Mean (SD)	11 24.3 (8.8)	10 26.4 (6.2)
At the end of the period (n) Mean (SD)	10 23.4 (9.8)	8 23.6 (6.7)
Change from baseline (n) Mean (SD)	10 −2.1 (8.9)	8 −3.3 (4.1)
SDMT scores
Baseline (n) Mean (SD)	11 46.5 (9.1)	11 50.7 (10.8)
At the end of the period (n) Mean (SD)	11 51.6 (12.0)	11 53.5 (8.9)
Change from baseline (n) Mean (SD)	11 5.2 (7.9)	11 2.8 (7.7)

BVMT: Brief Visuospatial Memory Test; DMT: disease-modifying therapy; N: total number of patients; n: number of patients; SD: standard deviation; SDMT: Symbol Digit Modality Test.

Pharmacodynamic parameters

The PD data showing T- and B-lymphocyte profiles reflect similar effects, as shown in the adult patients treated with alemtuzumab, with noticeable depletion after each course of drug administration (Figure 3).

Safety

All patients treated with alemtuzumab experienced at least one AE; 10 patients (90.9%) had treatment-related AEs (Table 6). Most AEs (n = 10, 90.9%) were mild in nature. The most frequent AEs were infections and infestations (n = 9, 81.8%), including nasopharyngitis (n = 6, 54.5%), rhinitis (n = 3, 27.3%), upper respiratory tract infection (n = 3, 27.3%), and urinary tract infection (n = 2, 18.2%). There was one case of mild hypothyroidism and another case of hyperglycemia after the first dose of alemtuzumab, and both resolved (Table 7). There were no AEs leading to treatment discontinuation and no deaths were reported in the study. Three patients experienced five SAEs (two events of generalized urticaria, which were considered related, and three events of increased creatine phosphokinase, MS relapse, and urolithiasis, which were considered unrelated). Three SAEs (MS relapse, urticaria, and calculus urinary) were moderate in nature and all of them were resolved. Seven patients reported 10 TEAEs of special interest; 1 event of herpes zoster, 1 event of hypothyroidism, 7 events of urticaria, and 1 event of allergic dermatitis. All events were resolved. Further details can be found in the Supplementary Material.

Table 6.

Pre-treatment and treatment-emergent adverse events.

	n (%)	Number of events
Pre-treatment adverse event
Patients with AEs
Patients with events	10 (62.5)	31
Related	0	0
Unrelated	10 (62.5)	31
Severity
Mild	9 (56.3)	25
Moderate	4 (25.0)	5
Severe	0	0
AEs leading to treatment discontinuation	0	0
AEs leading to death	0	0
Patients with SAEs
Patients with events	3 (18.8)	5
Related	0	0
Unrelated	3 (18.8)	5
Severity
Mild	2 (12.5)	2
Moderate	2 (12.5)	2
Severe	0	0
SAEs leading to treatment discontinuation	0	0
SAEs leading to death	0	0
Treatment emergent Adverse event
Patients with AEs
Patients with events	11 (100)	187
Related	10 (90.9)	77
Unrelated	9 (81.8)	110
Severity
Mild	10 (90.9)	152
Moderate	9 (81.8)	27
Severe	1 (9.1)	2
AEs leading to treatment discontinuation	0	0
AEs leading to death	0	0
Patients with SAEs
Patients with events	3 (27.3)	5
Related	2 (18.2)	2
Unrelated	2 (18.2)	3
Severity
Mild	0	0
Moderate	3 (27.3)	3
Severe	1 (9.1)	2
SAEs leading to treatment discontinuation	0	0
SAEs leading to death	0	0

AEs: adverse events; n: number of patients with AEs; SAEs: serious adverse events.

Pretreatment AEs were defined as those AEs that developed or worsened prior to the first alemtuzumab dose. Treatment emergent AEs were defined as those AEs that developed or worsened after the first alemtuzumab dose and until the end of the study (Month 60).

Table 7.

Most frequent TEAEs as per primary system organ class preferred term^a occurring in at least one patient.

