由护理伙伴在家中为早期阿尔茨海默病患者注射甘特纳单抗:可行性、安全性和药效学影响

Frank G. Boess, M. A. Scelsi, T. Grimmer, R. J. Perry, M. Tonietto, G. Klein, C. Hofmann, M. Salami, J. Wojtowicz, C. J. Lansdall, C. Lane, G. A. Kerchner, J. Smith, R. S. Doody
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引用次数: 0

摘要

背景以淀粉样蛋白-β为靶点并清除淀粉样蛋白斑块的单克隆抗体可减缓早期阿尔茨海默氏症患者的认知和功能衰退。Gantenerumab是一种皮下注射的全人源抗淀粉样蛋白-β单克隆抗体,对聚集的淀粉样蛋白-β具有最高的亲和力。由于 3 期 GRADUATE 试验未达到主要终点(临床痴呆评分量表-方框总和从基线到第 116 周的变化),Gantenerumab 在散发性阿尔茨海默病领域的开发已停止,所有正在进行的试验也因赞助商的决定而提前终止。为了提高灵活性并减轻总体负担,在诊所或由护理伙伴在家进行皮下注射将成为该类其他疗法的重要选择。目标评估每周一次皮下注射甘特奈鲁单抗对脑淀粉样蛋白负荷的药效学影响,以及由护理伙伴在家给药的安全性和可行性。设计2期、开放标签、单臂研究。参与者年龄在50至90岁之间,患有早期症状性阿尔茨海默病(轻度认知障碍/阿尔茨海默病导致的轻度痴呆),且有证据表明淀粉样蛋白正电子发射断层扫描呈阳性。干预措施参与者可接受最多255毫克的甘特瑞单抗,每周一次,由医疗保健专业人员或非医疗保健专业护理伙伴在现场或家中皮下注射。次要终点是对家庭管理问卷的答复、血浆浓度和安全性。结果参加研究的总人数为 192 人,基线时淀粉样蛋白 PET 负荷的平均值(标准差)为 101.80 (29.80) centiloids。在申办者提前终止研究时,149名参与者拥有第52周有效的淀粉样蛋白PET数据(主要终点),12名参与者的提前终止PET在第104周的预定时间范围内。从基线到第52周和第104周,淀粉样蛋白PET的平均变化分别为-26.19厘立德(范围:-75.6-15.8;n=149)和-35.48厘立德(范围:-63.2--7.0;n=12)。第 52 周的居家用药问卷调查(样本数=148)显示,大多数护理伙伴(88%-97%)认为居家用药容易(30.4%)或非常容易(57.4%),方便(25.7%)或非常方便(70.9%)。护理伙伴对在家注射有信心(31.1%)或非常有信心(62.2%),满意(29.7%)或非常满意(64.9%)。护理伙伴在第 36 周(72 人)、第 76 周(126 人)和第 104 周(29 人)的反应以及参与者(患者)在这些时间点对方便性和满意度的评价相似。结论由非医疗保健专业护理伙伴为早期阿尔茨海默病参与者每周一次皮下注射抗淀粉样蛋白-β抗体甘特纳鲁单抗是可行的、安全的、耐受性良好的,护理伙伴和阿尔茨海默病参与者都认为这是一种方便的选择。虽然 gantenerumab 的开发因缺乏疗效而停止,但这种方法有可能减少其他抗淀粉样蛋白-β 抗体治疗所需的医院/门诊就诊次数,并能提高阿尔茨海默病患者及其家人用药的灵活性。
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At-home Administration of Gantenerumab by Care Partners to People with Early Alzheimer’s Disease: Feasibility, Safety and Pharmacodynamic Impact

Background

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer’s disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale–Sum of Boxes), development of gantenerumab in sporadic Alzheimer’s disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies.

Objectives

To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners.

Design

Phase 2, open-label, single arm study.

Setting

Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023.

Participants

Participants aged 50 to 90 with early symptomatic Alzheimer’s disease (mild cognitive impairment/ mild dementia due to Alzheimer’s disease), and evidence of amyloid positron emission tomography positivity.

Intervention

Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners.

Measurements

The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety.

Results

The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was −26.19 centiloids (range: −75.6–15.8; n=149) and −35.48 centiloids (range: −63.2–−7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88–97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners.

Conclusions

Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer’s disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer’s disease. Although gantenerumab’s development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer’s disease and their families.

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来源期刊
The Journal of Prevention of Alzheimer's Disease
The Journal of Prevention of Alzheimer's Disease Medicine-Psychiatry and Mental Health
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9.20
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期刊介绍: The JPAD Journal of Prevention of Alzheimer’Disease will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including: neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.We hope that JPAD with your contribution will play a role in the development of Alzheimer prevention.
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