Efficacy of subcutaneous interferon β-1a on MRI outcomes for multiple sclerosis: a short communication
Dr Mamuda Aminu (MBBS, MPH, PhD)
Background
Multiple sclerosis (MS) is one of the world’s most common neurologic disorders, affecting 2.3 million young adults worldwide. It is characterised by demyelination of the central nervous system, causing neuronal damage and progressive neurological dysfunction, leading to serious disability.
The majority of MS cases experience relapses and remissions, after which they typically develop secondary progression. A smaller group of cases, however, present with gradual progression and accumulation of disability without relapses (primary progressive MS).
The REFLEX trial found that interferon (IFN) β-1a, 44 µg given subcutaneously three times a week or once a week, reduced the risk of conversion from clinically isolated syndromes (CIS) to clinically definite MS (CDMS). The study also showed a significant dose-response relationship between IFN and the onset of MS, but no significant difference in time to CDMS. The observation was attributed to the increased likelihood of MS diagnosis aided by MRI.
This article summarises the key MRI findings that substantiate the results of the original REFLEX trial and examines the available evidence for early treatment to improve clinical outcomes in light of recent findings for IFN and newer MS drugs.
Methods for the REFLEX trial
Ethics, patients and procedures
The institutional review boards of all participating centres approved the protocol for the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352). All patients provided written informed consent before participating in the trial.
Eligible patients were aged 18–50 years with an Expanded Disability Status Scale score of 0.0–5.0, had experienced a single demyelinating event suggestive of MS within 60 days prior to study entry and had ≥ 2 clinically silent lesions on a T2-weighted brain MRI scan with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial.
Patients were randomised (1:1:1) to receive the serum-free formulation of IFN β-1a, 44 µg subcutaneously three times a week or once a week, or placebo for 24 months or until conversion to CDMS. The double-blind (DB) period was defined as the interval between randomisation and conversion to CDMS, or study discontinuation, or 24 months, whichever occurred first.
MRI assessments and endpoint
MRI assessments were made every 3 months from baseline to Month 24. For patients who converted to CDMS before Month 24, MRI scans were subsequently performed at 6-month intervals at predefined time points with respect to the baseline MRI (at Month 6, Month 12, Month 18 and Month 24). The same MRI machine at each centre was used for all scans for each patient throughout the study. Analysis and evaluation of MRI scans were performed centrally at the VU University Medical Center, Amsterdam, The Netherlands.
The primary MRI endpoint of the study was the mean number of combined unique active (CUA) lesions per patient per scan. Other outcomes assessed and reported in this paper were: treatment effect on CUA lesions, MRI lesion volume and brain volume.
Statistical analyses
Efficacy analyses were performed on the intent-to-treat (ITT) population, which consisted of all randomised patients, analysed by their original allocation.
Results
Patients, conversion to MS and safety
A total of 517 patients were randomised ITT population: subcutaneous IFN β-1a three times a week, n=171; subcutaneous IFN β-1a once a week, n=175; placebo, n=171); 515 patients received the study drug or placebo. The groups showed similar baseline demographics, disease and MRI characteristics. In the IFN β-1a three times a week, once a week and placebo groups, 146 (85.4%), 156 (89.1%) and 146 (85.4%) patients, respectively, completed the whole treatment period.
Results of conversion to MS have been reported elsewhere. No new or unexpected safety signals were observed during the study.
Lesions per patient per scan
The mean (SD) number of CUA lesions per patient per scan in the ITT population during the DB treatment period (Figure 1) was 0.6 (1.15) in the three times a week group, 1.23 (4.26) in the once a week group and 2.70 (5.23) in the placebo group, corresponding to reductions versus placebo of 2.10 and 1.47 lesions per patient per scan for three times a week and once a week, respectively (p<0.001 for three times a week and once a week vs placebo; p=0.002 for three times a week vs once a week).
Figure 1: Mean number of CUA lesions during the double-blind period (intent-to-treat population). CUA, combined unique active; IFN, interferon; sc, subcutaneous; tiw, three times a week; qw, once a week (De Stefano et al, 2013).
