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Objectives Toll-like receptor (TLR)7 is a pattern recognition receptor that contributes to SLE pathogenesis. DS-7011a is an anti-TLR7 monoclonal antibody (mAb) that inhibits TLR7 signaling. The aim of this study was to explore safety and PK and to detect initial efficacy of DS-7011a in SLE patients.Methods This was a randomized, placebo-controlled, double-blind Phase 1b/2 study [ NCT05638802]. Patients were: 1) globally enrolled and randomized 2:1 to DS-7011a or placebo; 2) required to have definite SLE according to the 2019 EULAR/ACR criteria, active CLE (CLASI-A score of at least 4), and no or inactive LN; 3) given DS-7011a (20 mg/kg) or placebo IV 3 times Q4W starting at Week 0; and 4) followed until Week 16 to assess treatment effect. Study primary objective was safety and secondary objectives were PK and initial efficacy. TEAE were safety endpoints. DS-7011a plasma concentrations were analyzed by Population PK to derive PK endpoints. CLASI-A was the main efficacy endpoint and IFN-I gene signature (GS) expression was scored to understand the mechanism of action. Statistics were descriptive.Results 25 patients were randomized and received at least one dose of DS-7011a (n=19) or placebo (n=6) ( table 1). DS-7011a decreased CLASI-A more than placebo with an effect that persisted until Week 16 [DS-7011a mean (SE) CLASI-A score change from Baseline to Week 16 = -10.1 (2.4), placebo = 1.0 (3.4); difference (95% CI) = -11.1 (-21.1, -1.0)] (figure 1) and was particularly remarkable in patients with chronic CLE or severe CLE or high IFN-I GS expression. CLASI-50 and CLASI-70 were 53% and 41% with DS-7011a, respectively, and both were 17% with placebo. DS-7011a also decreased CLA-IGA, SLEDAI-2K, and PGA-SLE more than placebo (figure 1). DS-7011a decreased IFN-I GS expression more than placebo, reducing it to levels close to those of healthy subjects. TEAE, none of which were severe, similarly occurred in patients treated with DS-7011a or placebo (table 2). No safety signal was identified. DS-7011a showed predictable PK typical of an IgG mAb, including long half-life.Abstract PO:11:280 Table 1–2Abstract PO:11:280 Figure 1Mean (#SE) CLASI-A, CLA-IGA, SLEDAI-2K, and PGA-SLE score changes from Baseline with DS-7011a and placebo^Conclusions DS-7011a was safe and well tolerated and showed favorable PK and initial efficacy. These results support DS-7011a further development for the treatment of SLE.