Primary system organ class preferred term	Patients with event, n (%)
Any AEs	11 (100)
Infections and infestations	9 (81.8)
Nasopharyngitis	6 (54.5)
Rhinitis	3 (27.3)
Upper respiratory tract infection	3 (27.3)
Urinary tract infection^b	2 (18.2)
Gastroenteritis	1 (9.1)
Genitourinary tract infection	1 (9.1)
Herpes zoster^c	1 (9.1)
Pharyngitis	1 (9.1)
Respiratory tract infection	1 (9.1)
Tinea versicolor	1 (9.1)
Immune system disorders	1 (9.1)
Mite allergy	1 (9.1)
Endocrine disorders	1 (9.1)
Hypothyroidism	1 (9.1)
Metabolism and nutrition disorders	1 (9.1)
Hyperglycemia	1 (9.1)

MedDRA: Medical Dictionary for Regulatory Activities; n: number of patients with adverse events; UTI: urinary tract infection.

MedDRA 24.0.

1 male, 1 female.

The episode of herpes zoster occurred in a patient with a known history of varicella, 2 years prior to alemtuzumab administration.

QoL and PK parameters were not analyzed.

Discussion

This phase 3, single-arm, open-label study was the first to evaluate the efficacy and safety of alemtuzumab in pediatric patients with RRMS who had disease activity on prior-DMT. There was a higher proportion of males in this study in contrast to previous MS studies,^19,21 likely due to the small sample size.

Although the study was terminated early due to low recruitment and an EMA Article-20 review of alemtuzumab in adult RRMS, the results are still insightful. Despite the small sample size, there was a reduction in the number of new or enlarging T2 lesions with alemtuzumab between pre- and post-treatment periods. New or enlarging T2 lesions were observed in three patients and four patients experienced relapses, suggesting patients had high disease activity.

The present findings are in line with two previous phase 3 randomized studies in adult patients with RRMS (CARE-MS 1 and CARE-MS 2), where alemtuzumab showed a reduction in the risk of new or enlarging T2 lesions (risk reduction over 2 years, 34% and 62%, respectively, both p < 0.05).²⁹

In CARE-MS 1 and CARE-MS 2, the administration of alemtuzumab led to a decrease in T- and B-lymphocytes in adult patients with MS. The reconstitution of B cells was observed within 6 months, while the recovery of T-cells occurred gradually, reaching the lower threshold of normalcy around 12 months after alemtuzumab treatment.

Our findings are consistent with the previous studies of alemtuzumab conducted in adult patients with MS.^21,22 There were no new safety signals reported in this study. One patient discontinued alemtuzumab due to intolerability; no deaths were reported, consistent with the safety profile reported in previous clinical trials in adults.^30,31

The regulatory decision made by the EMA in April 2019, which initiated an Article-20 referral procedure to examine the benefits and risks of alemtuzumab and restricted its use due to safety concerns (serious cardiovascular reactions, newly identified autoimmune hepatitis, and hemophagocytic lymphohistiocytosis),³² was one of the reasons for low recruitment. Recruitment for LemKids was voluntarily paused in May 2019 at the start of the EMA safety review. In January 2020, temporary restrictions were lifted for alemtuzumab in adult patients with updates in the summary of product characteristics;²⁰ however, recruitment for LemKids was permanently closed due to the ongoing challenges with low recruitment rates, compounded by the COVID-19 pandemic.

Considering the rarity of pediatric MS, there might have been a limited potential enrollment population. In addition, the stringent eligibility criteria for enrollment, to conduct a superiority analysis as recommended by the EMA, required the presence of disease activity despite treatment with IFN-β/GA for at least 6 months. During the course of the trial, new treatments including fingolimod³³ and teriflunomide³⁴ were approved for pediatric population, and competing trials with other investigational agents (ocrelizumab and dimethyl fumarate)^35,36 may have added to the difficulty in recruiting patients.

