Donanemab in Early Symptomatic Alzheimer Disease

JAMA, Год журнала: 2023, Номер 330(6), С. 512 - 512

Опубликована: Июль 17, 2023

Importance There are limited efficacious treatments for Alzheimer disease. Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, Participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic disease (mild cognitive impairment/mild dementia) low/medium or high tau pathology based on positron emission tomography imaging from June 2020 November 2021 (last patient visit primary outcome April 2023). Interventions were randomized a 1:1 ratio receive donanemab (n = 860) placebo 876) intravenously every 4 weeks 72 weeks. the group switched blinded manner if dose completion criteria met. Main Outcomes Measures The was change integrated Disease Rating Scale (iADRS) score baseline 76 (range, 0-144; lower scores indicate greater impairment). 24 gated outcomes (primary, secondary, exploratory), including secondary sum boxes Clinical Dementia (CDR-SB) 0-18; higher Statistical testing allocated α .04 population outcomes, remainder (.01) combined outcomes. Results Among (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] 552 [31.8%] pathology), 1320 (76%) completed trial. Of 23 statistically significant. least-squares mean (LSM) iADRS at −6.02 (95% CI, −7.01 −5.03) −9.27 −10.23 −8.31) (difference, 3.25 [95% 1.88-4.62]; P < .001) −10.2 −11.22 −9.16) −13.1 −14.10 −12.13) 2.92 1.51-4.33]; population. LSM CDR-SB 1.20 1.00-1.41) 1.88 1.68-2.08) −0.67 −0.95 −0.40]; 1.72 1.53-1.91) 2.42 2.24-2.60) −0.7 −0.45]; Amyloid-related abnormalities edema effusion occurred 205 (24.0%; 52 symptomatic) 18 (2.1%; 0 during study) infusion-related reactions 74 (8.7%) (0.5%) placebo. Three deaths 1 considered treatment related. Conclusions Relevance pathology, significantly slowed clinical progression those Trial Registration ClinicalTrials.gov Identifier: NCT04437511

Язык: Английский

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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Язык: Английский

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Emerging diagnostics and therapeutics for Alzheimer disease

Nature Medicine, Год журнала: 2023, Номер 29(9), С. 2187 - 2199

Опубликована: Сен. 1, 2023

Язык: Английский

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Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease

New England Journal of Medicine, Год журнала: 2023, Номер 389(20), С. 1862 - 1876

Опубликована: Ноя. 15, 2023

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody highest affinity for aggregated Aβ has been tested treatment of Download PDF Research Summary. We conducted two phase 3 trials (GRADUATE I II) involving participants 50 90 years age mild impairment or dementia due disease evidence amyloid plaques on positron-emission tomography (PET) cerebrospinal fluid (CSF) testing. Participants were randomly assigned receive gantenerumab placebo every 2 weeks. The primary outcome was change from baseline score Clinical Dementia Rating scale–Sum Boxes (CDR-SB; range, 0 18, higher scores indicating greater impairment) at week 116. A total 985 980 enrolled GRADUATE II trials, respectively. CDR-SB 3.7 trial 3.6 trial. 116 3.35 3.65 (difference, –0.31; 95% confidence interval [CI], –0.66 0.05; P=0.10) 2.82 3.01 –0.19; CI, –0.55 0.17; P=0.30). At 116, difference level PET between group –66.44 –56.46 centiloids respectively, amyloid-negative status attained 28.0% 26.8% receiving trials. Across both had lower CSF levels phosphorylated tau 181 Aβ42 than those placebo; accumulation similar groups. Amyloid-related imaging abnormalities edema (ARIA-E) occurred 24.9% gantenerumab, symptomatic ARIA-E 5.0%. Among disease, use led plaque burden weeks but not associated slower clinical decline. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov numbers, NCT03444870 NCT03443973, respectively.) QUICK TAKE VIDEO SUMMARYGantenerumab Early Disease 02:01

Язык: Английский

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Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

BioDrugs, Год журнала: 2023, Номер 38(1), С. 5 - 22

Опубликована: Ноя. 13, 2023

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who proven β-amyloid pathology (Aβ). One these, has subsequently full other are poised positive review approval. Anti-amyloid mAbs share feature producing a marked reduction total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing cognitive decline achieved measurable plaque range 15–25 centiloids; trials agents that did not reach this threshold were benefit. differences terms titration schedules, MRI monitoring schedules amyloid-related imaging abnormalities (ARIA), continuing versus interrupted therapy. The approximate 30% observed is clinically meaningful extended integrity delay onset more severe dementia phases disease. Approval these initiates new era therapeutics disease-modifying properties. Further advances needed, i.e. greater efficacy, improved safety, enhanced convenience, better understanding ill-understood observations such as volume loss.

