Neutralizing anti-IFN-beta antibodies: how much more evidence do we need to use them in practice?

Neutralizing antibodies (NAbs) are a major hurdle to the successful use of biologics in clinical practice. The impact of NAbs is obvious in biologic systems with no redundancy. NAbs induced in response to treatment with recombinant erythropoietin or thrombopoietin cause life-threatening complications of pure red cell aplasia and thrombocytopenia as a direct result of inhibiting the activity of the endogenous hormones. For the type 1 interferons ( and ), NAbs have not yet been shown to have untoward biologic effects. This may relate to the fact that IFN and IFN have overlapping biologic activities or that they are produced locally as autocrine or paracrine mediators and are therefore less likely to be exposed to NAbs. In comparison, the evidence that NAbs interfere with the therapeutic effect of type 1 interferons is much clearer. In subjects with multiple sclerosis (MS), NAbs inhibit the induction of IFN specific gene products and lessen the benefit of IFN on both MRI activity and relapse rate. Furthermore, three articles in this issue of Neurology show that NAbs1,2 impact negatively on disease progression and are likely to persist.3 NAbs do not appear until 6 to 24 months after IFN is initiated and do not have consistently measurable effects in trials of less than 2 years’ duration. In the pivotal IFN -1b study (Betaseron/Betaferon), the clinical impact of NAbs on MS relapse rate only became apparent after 18 months of therapy.4 In the subcutaneous IFN -1a PRISMS study (Rebif) there were no reported differences in the clinical and MRI endpoints between NAb and NAb patients at 2 years.5 However, in the 4-year extension phase of PRISMS, the relapse rate was 60% greater (0.81 vs 0.50, p 0.002), the median number of T2 active lesions was five times greater (1.4 vs 0.3, p 0.01), and the median change from baseline in the MRI burden of disease was three times greater ( 17.6% vs –8.5%, p 0.001) in NAb compared with NAb subjects.6 In the pivotal once-weekly IM IFN -1a (Avonex) trial, which was terminated early, a strong trend toward reduced treatment benefit on MRI, but not clinical disease activity, was seen in NAb patients.7 Data on the impact of NAbs on MS disease progression have been less clear. In fact, none of the phase III IFN trials was powered to detect an effect of NAbs on disease progression. Despite this, data have now demonstrated an impact of NAbs on disease progression. In a recently published open-label study of 78 IFN -treated MS subjects followed for a median of 3 years, a higher percentage of NAb patients vs NAb patients had worsening of Expanded Disability Status Scale (EDSS) scores during the period of follow-up (p 0.013).8 Similarly, in a second open-label study of 65 subjects followed for up to 4 years, the mean EDSS score increased from 2.2 0.8 at baseline to 3.6 1.2 at year 2 in the 10 subjects with high-titer NAbs compared with NAb subjects in whom there was no significant change in their EDSS scores (p 0.01).9 A re-analysis of the impact of NAbs in the PRISMS study, published in this issue of the Journal,1 shows that over the entire 4 years of study, relapse and disability measures were similar between NAb and NAb patients. However, once NAbs developed, significant differences were noted between NAb and NAb groups on MRI, relapse, and disability outcome measures. As expected, the impact on disability was less predictable than on the other outcomes. In fact, it was only significant in the “interval-positive analysis,” in which subjects provide data to both the NAb and NAb– groups depending on their status at the time data were collected. Using this method, the difference between NAb and NAb– groups in the rate of confirmed 1-point EDSS change was significant over the 4 years of the study (NAb /NAb rate ratio 1.50,