The data and facts on pediatric MS show that consistent immunotherapy is indicated even in childhood to control the further course of the disease. This is contrasted by the fact that most MS therapies approved for adults have not been tested in randomized, controlled studies in children. Understandably, therefore, there is some reluctance to prescribe immunosuppressive therapies to children given the limited data available. And it remains to be noted that until 2018 there was also no randomized, controlled study for the treatment of children and adolescents with MS.
In the past, children and adolescents with MS were primarily treated with interferons and glatiramer acetate (i.e., non-immunosuppressive basic therapeutics) – case reports and uncontrolled studies confirmed the efficacy and safety of these substances. In view of the many years of experience and the lack of new and unexpected side effects compared to adults, these active substances were finally approved in 2006 for the treatment of adolescents from the age of 12 (Betaferon®, Avonex®, Copaxone®) or children from the age of 2 (Rebif®).
Treatment of pediatric MS with and without immunosuppression
The first randomized controlled multicenter double-blind phase III study in children and adolescents with MS was the PARADIGMS studies, in which 215 patients between the ages of 10 and 18 were treated with Fingolimod (Gilenya®) or Interferon beta-1a i.m. (Avonex®) over a period of 2 years. Here, a superiority of 0.5 mg (in children under 40 kg KG 0.25 mg) Fingolimod was shown compared to 30 µg Interferon-beta 1a intramuscular in reducing relapse rates (82% relative risk reduction) and reducing MRI lesion load (53% relative risk reduction).
Overall, the side effects of Fingolimod treatment were even slightly lower at 88% compared to 95.3% in the Interferon group, but 7 children experienced serious side effects during treatment with Fingolimod compared to only 2 children in the Interferon group. These overall very good results led to the approval of 0.5 mg Gilenya® (in children under 40 kg 0.25 mg) for the treatment of (highly) active relapsing MS in 10-18 year old children and adolescents.
Before Gilenya was approved, Natalizumab (Tysabri®) was also considered for highly active pediatric MS, as retrospective data suggested a good response in this age group and young patients were less likely to test positive for the JC virus (the cause of PML) compared to adults. However, this option is now somewhat in the background due to the study situation in individuals < 18 – but remains an option for very pronounced activity.
Child-friendly study design for children with MS
Given the limited number of studies, it is always significant for the treatment of pediatric MS when new studies are published, as is now the case with the so-called TERIKIDS study, which has investigated the effect of Teriflunomide (Aubagio®) on pediatric MS (Chitnis et al. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomized, placebo-controlled trial. Lancet Neurol 2021 Dec;20(12):1001-1011). However, within the study, Teriflunomide was tested against placebo, with study patients being allowed a low-threshold transfer to open treatment with Teflunomide in case of clinical relapses or high MRI activity.
This design may have led to the primary endpoint of the study (time until the first confirmed relapse) not being statistically achieved, although the proportion of patients with relapses was numerically lower when Teriflunomide was given. However, there was a highly significant reduction in MRI activity when Teriflunomide was given compared to placebo, and the substance was also well tolerated and showed an acceptable safety profile in pediatric MS. This ultimately led to the approval of the substance for the treatment of 10 – 17-year-old MS patients in the summer of 2021.
Despite the study (whose implementation is generally to be praised), the question arises as to whether Teriflunomide offers an advantage over the use of interferons and Copaxone in terms of safety and efficacy, which have been in use for a long time and have proven to be very safe. However, I can imagine that for some children and adolescents (and also for the parents concerned), the availability of an oral medication could be advantageous and lead to relief for the family.
What is pediatric MS? I summarized this in the previous post.
