Professor Richard Furie is the chief of the Division of Rheumatology of the North Shore-Long Island Jewish Health System in New York. His research in the field of SLE is profound. At the 2015 ACR Annual Meeting in San Francisco, professor Furie presented results from a phase II trial of anifrolumab, a type I IFN receptor antagonist.
– Professor Furie, what is your general impression about this upcoming medication?
– Never before have we seen such a successful phase II study in SLE. The magnitude, consistency, and breadth of responses were quite striking. Although the primary endpoint was a composite of the SRI at Day 169 and the requirement by Day 85 to reduce the prednisone dose to <10 mg/day (and not exceed the Day 1 dose) and sustain this dose until Day 169, other successful outcomes included the SRI without the steroid taper requirement, the BICLA, modified SRI’s, CLASI, and steroid tapering (300 mg group only). The results were more dramatic in those subjects with high baseline IFN gene signatures. If the same degree of efficacy occurs in phase III, the lupus community will have another drug.
– Looking at the results of this study, an apparent concern is the lack of dose response. Have any possible explanations been proposed?
– Given that the two doses (300 mg and 1000 mg) inhibited the IFN gene signature to similar degrees, I believe that there was a plateau effect and not an inverse dose response. That is, the lower dose was sufficient to inhibit the type I IFN pathway and provide the observed efficacy. Another potential explanation lies in the fact that there were more dropouts in the 1000 mg dose group. In the analysis, subjects who withdrew early were considered non-responders. Using other methods of imputation, the results were very similar between the 300 and 1000 mg dose groups. Perhaps there might be a biological explanation for why the outcomes with the higher dose were not as robust; however, this was not obvious.
– The development and approval of belimumab has signified an evolution in the therapeutic management of SLE. What are the main differences between these two therapeutic approaches? Are we moving towards tailored treatments, based on specific disease phenotypes?
– Belimumab and anifrolumab target different components of the immune system. Belimumab targets BLyS (B lymphocyte stimulator, also known as BAFF), whereas anifrolumab targets the type I IFN receptor. Belimumab’s assault is on B cells and thus affects the adaptive immune system; anifrolumab directly affects the innate immune system. We learned from the belimumab development program that patients who were serologically active were more likely to benefit than those who were not. We also learned from the belimumab program that the effect size was greater when the subset of patients with high disease activity at baseline was evaluated. These observations suggested that certain phenotypes were more likely to respond to the therapeutic intervention. Similarly, the phenotype in the anifrolumab phase II study that appeared to be more responsive was established by the baseline IFN gene signature. With anifrolumab, those with high baseline IFN gene signatures were less likely to respond to placebo compared to the overall cohort, whereas those with low baseline IFN gene signatures were more responsive to placebo than the overall cohort. The response rates to treatment were very similar in the IFN high and low groups; however, it was the differential response to placebo that led to the far greater odds ratios in the IFN high group. But caution should be exercised as the IFN low group comprised just 25% of the overall population, and thus the sample size in this subpopulation was relatively small. The fact that these two very different approaches are both effective speaks to the complexity of the immune abnormalities in SLE and the need to eventually target multiple pathways simultaneously. Predictive biomarkers are sorely needed in the management of our patients with all rheumatic diseases, and the IFN gene signature may represent such a breakthrough in SLE.
– Do you believe in patient-specific treatments, organ manifestation-specific treatments, or a combination of both?
– As discussed above, I think we will eventually be moving to patient-specific treatments with the use of predictive biomarkers. With regard to organ manifestation-specific treatments, the large phase II and III programs have generally allowed all active patients into the studies and have used composite clinical outcomes. While post-hoc analyses examined effects in specific domains, detailed prospective evaluations using instruments such as CLASI or joint scores were often lacking. However, I believe there will be a move towards measuring organ-specific responses as they were done with the anifrolumab study and some of the other programs.
– Are there any large trials for lupus nephritis in the pipeline?
– It is gratifying to see that there are several therapies being tested in lupus nephritis as the need is great for our patients with kidney involvement. We need to prevent renal insufficiency, renal failure, and all the complications from therapies used in lupus nephritis. Like with extra-renal lupus, the therapeutic strategies are quite varied.
– Professor Furie, with your research you have contributed significantly to drug development for SLE and to the understanding of its pathogenetic mechanisms. Do you have any visions for the future? Why do trials fail and what’s the secret for success?
– First of all, I should emphasize that although I have been the “spokesperson” for many of these studies, the credit really goes to the team. The drug development team is huge consisting of the basic and clinical scientists, both in academia and industry, the research coordination staff, and of course the patients who participate in these studies of experimental drugs. Developing drugs in SLE has been quite humbling with far many more trial failures than successes. However, with the success of the belimumab program, it was proven that the lupus “nut” could be cracked. There will no doubt be more successes in the future, safer and more efficacious therapies, and overall better outcomes for patients with SLE.
– Thank you very much for sharing your insights with the readers of Lupus Science & Medicine. We look forward to hosting your work!