Язык: Английский

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Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update

Neurotherapeutics, Год журнала: 2023, Номер 20(4), С. 914 - 931

Опубликована: Июль 1, 2023

The amyloid cascade hypothesis is a useful framework for therapeutic development in Alzheimer's disease (AD). Amyloid b1-42 (Aβ) has been the main target of experimental therapies, based on evidence neurotoxic effects Aβ, and potential adverse brain Aβ burden detected humans vivo by positron emission tomography (PET). Progress passive anti-amyloid immunotherapy research includes identification antibodies that facilitate microglial activation, catalytical disaggregation, increased flow from cerebrospinal fluid (CSF) to plasma, thus decreasing Aβ. Recently completed phase 2 3 trials 3rd generation immunotherapies are supportive their clinical efficacy reducing preventing cognitive decline. Data recent implicate these agents as first effective disease-modifying therapies against AD led US Food Drug Administration (FDA) approval aducanumab lecanemab, under an accelerated pathway. modest, however, associated with amyloid-related imaging abnormalities (ARIA). Testing anti-Aβ pre-symptomatic populations more potent safer scope ongoing future research. Innovations trial design will be key efficient equitable novel immunotherapies. progress field therapeutics bring new clinical, logistical, ethical challenges, which pose revolutionize practice neurology, dementia care, preventive healthcare.

Язык: Английский

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Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Авг. 3, 2023

Alzheimer’s disease (AD) is the most common chronic neurodegenerative worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, mental symptoms, behavioral abnormalities; all of which place a significant psychological economic burden on patients’ families. No specific drugs are currently available for treatment AD, current AD only delay onset progression. The pathophysiological basis involves abnormal deposition beta-amyloid protein (Aβ), tau phosphorylation, decreased activity acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, multi-targets. US Food Drug Administration (FDA) has approved five clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, lecanemab. We have focused newer that undergone trials, not been successful result excessive side effects or poor efficacy. Although aducanumab received rapid approval from FDA 7 June 2021, its long-term safety tolerability require further monitoring confirmation. In this literature review, we aimed to explore possible mechanisms underlying occurrence development AD. anti-Aβ anti-tau drugs, mitochondria-targeting multi-targets, commercially bottlenecks encountered in drug development, targets therapeutic strategies future development. hope present new concepts methods therapies

Язык: Английский

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Alzheimer’s Disease: A Brief History of Immunotherapies Targeting Amyloid β

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3895 - 3895

Опубликована: Фев. 15, 2023

Alzheimer's disease (AD) is the most common form of dementia and may contribute to 60-70% cases. Worldwide, around 50 million people suffer from prediction that number will more than triple by 2050, as population ages. Extracellular protein aggregation plaque deposition well accumulation intracellular neurofibrillary tangles, all leading neurodegeneration, are hallmarks brains with disease. Therapeutic strategies including active passive immunizations have been widely explored in last two decades. Several compounds shown promising results many AD animal models. To date, only symptomatic treatments available because alarming epidemiological data, novel therapeutic prevent, mitigate, or delay onset required. In this mini-review, we focus on our understanding pathobiology discuss current immunomodulating therapies targeting amyloid-β protein.

Язык: Английский

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Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis

The Annals of Family Medicine, Год журнала: 2024, Номер 22(1), С. 50 - 62

Опубликована: Янв. 1, 2024

PURPOSE

We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

METHODS

searched PubMed, Cochrane CENTRAL, 5 trial registries, as well the reference lists identified studies. included randomized controlled trials comparing antibody placebo at dose consistent that used phase 3 or for Food Drug Administration approval. Studies had report least 1 relevant benefit harm. Data were extracted independently by 2 researchers random effects meta-analysis. Changes cognitive functional scales compared between groups, each difference was assessed determine if it met minimal important (MCID).

RESULTS

19 publications 23,202 total participants evaluated 8 anti-amyloid antibodies. There small improvements over Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 -14 score (standardized mean = −0.07; 95% CI, −0.10 −0.04), Mini Mental State Examination (0.32 points; 0.13 0.50), Clinical Dementia Rating-Sum Boxes scale (mean =−0.18 −0.34 −0.03), combined scores 0.09; 0.05 0.13). None changes, including those lecanemab, aducanumab, donanemab, exceeded MCID. Harms significantly increased risks amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] 10.29; number needed harm [NNH] 9), ARIA-hemorrhage (RR 1.74; NNH 13), symptomatic ARIA-edema 24.3; 86).

CONCLUSIONS

Although provide on dementia, these are far below MCID outcome accompanied harms.

Язык: Английский

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The neuroprotective effects of targeting key factors of neuronal cell death in neurodegenerative diseases: The role of ER stress, oxidative stress, and neuroinflammation

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 6, 2023

Neuronal loss is one of the striking causes various central nervous system (CNS) disorders, including major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), and Amyotrophic lateral sclerosis (ALS). Although these diseases have different features clinical manifestations, they share some common mechanisms pathology. Progressive regional neurons in patients responsible for motor, memory, cognitive dysfunctions, leading to disabilities death. cell death linked pathways conditions. Protein misfolding aggregation, mitochondrial dysfunction, generation reactive oxygen species (ROS), activation innate immune response are most critical hallmarks diseases. Thus, endoplasmic reticulum (ER) stress, oxidative neuroinflammation pathological factors neuronal Even though exact not fully discovered, notable role mentioned well known. On this basis, researchers been prompted investigate neuroprotective effects targeting underlying determine a promising therapeutic approach treatment. This review provides an overview ER death, mainly discussing or molecules involved factors.

Язык: Английский

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