Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Lancet Neurology Pub Date : 2024-09-01 Epub Date: 2024-07-23 DOI:10.1016/S1474-4422(24)00216-3
Leonard H van den Berg, Jeffrey D Rothstein, Pamela J Shaw, Suma Babu, Michael Benatar, Robert C Bucelli, Angela Genge, Jonathan D Glass, Orla Hardiman, Vincenzo Libri, Theodore Mobach, Björn Oskarsson, Gary L Pattee, John Ravits, Christopher E Shaw, Markus Weber, Lorne Zinman, Paymaan Jafar-Nejad, Frank Rigo, Luan Lin, Toby A Ferguson, Anthony L Gotter, Danielle Graham, Michael Monine, Jennifer Inra, Susie Sinks, Satish Eraly, Steve Garafalo, Stephanie Fradette
{"title":"Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study.","authors":"Leonard H van den Berg, Jeffrey D Rothstein, Pamela J Shaw, Suma Babu, Michael Benatar, Robert C Bucelli, Angela Genge, Jonathan D Glass, Orla Hardiman, Vincenzo Libri, Theodore Mobach, Björn Oskarsson, Gary L Pattee, John Ravits, Christopher E Shaw, Markus Weber, Lorne Zinman, Paymaan Jafar-Nejad, Frank Rigo, Luan Lin, Toby A Ferguson, Anthony L Gotter, Danielle Graham, Michael Monine, Jennifer Inra, Susie Sinks, Satish Eraly, Steve Garafalo, Stephanie Fradette","doi":"10.1016/S1474-4422(24)00216-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>Biogen.</p>","PeriodicalId":17989,"journal":{"name":"Lancet Neurology","volume":null,"pages":null},"PeriodicalIF":46.5000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lancet Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/S1474-4422(24)00216-3","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

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.

Findings: 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.

Interpretation: 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.

Funding: Biogen.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
反义寡核苷酸 BIIB078 在 C9orf72 相关肌萎缩性脊髓侧索硬化症成人患者中的安全性、耐受性和药代动力学:1 期随机、双盲、安慰剂对照、多剂量递增研究。
背景:C9orf72 的六核苷酸重复扩增是肌萎缩性脊髓侧索硬化症(ALS)的常见遗传病因。目前还没有针对 C9orf72 的治疗方法。BIIB078是一种靶向C9orf72有义RNA的研究性反义寡核苷酸。我们旨在评估BIIB078在C9orf72相关ALS患者中的安全性、耐受性和药代动力学:这项 1 期随机对照试验在 6 个国家(加拿大、爱尔兰、荷兰、瑞士、英国和美国)的 22 个地点进行。患有肌萎缩性脊髓侧索硬化症且C9orf72存在致病性重复扩增的成年人通过互动反应技术以3:1的比例被随机分配到六个队列中,通过鞘内注射的方式接受BIIB078(1-6队列中分别为5毫克、10毫克、20毫克、35毫克、60毫克或90毫克)或安慰剂治疗。治疗期间,1-3 组患者大约每 2 周接受一次 3 次负荷剂量的研究治疗,然后在大约 3 个月的治疗期内每月接受一次维持剂量的治疗,4-6 组患者大约在 6 个月的治疗期内每月接受一次维持剂量的治疗。患者和研究人员对治疗分配均蒙面。主要终点是不良事件和严重不良事件的发生率。该试验已在ClinicalTrials.gov(NCT03626012)注册,目前已完成:2018年9月10日至2021年11月17日期间,共筛选出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5毫克(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名患者中有58名(55%)为女性。所有患者都接受了至少一个剂量的研究治疗,并纳入所有分析。所有参与者都至少出现过一次不良事件;大多数不良事件的严重程度为轻度或中度,不会导致治疗中断。BIIB078治疗参与者最常见的不良事件是跌倒、手术疼痛、头痛和腰椎穿刺后综合征。79名接受任何剂量BIIB078治疗的患者中有14人(18%)报告了严重不良事件,而27名接受安慰剂治疗的患者中有9人(33%)报告了严重不良事件。5名接受BIIB078治疗的患者和3名接受安慰剂治疗的患者出现了致命不良事件:1名接受10毫克BIIB078治疗的患者出现呼吸衰竭,2名接受35毫克BIIB078治疗的患者出现ALS恶化,1名接受35毫克BIIB078治疗的患者出现外伤性脑内出血,1名接受60毫克BIIB078治疗的患者出现肺栓塞,3名接受安慰剂治疗的患者出现呼吸衰竭。所有死亡病例均被报告研究者评估为与研究治疗无关:根据这些1期研究结果,包括次要和探索性研究结果显示神经丝蛋白水平没有降低,而且与安慰剂组相比,BIIB078对临床结果没有益处,因此已停止BIIB078的临床开发。不过,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:资金来源:Biogen。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
期刊最新文献
On how a brain beholds beauty. Equitable access to levetiracetam for people with epilepsy. Evobrutinib in multiple sclerosis: challenges and unmet goals. Frailty for neurologists: perspectives on how frailty influences care planning. Learning to be an adult with a disability.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1