Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial

Randall J Bateman, Yan Li, Eric M McDade, Jorge J Llibre-Guerra, David B Clifford, Alireza Atri, Susan L Mills, Anna M Santacruz, Guoqiao Wang, Charlene Supnet, Tammie L S Benzinger, Brian A Gordon, Laura Ibanez, Gregory Klein, Monika Baudler, Rachelle S Doody, Paul Delmar, Geoffrey A Kerchner, Tobias Bittner, Jakub Wojtowicz, Peter R Schofield
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The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.<h3>Methods</h3>The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure <sup>11</sup>C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. 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引用次数: 0

Abstract

Background

Amyloid plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.

Methods

The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure 11C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with ClinicalTrials.gov.

Findings

Of 74 participants who were recruited into the OLE study between June 3, 2020, and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons; 13 people completed 3 years of treatment. The mITT group for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0·79 (n=53 [95% CI 0·47 to 1·32]) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0·53 (n=22 [0·27 to 1·03]) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was –0·71 SUVR (95% CI –0·88 to –0·53, p<0·0001). Amyloid-related imaging abnormalities occurred in 53% (39 of 73) of participants: 47% (34 of 73) with microhaemorrhages, 30% (22 of 73) with oedema, and 6% (five of 73) were associated with superficial siderosis. No treatment-associated macrohaemorrhages or deaths occurred.

Interpretation

Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Our conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long-term trials.

Funding

National Institute on Aging, Alzheimer's Association, GHR Foundation, and F Hoffmann-La Roche/Genentech.
gantenerumab长期治疗显性遗传性阿尔茨海默病的安全性和有效性:2/3期多中心、随机、双盲、安慰剂对照平台DIAN-TU试验的开放标签扩展
背景:单克隆抗体疗法去除髓样斑块可减缓症状性阿尔茨海默病的临床进展;然而,在无症状人群中延迟临床症状发作的可能性尚不清楚。显性遗传性阿尔茨海默病网络试验单元(DIAN-TU)是一项正在进行的平台试验,评估多种研究产品在显性遗传性阿尔茨海默病(DIAD)患者中的安全性和有效性。基于平台试验中gantenerumab组的淀粉样蛋白去除和下游生物学效应的发现,我们继续进行了一项为期3年的开放标签扩展(OLE)研究,以评估高剂量gantenerumab长期治疗的安全性和有效性。方法:随机、安慰剂对照、双盲、2/3期多组试验(DIAN-TU-001)评估了solanezumab或gantenerumab与安慰剂在症状出现前15年至10年之间,临床痴呆评分(CDR)总体评分为0(认知正常)至1(轻度痴呆)的参与者中的效果。在这项研究之后,在澳大利亚、加拿大、法国、爱尔兰、波多黎各、西班牙、英国和美国的18个研究地点进行了一项关于gantenerumab治疗的OLE研究。为了纳入OLE,有DIAD风险的参与者已经参加了DIAN-TU-001的双盲期,并被要求知道他们的突变状态。我们研究了每2周增加皮下给药剂量至1500mg。由于gantenerumab缺乏监管途径,该研究在预先指定的临床测量CDR-Sum of Boxes (CDR-SB)的中期分析(当大多数参与者完成2年治疗时)后提前停止。最终分析的主要结果是淀粉样斑块测量3年11c -匹兹堡化合物- b正电子发射断层扫描(PiB-PET)标准化摄取值比(SUVR [PiB-PET SUVR]),在改良意向治疗组(mITT;定义为在ole基线后接受任何gantenerumab治疗的参与者,在gantenerumab治疗前至少进行一次PiB-PET SUVR评估,以及基线后评估)。所有在OLE中接受至少一剂研究药物的参与者都被纳入安全性分析。DIAN-TU-001 (NCT01760005)和OLE (NCT06424236)已在clinicaltrials .gov.注册。研究结果:在2020年6月3日至2021年4月22日期间招募的74名参与者中,73名参与者入组并接受了更纳单抗治疗。47例(64%)因申办者提前终止研究而停止给药,13例(18%)因其他原因过早停止研究;13人完成了3年的治疗。初步分析的mITT组包括55名参与者。在中期分析中,无症状突变携带者CDR-SB临床下降的风险比在双盲期或OLE期(Any Gant)中接受genantenerumab治疗的参与者(Any Gant)为0.79 (n=53 [95% CI 0.47至1.32]),在接受genantenerumab治疗时间最长的参与者(longest Gant)中为0.53 (n=22[0.27至1.03])。在最终分析中,PiB-PET SUVR从OLE基线到第3年的调整平均变化为- 0.71 SUVR (95% CI - 0.88至- 0.53,p< 0.0001)。淀粉样蛋白相关的影像学异常发生在53%(73人中有39人)的参与者中:47%(73人中有34人)出现微出血,30%(73人中有22人)出现水肿,6%(73人中有5人)出现浅表性铁沉着。无治疗相关大出血或死亡发生。解释:部分或短期淀粉样蛋白去除没有显着的临床效果。然而,长期完全去除淀粉样蛋白可能会延迟症状的发作和痴呆的进展。由于OLE设计和外部控制的使用,我们的结论是有限的,需要在长期试验中得到证实。资助:国家老龄研究所,阿尔茨海默病协会,GHR基金会,霍夫曼罗氏/基因泰克。
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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