Treatment Effectiveness of Oral Disease-Modifying Agent in Multiple Sclerosis Adjusting for Adherence Trajectories

Background: Evidence from clinical trials indicates that oral Disease Modifying Agents (DMA), such as fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF), are comparable or superior to conventional injectable DMAs in reducing annualized relapse rate (ARR) in multiple sclerosis (MS). In the real world, where adherence could be suboptimal among MS patients, the clinical outcomes are likely to be influenced by treatment adherence; however, previous observational studies evaluated the treatment effectiveness of oral DMAs only through relapse-based outcome measures and did not consider adjusting for the initial adherence patterns among individuals with MS.

Objectives: This study compared the real-world effectiveness of oral DMAs using ARR while controlling for the initial adherence trajectories in MS.

Methods: A retrospective longitudinal study was conducted using adults (18-64 years) identified with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥1 oral DMA prescription from the 2015-2019 IBM MarketScan Commercial Claims and Encounters Database. Patients were grouped into incident FIN, TER, and DMF users based on the index DMA with one year of washout period. The annual DMA adherence trajectories based on monthly Proportion Days Covered (PDC) were examined using Group-Based Trajectory Modeling (GBTM) after treatment initiation. The ARR was measured after one year of the initial adherence assessment following the index date. The negative binomial regression model with generalized boosting models (GBM)-based Inverse Probability Treatment Weights (IPTW) was used to compare the ARR across oral DMAs (DMF and TER vs. FIN).

Results: The study cohort consisted of 994 MS patients who were initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. The GBTM grouped study subjects into three adherence trajectories: Complete Adherers (58.2%), Slow Decliners (24.5%), and Rapid Discontinuers (17.4%). The complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The GBM-based IPTW weighted, negative binomial regression model revealed that DMF (adjusted incidence rate ratio[aIRR]-1.71, 95% CI:1.02-2.89) users had a higher rate of relapses compared to FIN users after controlling for the initial adherence trajectories.

Conclusions: Dimethyl fumarate was associated with higher ARR compared to fingolimod after adjusting the initial adherence trajectories. More research is needed that accounts for the adherence patterns while evaluating clinical outcomes in MS.