WS05.04Comparison of preclinical and preliminary clinical safety profile of SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C -> T mutation, supporting an ongoing Phase 2 study

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.519

L. Friedman , E. Ozeri-Galai , A. Cohen , G. Hart , Y. Caraco , M. Wanounou , E. Kerem

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Abstract

Background

SpliSense is developing SPL84, an inhaled ASO for the treatment of pwCF carrying the 3849 +10kb C->T (3849) mutation. SPL84 fully restored CFTR function in patient-derived HNEs and HBEs. Preclinical toxicology studies in mice and monkeys and a Phase 1 study in healthy volunteers (HVs) were conducted to support the ongoing Phase 2 study in 3849 pwCF.

Methods

In the preclinical toxicology studies, SPL84 was given via inhalation once a week for 9 weeks to mice and monkeys at dose levels of up to 54.4 mg/kg/week and 20.8 mg/kg/week, respectively. In the Phase 1 study, 32 subjects received a single inhaled dose of SPL84 at either 20, 40, 80, 160 mg or placebo (n=8 per cohort; 3:1 active:placebo). The primary objective was to evaluate the safety and tolerability of SPL84, and the secondary objective was to characterize the pharmacokinetics of SPL84.

Results

No SPL84-related clinical signs were observed in the preclinical toxicology studies. All of the microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled material. Systemic exposure in both species was low and the no observed adverse effect level for mice and monkeys was 54.4 and 20.8 mg/kg/week, respectively, which provided sufficient safety margins for the Phase 1 clinical doses.

SPL84 was well tolerated in the Phase 1 HV study, with no significant SPL84-related adverse events, and no significant effect on vital signs, clinical laboratory values, electrocardiogram, physical examination, or pulmonary function. Systemic exposure of SPL84 was low, as expected for an inhaled product, and tended to be dose dependent.

Conclusions

The safety and systemic exposure profile of SPL84 is similar across species (mice, monkeys, and humans). The preclinical and clinical safety profile of SPL84 is promising, with no clinical signs as well as low systemic exposure. This supported the initiation of an ongoing global Phase 2 study for the treatment of 3849 pwCF.

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用于治疗携带3849 +10 Kb C -> T突变的CF患者的ASO SPL84的临床前和初步临床安全性比较，支持正在进行的2期研究

splisense正在开发SPL84，一种用于治疗携带3849 +10kb C->；T（3849）突变的pwCF的吸入ASO。SPL84完全恢复了患者源性hne和HBEs的CFTR功能。为了支持3849 pwCF正在进行的2期研究，在小鼠和猴子身上进行了临床前毒理学研究，并在健康志愿者（HVs）身上进行了1期研究。方法在临床前毒理学研究中，小鼠和猴子分别以高达54.4 mg/kg/周和20.8 mg/kg/周的剂量，每周一次吸入SPL84，持续9周。在1期研究中，32名受试者接受单次吸入剂量的SPL84，剂量分别为20、40、80、160 mg或安慰剂(n=8 /队列；3:1活跃:安慰剂)。主要目的是评价SPL84的安全性和耐受性，次要目的是表征SPL84的药代动力学。结果临床前毒理学研究未发现与spl84相关的临床体征。所有肺部的显微镜变化都被认为是非不良的，反映了吸入物质的正常清除过程。两种动物的全身暴露量都很低，小鼠和猴子的未观察到的不良反应水平分别为54.4毫克/公斤/周和20.8毫克/公斤/周，这为1期临床剂量提供了足够的安全边际。在1期HV研究中，SPL84耐受性良好，没有明显的SPL84相关不良事件，对生命体征、临床实验室值、心电图、体格检查或肺功能没有显著影响。SPL84的全身暴露量很低，与预期的吸入产品一样，并且倾向于剂量依赖。结论SPL84的安全性和全身暴露特征在不同物种（小鼠、猴子和人类）中是相似的。SPL84的临床前和临床安全性很有希望，没有临床症状，全身暴露率低。这支持了一项正在进行的治疗3849 pwCF的全球2期研究的启动。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.