Multiple sclerosis (MS) patients treated initially with fingolimod (Gilenya), natalizumab (Tysabri), or alemtuzumab (Lemtrada) had a lower risk of converting to secondary progressive MS than patients who started with glatiramer acetate (Copaxone) or interferon beta (Rebif), researchers reported.
And compared to MS patients who were untreated, patients initially treated with any of these therapies — including glatiramer acetate or interferon beta — had a lower risk secondary progressive MS conversion, according to Tomas Kalincik, PhD, of the Royal Melbourne Hospital in Australia, and colleagues.
The effects were more significant when treatments were started within the first 5 years of disease onset, they wrote in JAMA.
“This has been a very large question for some time: Can we really show that earlier use of these disease-modifying therapies actually results in a delay of entry into secondary progressive phase of the illness?” said John Corboy, MD, of the University of Colorado, who was not part of the study.
When MS patients are younger and have relapses, they often have very good recovery and a significant part of their functionality remains, but once they go into a secondary progressive phase and reach certain points, disability accrues, Corboy said. “With the median age of onset of that phase being 40 to 45, that means that still quite young individuals are developing significant irreversible disability,” he told MedPage Today.
The study, which was not directly funded by drugmakers, examined 1,555 patients with clinically definite MS (72% female, mean baseline age 35) from 1998 to 2012 from three data sources: untreated patients from the University Hospital of Wales; treated patients from MSBase, an observational cohort of real-world data of MS patients in 29 countries; and additional patients in Europe treated with alemtuzumab before it was licensed.
Patients had at least one Expanded Disability Status Scale (EDSS) score within 6 months before baseline and at least two EDSS scores after baseline. The untreated cohort received no disease-modifying therapies (DMTs); the treated cohort followed published protocols. Patients were followed for a minimum of 4 years.
Using a validated definition of secondary progressive MS based on disability progression and preceding relapses, the researchers looked at the rate of conversion between different DMTs and untreated patients; the rate of conversion with fingolimod, natalizumab, or alemtuzumab versus glatiramer acetate or interferon beta; and treatment within versus after 5 years of disease onset. They propensity-matched untreated to treated patients on age, sex, annualized relapse rate in the year before baseline, EDSS score, and disease duration.
Key findings included:
- Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR 0.66, 95% CI 0.44-0.99, P=0.046; 5-year absolute risk 7% vs 12%, median follow-up 5.8 years)
- Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR 0.71, 95% CI 0.61-0.81, P<0.001; 5-year absolute risk 12% vs 27%, median follow-up 7.6 years)
- Patients started on fingolimod (HR 0.37, 95% CI 0.22-0.62, P<0.001), natalizumab (HR 0.61, 95% CI 0.43-0.86, P=0.005), or alemtuzumab (HR 0.52, 95% CI 0.32-0.85, P=0.009) also had a lower risk of conversion than untreated patients
- Risk of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset versus later (HR 0.77, 95% CI 0.61-0.98, P=0.03; 5-year absolute risk 3% vs 6%, median follow-up 13.4 years)
- When glatiramer acetate or interferon beta treatments were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years versus later, the HR was 0.76 (95% CI 0.66-0.88, P<0.001; 5-year absolute risk 8% vs 14%, median follow-up 5.3 years)
“Recognizing there are significant limitations to this approach and that there always are going to be some biases based on who started what medication when, this study is important and is an argument to continue the use of these long-term databases,” Corboy observed. “They collect real-world information that otherwise is extremely difficult to obtain.”
Kalincik and colleagues noted that the study limitations included its observational design: they could not ascribe causality nor distinguish between prevention and delay of secondary progressive MS. Not having EDSS functional score components precluded using the secondary progressive MS definition with the highest combination of sensitivity, specificity, and accuracy, they added. The glatiramer acetate and interferon beta cohorts came from an earlier period, and different care practices at the time may have influenced results. The study also did not assess risks associated with DMTs.
Thes study was supported by the National Health and Medical Research Council (NHMRC) of Australia, the University of Melbourne, a Next Generation Fellowship funded by the Grand Charity of the Freemasons, and the MSBase.
The MSBase Foundation is supported by Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva.
Alemtuzumab studies were supported by the NIHR Cambridge Biomedical Research Centre and the MS Society UK.
Kalincik disclosed relevant relationships with WebMD Global, Roche, Sanofi Genzyme, Novartis, Teva, BioCSL, Merck, and Biogen, as well as support from the NHMRC, the Faculty of Medicine, Dentistry, and Health Sciences of the University of Melbourne, Fondation d’Aide pour la Recherche sur la Sclerose en Plaques, and Biogen. Co-authors disclosed relevant relationships with Biogen, Novartis, Sanofi-Genzyme, Merck, Roche, Teva, Celgene Actelion, Almirall, EMD Serono, Bayer, GlaxoSmithKline, and Oxford Pharmagenesis.