After nearly 13 years of follow-up, 36% of patients with relapsing multiple sclerosis had a confirmed Expanded Disability Status Scale score worsening.
A recently published Danish nationwide study using patients with relapsing multiple sclerosis (MS) treated with natalizumab (Tysabri; Biogen) highlighted the clinical effectiveness of the agent over a 13-year follow-up. All told, tolerability was high, discontinuations due to disease activity or adverse events (AEs) were low, and efficient suppression of clinical relapses and radiological activity was observed.
The trial featured 2424 patients who initiated natalizumab between June 2006 and April 2020, with a median follow-up time of 2.7 years (IQR, 1.2-5.1). Among those with 2 subsequent Expanded Disability Status Scale (EDSS) scores (n = 1774), 19.8% (n = 352) had 24-week confirmed disability worsening (CDW), with an average time of 2.4 years (SD, 2.5) between CDW confirmation date and last available EDSS for sustained events. At 5 and 13 years of follow-up, 24.5% and 36.0% of patients had met the outcome of confirmed EDSS worsening.
Led by Mathias Buron, PhD, doctor of medicine at the University of Copenhagen, the study assessed patient characteristics, annualized relapse rates (ARRs), confirmed EDSS score worsening, MRI activity, and safety of natalizumab-treated individuals. The analysis was also stratified into 3 time periods, or epochs: 2006-2011 (n = 961), 2012-2018 (n = 1252), and 2019-2020 (n = 211). Among the sample, 1774 were eligible for the analysis of EDSS worsening and 1715 were eligible for the analysis of EDSS improvement.
With every calendar year, investigators observed a decrease in the age at treatment start, a corresponding decrease in disease duration, a higher proportion of treatment naïve patients, a decreasing baseline relapse rate, and a lower baseline EDSS. At data extraction, 915 patientd were currently continuing natalizumab treatment while 1509 had discontinued. The most common reasons for discontinuation included JCV antibodies (41%), pregnancy (11%), anti-natalizumab antibodies (9.3%), disease activity (9%), and AEs (9%).
In time to 24-weeks confirmed disability improvement (CDI) analyses, 589 total events occurred; however, 71.5% of these were sustained at the last available EDSS score. At 5 and 13 years of follow-up, 40% and 47.7% had met the outcome of improvement. The proportion of patients with CDI improved over time, with greater numbers in the intermediate epoch compared with the earliest epoch. Cox regression models showed increased hazard of CDI in females, higher age at onset, lower age at natalizumab initiation, treatment-naïve patients, and with higher baseline EDSS.
After initiating natalizumab, overall ARR rates decreased from 1.11 (CI, 1.07-1.15) to 0.3 (CI, 0.28-0.32), or a 72% reduction (P <.0001). Results also showed an ARR reduction of 64% (P <.0001) in the earliest epoch, during which high disease activity was required to receive natalizumab. These rates continued to increase over time, with reductions of 84% (P <.0001) and 91% (P <.0001), respectively, in the intermediate and latest epoch. A total of 203 patients experienced a relapse within 6 months after stopping natalizumab, accounting for 13.5% of total stops.
Among those with at least 1 MRI within 2-14 months after treatment start (n = 263), 6.8% (n = 18) showed signs of activity such as new or enlarging T2 lesions or any gadolinium-enhancing lesions. Additionally, 3.4% (n = 29) and 2.7% (n = 22) of patients showed signs of activity on MRI between 14-26 months and 26-38 months, respectively.
"The mandatory data collection performed at every clinical visit ensure uniform data capture at every clinical site," Buron et al wrote. "Combined, these factors provide good generalizability and validity of results. This study cohort of patients treated with natalizumab is among the largest published, making it less prone to random variation. Further, as natalizumab has been standard drug-of-choice in the high efficacy-tier in Denmark, and medicine is freely available, the patients fulfilling the drug indications are relatively unselected."
In terms of safety, 85.9% of the cohort reported no AEs during their treatment period, 10.1% reported 1, and 4.0% reported multiple. Cephalalgia, occurring 368 times, was the most reported AE, followed by "unspecified infusion-related complications" (n = 42), respiratory tract-related events (n = 14), and urinary tract infections (n = 12). Investigators found less than 3 cases of progressive multifocal leukoencephalopathy, toxic liver disease, post-zoster neuralgia, and influenza-like symptoms.