Efficacy and Safety of Teriflunomide in the Treatment of Multiple Sclerosis in Children – Results of the TERIKIDS Study
Therapeutic options for multiple sclerosis in the pediatric population are limited. However, in June 2021, teriflunomide was approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in pediatric patients aged 10–17 years in the European Union. The basis for this registration was the favorable results of the TERIKIDS study, which we summarize below. Teriflunomide thus became the first oral medication for 1st line treatment of RRMS in children and adolescents within the EU.
Mechanisms of Action of Teriflunomide in RRMS Treatment
Teriflunomide is an oral immunomodulatory drug with anti-inflammatory effects, which has been available for the treatment of RRMS in adult patients in over 80 countries worldwide. It is a molecule that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), functionally related to the respiratory chain. As a result of inhibiting this enzyme, the proliferation of rapidly dividing cells, which depend on de novo pyrimidine synthesis, is reduced. The principle of the drug's action is to reduce the number of lymphocytes, but the exact mechanism of action in multiple sclerosis is not entirely known.
Although the incidence of MS in the population under 18 years of age is rare, early onset of this progressive demyelinating disease means earlier development of irreversible disability and secondary progression. Therefore, it is a group of patients with significant unmet medical needs.
Methodology, Course, and Objectives of the Study
Multicenter randomized double-blind placebo-controlled phase III clinical study TERIKIDS evaluated the efficacy and safety of teriflunomide in patients aged 10–17 years across 57 clinical centers in 22 countries in Europe, North America, Africa, and Asia.
Patients with a diagnosis of RRMS with at least one relapse in the year before screening or at least two relapses in the two years before screening were included in the study. Patients were randomly assigned to teriflunomide therapy (at a dose equivalent to 14 mg in adult patients) or placebo for up to 96 weeks in a 2:1 ratio.
Neurological examinations were conducted at screening and every 24 weeks thereafter or upon suspected relapse. Early entry into the subsequent open-label extension phase lasting another 96 weeks was possible upon confirmed disease relapse or high activity assessed by MRI (at least 5 new or enlarged T2 lesions on 2 consecutive scans).
The primary objective was to assess the time to disease relapse at the end of the double-blind phase of the study. Key secondary objectives included assessing the number of new or enlarged T2 lesions and the number of gadolinium-enhancing lesions.
Findings
A total of 166 patients were randomized to therapy, with 109 assigned to teriflunomide therapy and 57 to placebo. The double-blind phase was completed by 102 (94%) patients on teriflunomide and 53 (93%) on placebo. Transition to the open-label phase before completing the double-blind phase due to high MRI lesion activity was unexpectedly higher in the placebo group (13% of patients on teriflunomide vs. 26% on placebo), reducing the study's power. After 96 weeks of therapy, no difference in the time to first relapse was observed in the teriflunomide group compared to the placebo group (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.39–1.11; p = 0.29).
Teriflunomide administration led to a significant reduction in the number of new or enlarged T2 lesions by 55% (relative risk [RR] 0.45; 95% CI 0.29–0.71; p = 0.00061) and the number of gadolinium-enhancing lesions by 75% (RR 0.25; 95% CI 0.13–0.51; p < 0.0001) compared to placebo.
Adverse events occurred in 96 (88%) patients on teriflunomide and 47 (82%) on placebo, with severe adverse events seen in 12 (11%) patients on teriflunomide and 6 (11%) on placebo. Adverse events were more frequent with teriflunomide compared to placebo, including nasopharyngitis, upper respiratory tract infection, alopecia, paresthesias, abdominal pain, and increased creatine kinase in blood. During the double-blind phase, 4 patients on teriflunomide experienced adverse events related to the pancreas (2 patients with acute pancreatitis and 2 with elevated pancreatic enzyme levels), leading to discontinuation in 3 of these patients.
Conclusion
No significant difference in the time to first relapse was observed, likely due to a higher number of patients moving early to the open-label phase because of high MRI lesion activity. Secondary study objectives suggested that teriflunomide might have a beneficial effect on pediatric patients with relapsing-remitting multiple sclerosis by reducing the risk of focal inflammatory activity.
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Sources:
- Chitnis T., Banwell B., Kappos L. et al.; TERIKIDS Investigators. Safety and efficacy of teriflunomide in pediatric multiple sclerosis (TERIKIDS): a multicenter, double-blind, phase 3, randomized, placebo-controlled trial. Lancet Neurol 2021 Dec; 20 (12): 1001–1011, doi: 10.1016/S1474-4422(21)00364-1.
- Paik J. Teriflunomide: pediatric first approval. Paediatr Drugs 2021 Nov; 23 (6): 609–613, doi: 10.1007/s40272-021-00471-1.
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