Treatment effect on CUA lesions, by patient baseline subgroups
Factors that significantly affected the accumulation of CUA lesions per patient per scan during the DB period were: age (HR for age <30 years vs ≥30 years: 1.69, 95% CI 1.31 to 2.18), presence of gadolinium-enhancing (Gd+) lesions (HR for ≥1 lesion vs 0 lesions: 2.67, 95% CI 2.05 to 3.47) and number of T2 lesions (HR for ≥9 lesions vs <9 lesions: 4.93, 95% CI 3.66 to 6.63).
The treatment effect was significantly lower in males than that in females for three times a week and once a week compared with placebo (p=0.003).
MRI lesion volume and brain volume
Median (IQR) T2 lesion volume decreased from baseline in the three times a week group by −128.7 mm3 (−721.0 mm3 to 42.5 mm3) and by −37.9 mm3 (−609.3 mm3 to 177.4 mm3) in the once a week group, but increased by 51.5 mm3 (−194.6 mm3 to 617.3 mm3) in the placebo group. No significant change in volume observed for T1-Gd+ and T1 hypointense lesions, except in the placebo group, where there was an increase in T1 hypointense lesion volume of 31.5 mm3 from baseline.
During the DB period, changes in brain volume from baseline at Month 12, Month 24 and the last observed value were similar across the different treatment groups (range −0.34% to −1.04%), although the greatest loss was in the three times a week group compared with the once a week and placebo groups. Observations over the whole study period were similar.
Discussion
In this study involving a population of patients with CIS, the MRI findings support the earlier results from the REFLEX trial, where IFN β-1a, 44 µg given subcutaneously three times a week or once a week, was found to reduce the risk of conversion from CIS to CDMS. A clear dose effect was observed, with a significantly greater reduction in the number of CUA lesions with the three times a week dose.
Findings from more recent studies support the results of the REFLEX trial. An exploratory analysis of the PRISMS study involving 560 patients was recently carried out to assess the effect of active T2 and T1 Gd+ lesions on relapses. The study found that the mean active T2 lesion number at Month 6 was significantly lower with IFN β-1a given subcutaneously 44 μg and 22 μg 3 times a week than with placebo (p < 0.0001). The authors concluded that active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a subcutaneously 22 μg, but not in those receiving IFN β-1a subcutaneously 44 μg.
Similarly, in an 11-year study from the randomised BENEFIT CIS trial, Kappos and colleagues assessed the outcomes of 278 patients treated with IFN β-1b immediately after CIS or after a short delay. They observed that the risk of CDMS was lower in the early-treatment arm compared with the delayed-treatment arm (p=0.0012), with longer time to first relapse (p=0.0005) and lower overall annualised relapse rate (0.21 vs 0.26; p=0.0018).
Prospect of newer MS drugs
Recent trials show promising results for the discovery of newer drugs to improve clinical outcomes for MS patients.
In two identical phase 3 trials, Hauser et al. investigated the effect of ocrelizumab, a humanised monoclonal antibody that selectively depletes CD20+ B cells, on MS outcomes. They reported a lower relapse rate with ocrelizumab than with IFN β-1a in both trials. The percentage of patients with disability progression was significantly lower with ocrelizumab than with IFN β-1a at both 12 weeks (p<0.001) and 24 weeks (p=0.003).
In another new trial, results indicate that fingolimod may lead to better control of MS if treatment is started early, thus supporting its potential as an early treatment for MS.
Other recent studies have reported favourable results for other drugs, including siponimod and evobrutinib, in improving clinical outcomes for MS.
Conclusion
The MRI evidence presented corroborates the findings of the REFLEX trial, which showed that IFN β-1a delay the conversion of CIS to CDMS. This evidence, as well as evidence from more recent studies, supports the use of IFN in early treatment for MS. Findings from new trials for MS drugs look promising and some support early treatment. However, more research is required to investigate the long term effect of their use.
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