背景:循环,细胞外RNA是系统性红斑狼疮(SLE)中I型干扰素的主要触发因素,已知干扰素在该疾病中起主要致病作用。RSLV-132是与人IgG1Fc融合的具有催化活性的人RNase分子,旨在消化RNA,从而减少与SLE相关的慢性炎症。该药物在具有中度-重度皮肤病活性和存在RNA免疫复合物的SLE患者队列中进行了评估。该研究的主要目的是评估在6个月内13剂10mg/kgRSLV-132对平均皮肤红斑狼疮疾病面积和严重程度指数(CLASI)评分的影响。
方法:65例符合基线CLASI评分为10或更高的入组标准且RNA结合蛋白的5种自身抗体(SM/RNP,SSA/Ro,SSB/La,Sm,RNP)被随机分配(2:1)接受13剂RSLV-13210mg/kg或安慰剂,分别。参与者在第1、8、15、29、43、57、71、85、99、113、127、141和155天接受研究药物24周,在第169天进行治疗结束访问,并在第215天进行随访。在第85天和第169天评估主要目标。次要目标包括使用系统性红斑狼疮疾病活动指数2000(SLEDAI-2K)评估系统性疾病活动,不列颠群岛狼疮评估小组2004指数和医师全球评估。来自这些仪器的数据用于计算SLE响应者指数4(SRI-4)和基于不列颠群岛狼疮评估组的综合狼疮评估(BICLA)得分。
结果:第169天,安慰剂组的平均CLASI评分从基线变化为-5.7(±7.0),RSLV-132组为-6.2(±8.5)。针对BICLA和SRI-4反应,分析了具有中重度全身性疾病活动性和高基线SLEDAI评分(≥9)的参与者亚组。与安慰剂相比,高SLEDAI亚组的RSLV-132治疗参与者的BICLA反应百分比更高(62%vs44%)和SRI-4反应百分比(23%vs11%)。对具有高基线CLASI评分(≥21)的第二亚组参与者的BICLA和SRI-4反应进行分析。与安慰剂相比,高CLASI亚组的RSLV-132治疗参与者的BICLA反应百分比更高(28%vs8%)和SRI-4反应百分比(39%vs8%)。
结论:6个月的RSLV-132治疗包括每周负荷剂量的RSLV-132治疗1个月,在SLE患者队列中,每两周一次给药5个月后,与安慰剂组相比,CLASI平均评分没有显著改善.研究进入标准选择了中度至重度皮肤病活动性且无最低SLEDAI评分的患者,通过SLEDAI测量,导致广泛的全身性疾病活动从不活跃到严重。当分析SLEDAI和CLASI得分较高的参与者时,观察到有利于RSLV-132的临床改善趋势.结果值得对SLE中的RSLV-132进行进一步评估,并表明患有更活跃的全身性疾病的患者最有可能从RNase治疗中受益。
BACKGROUND: Circulating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132 is a catalytically active human RNase molecule fused to human IgG1 Fc designed to digest RNA and thereby decrease the chronic inflammation associated with SLE. The drug was evaluated in a cohort of patients with SLE with moderate-severe cutaneous disease activity and the presence of RNA immune complexes. The primary objective of the
study was the assessment of the impact of 13 doses of 10 mg/kg RSLV-132 over 6 months on the mean Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score.
METHODS: Sixty-five patients meeting the entry criteria of a baseline CLASI score of 10 or greater and positivity of at least one of five autoantibodies to RNA-binding proteins (SM/RNP, SSA/Ro, SSB/La, Sm, RNP) were randomly assigned (2:1) to receive 13 doses of RSLV-132 10 mg/kg or placebo, respectively. Participants received
study drug for 24 weeks on days 1, 8, 15, 29, 43, 57, 71, 85, 99, 113, 127, 141 and 155 with an end-of-treatment visit on day 169 and a follow-up visit at the end of the
study on day 215. The primary objective was assessed on days 85 and 169. Secondary objectives included assessment of systemic disease activity using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), the British Isles Lupus Assessment Group 2004 Index and the Physician\'s Global Assessment. Data from these instruments were used to calculate the SLE Responder Index 4 (SRI-4) and the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) scores.
RESULTS: The mean CLASI score change from baseline at day 169 was -5.7 (±7.0) in the placebo group and -6.2 (±8.5) in the RSLV-132 group. A subgroup of participants with moderate-severe systemic disease activity and high baseline SLEDAI scores (≥9) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high SLEDAI subgroup had a greater percentage of BICLA responses (62% vs 44%) and SRI-4 responses (23% vs 11%) as compared with placebo. A second subgroup of participants with high baseline CLASI scores (≥21) were analysed with respect to BICLA and SRI-4 responses. The RSLV-132 treated participants in the high CLASI subgroup had a greater percentage of BICLA responses (28% vs 8%) and SRI-4 responses (39% vs 8%) as compared with placebo.
CONCLUSIONS: Six months of RSLV-132 therapy consisting of a weekly loading dose of RSLV-132 for 1 month, followed by 5 months of biweekly administrations did not significantly improve the mean CLASI score relative to placebo in this cohort of patients with SLE. The
study entry criteria selected patients with moderate-severe cutaneous disease activity and no minimum SLEDAI score, which resulted in a wide range of systemic disease activity from inactive to severe as measured by SLEDAI. When the participants with higher SLEDAI and CLASI scores were analysed, a trend towards clinical improvement favouring RSLV-132 was observed. The results warrant further evaluation of RSLV-132 in SLE and suggest that patients with more active systemic disease are most likely to benefit from RNase therapy.