State of the Art REVIEW
positive phase 2 results, phase 3 trials of the JAK inhibitor baricitinib returned mixed results, with one showing superior attainment of SRI compared with placebo, 142 but the other parallel and effectively identical trial showing no difference. 143 Trials of the anti-BAFF antibody tabalumab, which had negative results in two phase 3 trials enrolling a total of 2288 patients, 128 228 resulted in its development being terminated, and a similar fate befell the interleukin 12/23 inhibitor ustekinumab, for which phase 3 trials were negative despite positive phase 2 studies. 140 141 Factors leading to negative trial results include high placebo response rates, and conflicting findings between studies on the same product; these factors drove a multinational panel to conclude recently that improved study design and endpoints are among the highest priorities in systemic lupus erythematosus. 229 230 Encouraging results in earlier stage trials continue to emerge. A potent CD20 targeting mAb, obinutuzumab, had a positive result in a phase 2 randomized trial in 125 patients with lupus nephritis, 155 and case series suggest it could be effective in patients with systemic lupus erythematosus who have failed rituximab 231 ; phase 3 trials of this agent in both systemic lupus erythematosus and in lupus nephritis are under way (NCT04963296, NCT05039619). This set of results suggests that deeper B cell depletion could be more effective in systemic lupus erythematosus, a concept further supported by remarkable reports of complete remission in highly treatment refractory patients with systemic lupus erythematosus treated with CD19 directed chimeric antigen receptor T cell (CAR-T) treatment 232 233 ; however, CAR-T treatment and other B cell depleting strategies have not been directly compared. A phase 2 trial randomized patients to placebo or the oral TYK2 inhibitor deucravacitinib 147 and found that the primary outcome measure of SRI and all secondary outcome measures, including attainment of LLDAS, were met. Guidelines Several national and international societies have published guidelines for treating systemic lupus erythematosus, including the American College of Rheumatology, and more recently, EULAR. 179 180 These guidelines are chiefly based on expert consensus, as prospective studies comparing treatment strategies for systemic lupus erythematosus are lacking. They emphasize important non-drug strategies, including avoidance of ultraviolet radiation, management of cardiovascular risk factors, vaccinations, and thromboprophylaxis where indicated. The most recent guidelines, 179 published in 2019 by a EULAR consensus group, define the overarching goal of systemic lupus erythematosus care as aiming to minimize disease activity across all organ systems while maintaining the lowest possible burden of treatment toxicity. In these guidelines, which predate the approval of anifrolumab and voclosporin, antimalarial use is
on these targets) improves outcomes; a protocol for such an intervention study has been published. 222 Importantly for using new treatments to achieve these goals, rates of LLDAS attainment were improved by the addition of biological treatment to standard of care; this finding comes from a post hoc analysis of responses to belimumab using data from 1684 patients enrolled in phase 3 trials, 221 and responses to anifrolumab using data from 305 and 819 patients from the phase 2 and pooled phase 3 trials, respectively. 169 171 LLDAS attainment was included a priori as an outcome measure in phase 2 trials of baricitinib and the tyrosine kinase 2 (TYK2) inhibitor deucravicitinib, and in both cases, superior rates of LLDAS attainment were observed with active In the absence of multiple new treatments with which to apply to a treat-to-target approach, other strategies rely on new combinations of existing treatments. For example, in a randomized open label trial in refractory lupus nephritis, the combination of rituximab with cyclophosphamide was followed by either placebo or monthly belimumab. 224 This study of 46 patients did not show any efficacy advantage for the addition of belimumab after induction treatment, but the lack of concerning safety signals was reassuring for future studies of combination or sequential treatments. Another study, whose design has been published 225 but results only reported in conference abstract form, 226 randomized 292 patients with active systemic lupus erythematosus to belimumab with or without the addition of two doses of rituximab or placebo, or belimumab plus standard of care. The addition of rituximab showed no advantage; as all patients received belimumab no further conclusions could be drawn. Finally, a small trial of 52 patients treated with rituximab were randomized to either placebo or belimumab for 52 weeks thereafter. 227 In this study, the primary outcome measure of lower anti-dsDNA antibody titer was met, and belimumab treatment was associated with a significantly lower rate of flares. Similar results have been shown with the use of belimumab alone; therefore, whether the sequential combination offers advantages is unclear. Reassuringly, no concerning safety signals were observed. treatment compared with placebo. 147 223 New combinations of existing treatments Emerging treatments The evolution of novel treatment development in systemic lupus erythematosus broadly parallels two sets of advances: increasing understanding of its pathogenesis and slowly improving execution of clinical trials. In table 2 , we summarize in chronological order the results of clinical trials of novel agents in systemic lupus erythematosus and lupus nephritis. The timeline suggests that while phase 2 trial success rates are improving over time, difficulties remain in translating positive phase 2 results into phase 3 and product registration. Despite
the bmj | BMJ 2023;383:073980 | doi: 10.1136/bmj-2022-073980
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