In the current post-hoc analysis, patients with RRMS who were treated with IFN beta-1a, 44 mcg sc tiw, had a greater reduction in T2 BOD after 48 weeks than those given IFN beta-1a, 30 mcg im qw. This finding is consistent with other clinical and MRI outcome measures in the prospective EVIDENCE study. Previous prospectively defined analyses showed that patients receiving IFN beta-1a, 44 mcg sc tiw, also had a reduced likelihood of relapse and had significant reductions in CUA and T2 active lesions compared with those randomized to IFN beta-1a, 30 mcg im qw [1–3].
In general, the impact of both IFNs on suppressing Gd-enhancing lesions on MRI is seen quite early, within the first 1–2 months of initiating therapy . Thus, it was considered reasonable to compare the overall change in T2 BOD for a relatively short duration of observation. Furthermore, from previous experience, looking at BOD differences over 12 months maximizes the group change over the 'noise' created by individual variability. For completeness, the data are presented as a histogram to show the spread of the response for both therapies. In this way it can be seen that both therapies can be associated with a stable MRI outcome or a worsening MRI outcome.
The distribution of absolute and percentage changes in BOD (Figures 2 and 3) in the current analysis indicates that patients in both treatment groups benefited from treatment with IFN beta-1a, but 14% more patients in the IFN beta-1a, 44 mcg sc tiw, treatment group had a stable or improved BOD compared with those treated with IFN beta-1a, 30 mcg im qw. In this 48-week analysis, there was an insufficient number of patients who had a clinical progression in EDSS to explore this relationship further.
A new formulation of IFN beta-1a, 44 mcg sc tiw, has been developed and is currently being studied in a large-scale, Phase III, clinical trial (protocol 25632). Initial data indicate that this new formulation has a reduced immunogenic potential, which should reduce the likelihood of NAb development .
It is unclear how much NAbs affect clinical efficacy. NAbs take time to develop and patients with NAbs at 48 weeks may not have had NAbs during most of the preceding time. Likewise, some patients who had developed NAbs earlier may have lost them by week 48. Although some studies suggest that treatment success rates may be curtailed by the development of high titres of persistent NAbs in a minority of patients following long-term treatment with IFN beta [8–10], other studies have shown that the clinical efficacy of IFN beta is the same in patients who are NAb+ as in those who are NAb- [1, 2, 11]. However, the studies that did not show an effect of NAbs were less than 2 years in duration, and thus may not have been of sufficient duration to show an effect of NAbs on clinical outcomes. In the current analysis, sample sizes were not large enough to allow a direct comparison between NAb+ patients in each treatment group. Still, a comparison of patients receiving IFN beta-1a, 44 mcg sc tiw, who developed NAbs, with all patients receiving IFN beta-1a, 30 mcg im qw (irrespective of NAb status), suggested that NAb+ patients in the IFN beta-1a, 44 mcg sc tiw, treatment group had a similar reduction in T2 BOD to the overall IFN beta-1a, 30 mcg im qw, treatment group. In other words, patients with NAbs who receive high-dose, high-frequency IFN beta still gain similar treatment benefits as those, regardless of NAb status, who receive low-dose, low-frequency IFN beta. This means that, although efficacy may be attenuated with NAbs, therapeutic effect is still provided by IFN beta-1a, 44 mcg sc tiw, on BOD suppression. At week 48, a similar number of T2 active lesions was seen in NAb+ patients in the IFN beta-1a, 44 mcg sc tiw, treatment group (mean 1.6 lesions/patient/scan) as overall (NAb+ and NAb-) in the IFN beta-1a, 30 mcg im qw, treatment group (mean 1.4 lesions/patient/scan). However, the reduction in BOD was smaller in the IFN beta-1a, 44 mcg sc tiw, NAb+ group than in the IFN beta-1a, 44 mcg sc tiw, NAb- group at 48 weeks. This may suggest that MRI is more sensitive than clinical outcomes in showing an early effect of NAbs on efficacy.
This study is probably too short to address adequately a delayed impact of NAbs on MRI outcomes. To some degree, this has been assessed in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study, in which results at 48 months showed an increase in BOD in the NAb+ group of 17.6% and a decrease of 8.5% in the NAb- group (p < 0.001) .
Interestingly, in the present study there was no apparent impact of NAbs on relapse outcomes at week 48. Thus, these MRI data indicate only a partial impact of NAbs on efficacy outcomes at this time.