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Competing Interests: Declaration of Competing Interest In the last 2 years, Gavin Giovannoni received compensation for serving as a consultant or speaker for or has received research support from , Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssens/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi and Roche/Genentech. He has also received research support from , Merck KGaA/EMD Serono, Novartis, Sanofi, Roche/Genentech and Takeda.

Background: Natalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic., Methods: A registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age., Results: 101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months. During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 (p < 0.001) at last NA infusion. Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit (p < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58% of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded., Discussion: NA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course., Conclusions: A relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58% of cases.

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the CNS in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize to attack myelin sheaths and injure underlying axons. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Of all the potential new oral MS agents in development, cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers targeted, sustained regulation of the immune system and that has a well-characterized safety profile, derived from more than 15 years of use of the parenteral formulation in oncology indications and MS. This paper discusses the need for new MS therapies to improve treatment adherence, and reviews the mechanism of action, existing efficacy and safety data, and the clinical development of oral cladribine. The need for continuous risk monitoring for all new potent immunoactive drugs under development is emphasized. Preliminary results of the 96-week, double-blind, randomized, placebo-controlled, multicenter CLARITY (CLAdRIbine Tablets Treating MS OrallY) study are encouraging and provide the first complete phase III data on an oral DMD for MS.