Conclusion

Despite the small patient population and early termination, the results of the LemKids study provide some insights into the efficacy and safety of alemtuzumab in pediatric patients with RRMS. Based on the available data, alemtuzumab treatment was associated with decreased MRI activity and lower ARR in pediatric patients. PD data, EDSS, and safety profiles were consistent with those in adults. Considering the limited dataset, further studies are required for a definitive conclusion.

Supplemental Material

sj-docx-1-msj-10.1177_13524585241295554 – Supplemental material for Safety, efficacy, and tolerability of alemtuzumab in pediatric patients with active relapsing-remitting multiple sclerosis: The LemKids study

Supplemental material, sj-docx-1-msj-10.1177_13524585241295554 for Safety, efficacy, and tolerability of alemtuzumab in pediatric patients with active relapsing-remitting multiple sclerosis: The LemKids study by Tanuja Chitnis, Douglas L Arnold, Pierre Quartier, Magdalena Chirieac, Wenruo Hu, Stephanie Jurgensen and Eva K Havrdova in Multiple Sclerosis Journal

Footnotes

Acknowledgements

The authors acknowledge Naji Salloum (Clinical Research Director, Sanofi) for his contribution in providing long-term follow-up data and review of the manuscript, and Miqun Robinson (Sanofi employee at the time this study was conducted) for her contributions to the planning, oversight, and execution of this study. Medical writing support for this manuscript was provided by Anubhav Mehra and Chiranjit Ghosh of Sanofi.

Author Contributions

Tanuja Chitnis: Contributed substantially to conception and design of the work related to this document; Contributed substantially to data acquisition for the work related to this document; Contributed substantially to data analysis or interpretation of data for the work related to this document.

Douglas L Arnold: Contributed substantially to conception and design of the work related to this document; Contributed substantially to data acquisition for the work related to this document; Contributed substantially to data analysis or interpretation of data for the work related to this document.

Pierre Quartier: Contributed substantially to data analysis or interpretation of data for the work related to this document.

Magdalena Chirieac: Contributed substantially to data analysis or interpretation of data for the work related to this document.

Wenruo Hu: Contributed substantially to data analysis or interpretation of data for the work related to this document.

Stephanie Jurgensen: Contributed substantially to data analysis or interpretation of data for the work related to this document.

Eva K Havrdova: Contributed substantially to data analysis or interpretation of data for the work related to this document.

All authors substantially contributed to the manuscript drafts and approved the final version.

Data Sharing Statement

Qualified researchers may request access to patientlevel data and related documents (including, for example, the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications). Patientlevel data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at .

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: T.C. received consulting fees from Genentech-Roche and Novartis; is member of advisory boards of Novartis, Roche-Genentech, and Sanofi; received research support from Novartis, Sanofi, Serono, and Verily; and received speaking fees from Medscape. D.L.A. received personal compensation for serving as a consultant for Alexion, Biogen, Celgene, Eli Lilly, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi; and holds an equity interest in NeuroRx. P.Q. received consultancy or speaking fees from AbbVie, Amgen, Bristol-Myers Squibb, Chugai-Roche, Eli Lilly, Novartis, Novimmune, Pfizer, and Swedish Orphan Biovitrum; and participated in two data safety monitoring boards for Sanofi. M.C., W.H., and S.J. are employees of Sanofi; may hold shares and/or stock options in the company. E.K.H. received honoraria and grant support from Actelion, Biogen, Merck Serono, Janssen, Novartis, Receptos, Roche, Sanofi, and Teva; and support from the Ministry of Education of Czech Republic project (Cooperation LF1, research area Neuroscience) and the National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107—funded by the European Union-Next Generation EU).

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Sanofi.

Trial Registration

ClinicalTrials.gov (A Study to Evaluate Efficacy, Safety, and Tolerability of Alemtuzumab in Pediatric Patients with RRMS With Disease Activity on Prior-DMT (LemKids); https://classic.clinicaltrials.gov/ct2/show/NCT03368664?term=NCT03368664&draw=2&rank=1; NCT03368664).

ORCID iDs

Tanuja Chitnis

Douglas L Arnold

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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