背景:C9orf72的六核苷酸重复扩增是肌萎缩侧索硬化症(ALS)的常见遗传原因。没有C9orf72靶向治疗可用。BIIB078是靶向C9orf72有义RNA的研究性反义寡核苷酸。我们的目的是评估安全性,耐受性,和BIIB078在C9orf72相关ALS参与者中的药代动力学。
方法:这项第一阶段随机对照试验在六个国家的22个地点进行(加拿大,爱尔兰,荷兰,瑞士,英国,和美国)。在六个队列中随机分配了患有ALS和C9orf72中致病性重复扩增的成年人,通过交互式响应技术,每个队列的比例为3:1,接受BIIB078(5毫克,10毫克,20毫克,35毫克,60mg,或队列1-6分别为90毫克)或安慰剂,通过鞘内推注。治疗期包括三个负荷剂量的研究治疗,大约每2周给药一次,随后在队列1-3约3个月和队列4-6约6个月的治疗期内每月维持剂量。患者和研究者对治疗分配进行了掩盖。主要终点是不良事件和严重不良事件的发生率。本试验已在ClinicalTrials.gov(NCT03626012)注册并已完成。
结果:在2018年9月10日至2021年11月17日之间,筛选了124名患者纳入研究。18名患者被排除在外,106名参与者被纳入并随机分配接受5mg(n=6),10毫克(n=9),20毫克(n=9),35毫克(n=19),60毫克(n=18),或90毫克(n=18)的BIIB078,或安慰剂(n=27)。106例患者中58例(55%)为女性。所有患者接受至少一个剂量的研究治疗,并包括在所有分析中。所有参与者至少有一个不良事件;大多数不良事件的严重程度为轻度或中度,并没有导致治疗中断。BIIB078治疗的参与者中最常见的不良事件是跌倒,程序性疼痛,头痛,和腰椎穿刺后综合征.接受任何剂量BIIB078的79例患者中有14例(18%)报告了严重不良事件,与接受安慰剂的27例患者中的9例(33%)相比。5名接受BIIB078的参与者和3名接受安慰剂的参与者出现了致命的不良事件:一名接受10mgBIIB078的参与者出现呼吸衰竭,两名接受35mgBIIB078的参与者出现ALS恶化,一名接受35mgBIIB078的参与者出现创伤性脑出血,一名接受60mgBIIB078的参与者出现肺栓塞,三名接受安慰剂的参与者出现呼吸衰竭。报告研究者评估所有死亡与研究治疗无关。
结论:根据这些第一阶段研究结果,包括次要和探索性发现,相对于安慰剂队列,神经丝水平没有降低,对临床结局没有益处,BIIB078临床开发已停止。然而,这些结果将有助于我们进一步了解C9orf72相关ALS的复杂病理生物学.
背景:Biogen.
BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS.
METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed.
RESULTS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator.
CONCLUSIONS: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS.
BACKGROUND: Biogen.