Safety of Disease-Modifying Therapies for Highly Active Relapsing-Remitting Multiple Sclerosis

The treatment of multiple sclerosis (MS) includes using disease-modifying therapies (DMTs) to prevent inflammatory disease activity. Patients with a highly active disease are at elevated risk for neurologic disability and are treated using DMTs with the highest expected efficacy. However, the use of these DMTs is limited by safety concerns. Measures to reduce medication-related harm in people with MS need to be further examined in the post marketing setting.

The aim of this thesis was to investigate the safety of four different DMTs for highly active relapsing-remitting MS in Finland using real-world patient data. The DMTs assessed in this thesis included the two anti-trafficking therapies, natalizumab (NTZ) and fingolimod (FNG), as well as the two immune reconstitution therapies, alemtuzumab (ALEM) and cladribine (CLAD) tablets. The specific aims of the four studies in this thesis included assessing disease reactivation after NTZ discontinuation (Study I), lipid profile alterations during FNG treatment (Study II), adverse events (AEs) after ALEM treatment (Study III) and clinical outcomes and treatment sequencing in patients treated with CLAD tablets (Study IV). Real-world data were acquired from patient information archives and the Finnish MS registry. Study I included data on 89 patients who had discontinued NTZ and had been followed-up for at least 12 months afterwards. Study II included data on 72 patients who had initiated FNG with a median follow- up of 12 months. Study III included data on 121 patients who had initiated ALEM with a median follow-up of 30.3 months. Study IV included data on 179 patients who had initiated CLAD tablets with a median follow-up of 19.0 months.

In Study I, we demonstrated that corticosteroid-treated relapses occurred in 20% and 30% of patients after six and 12 months after discontinuing NTZ respectively, whereas any relapse was observed in 27% and 36% of patients respectively. A higher number of relapses and an EDSS score of 5.5 or above prior to initiating NTZ predicted the risk of reactivation at six months. Initiating a subsequent DMT after a washout period longer than three months was associated with an increased risk for reactivation at six months when compared to not initiating any subsequent DMTs. In Study II, we observed minor elevation in the concentrations of total cholesterol (0.40 mmol/L/year) and high-density lipoprotein (0.17 mmol/L/year) during a median follow-up of 12 months after the initiation of FNG. No statistically significant alterations in the concentrations of low-density lipoprotein or triglycerides were observed. In Study III, we showed that serious infusion-associated reactions (IARs) were observed in 11% of patients during the first course of ALEM, and in 0-3% of patients during subsequent courses. Serious adverse events (SAEs) other than IARs occurred in 23% of patients during a median follow-up of 30 months after the initiation of ALEM. Autoimmune AEs, infections, hepatobiliary AEs and malignancies were reported. In Study IV, we found that median time to first relapse was shorter in patients switching to CLAD tablets after receiving at least two previous DMTs when compared to patients with 0-1 previous DMTs prior to CLAD tablets. A subgroup analysis showed that this was most likely due to disease reactivation in patients switching from FNG. The most frequent AEs reported after receiving treatment with CLAD tablets were headache, Herpes simplex and nausea.

The main contributions of this thesis include describing disease reactivation after anti-trafficking therapies as well as safety issues associated with the use of immune reconstitution therapies. Exit strategies for patients discontinuing anti- trafficking therapies need to be developed, and the newly proposed risk factor for predicting the risk of reactivation after NTZ discontinuation based on EDSS should be taken into account when discontinuing NTZ in patients with early disability. We confirmed existing safety findings regarding the use of immune reconstitution therapies, but according to the results from Study III, considered ALEM a risky approach in the treatment of MS. Finally, the findings from Study II suggest that the overall risk of atherosclerosis may be unaltered by the small alterations in lipid concentrations observed during FNG treatment. However, more research is warranted to explore whether other similar drugs could have an effect on the lipoprotein concentrations or the risk of atherosclerosis in people with MS.