Donanemab in Early Alzheimer’s Disease Mintun, Mark A; Lo, Albert C; Duggan Evans, Cynthia ...
The New England journal of medicine,
05/2021, Letnik:
384, Številka:
18
Journal Article
Recenzirano
Odprti dostop
A phase 2 trial of donanemab, an antibody that targets amyloid deposited in the brain, showed a better composite score for cognition and for the ability to perform activities of daily living than ...placebo at 76 weeks in patients with early Alzheimer’s disease. Results for secondary outcomes were generally similar in the two trial groups.
The Centers for Medicare & Medicaid Services (CMS) established a class‐based National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for Alzheimer's disease (AD) with ...patient access through Coverage with Evidence Development (CED) based on three questions. This review, focused on donanemab, answers each of these CED questions with quality evidence. TRAILBLAZER‐ALZ registration trials are presented with supporting literature and real‐world data to answer CED questions for donanemab. TRAILBLAZER‐ALZ registration trials demonstrated that donanemab significantly slowed cognitive and functional decline in amyloid‐positive early symptomatic AD participants, and lowered their risk of disease progression while key safety risks occurred primarily within the first 6 months and then declined. Donanemab meaningfully improved health outcomes with a manageable safety profile in an early symptomatic AD population, representative of Medicare populations across diverse practice settings. The donanemab data provide the necessary level of evidence for CMS to open a reconsideration of their NCD.
Highlights
Donanemab meaningfully improved outcomes in trial participants with early symptomatic Alzheimer's disease.
Comorbidities in trial participants were consistent with the Medicare population.
Co‐medications in trial participants were consistent with the Medicare population.
Risks associated with treatment tended to occur in the first 6 months.
Risks of amyloid‐related imaging abnormalities were managed with careful observation and magnetic resonance imaging monitoring.
IMPORTANCE: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic ...improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. OBJECTIVE: To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. DESIGN, SETTING, AND PARTICIPANTS: AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. INTERVENTIONS: Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. RESULTS: Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. CONCLUSIONS AND RELEVANCE: Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573
Introduction
The APECS and AMARANTH trials showed that beta‐secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or ...early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported.
Methods
APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double‐blind, placebo‐controlled, parallel‐group, 104‐week clinical trials conducted by different sponsors. Measures included the 3‐Domain Composite Cognition Score (CCS‐3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding.
Results
Verubecestat showed worsening on the CCS‐3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency.
Discussion
In both studies, many measures showed treatment‐associated cognitive worsening, whereas verbal fluency tasks showed improvement.
Introduction
The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to ...enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS.
Methods
Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor‐based, distribution‐based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating—Sum of Boxes, Mini‐Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia.
Results
All three anchors met criteria for “sufficiently associated” (|r| = 0.4–0.7). Cumulatively, results from anchor‐based and distribution‐based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values.
Discussion
These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression.
Introduction
An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS).
Methods
Data from 3483 placebo participants ...in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD.
Results
Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini‐Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression.
Discussion
These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation.
Highlights
A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease.
Using the linear regression model, iADRS scores can be calculated for Mini‐Mental State Examination scores.
Results can help optimize future clinical trial design and aid in understanding treatment effects.
•Over 99% of all Alzheimer’s disease drug trials reported negative results.•Go/No-Go decision making in clinical Alzheimer’s trials remains challenging.•Cognitive data might provide insights at ...various points during drug development.•This review describes ways of utilizing cognitive data for Go/No-Go decisions.
Go/No-Go decision making in early phase clinical trials is challenging for drug developers working in Alzheimer’s disease. Recent negative trial results have been attributed to a lack of efficacy and important safety concerns. Furthermore, demonstrated target engagement has rarely translated into demonstrable clinical efficacy. Cognitive data might provide valuable insights at various points during drug development, and a thoughtful and robust set of decision-making criteria, specified a priori, can and should be applied under many circumstances. This review provides insights into how to utilize cognitive data for Go/No-Go decisions, with an emphasis on how these cognitive criteria differ depending on the context (e.g., stage of development, mechanism of action and trial design).
Individuals with type 1 diabetes show mild performance deficits in a range of neuropsychological tests compared to healthy controls, but the mechanisms underlying this cognitive deterioration are ...still poorly understood. Basically, two diabetes-related mechanisms can be postulated: recurrent severe hypoglycaemia and/or chronic hyperglycaemia. Intensive insulin therapy in type 1 diabetes, resulting in a durable improvement of glycaemic control, has been shown to lower the risk of long-term microvascular and macrovascular complications. The down side of striving for strict glycaemic control is the considerably elevated risk of severe hypoglycaemia, sometimes leading to seizure or coma. While retrospective studies in adult patients with type 1 diabetes have suggested an association between a history of recurrent severe hypoglycaemia and a modest or even severe degree of cognitive impairment, large prospective studies have failed to confirm this association. Only fairly recently, better appreciation of the possible deleterious effects of chronic hyperglycaemia on brain function and structure is emerging. In addition, it can be hypothesized that hyperglycaemia associated microvascular changes in the brain are responsible for the cognitive decline in patients with type 1 diabetes. This review presents various pathophysiological considerations concerning the cognitive decline in patients with type 1 diabetes.
To provide relevant background of the Integrated Alzheimer's Disease Rating Scale (iADRS), with examples, to assist the reader with the interpretation of iADRS findings from the TRAILBLAZER-ALZ ...study.
The iADRS is an integrated measure of global Alzheimer disease (AD) severity for use in the clinical trial environment. It provides a single score that captures commonalities across cognitive and functional ability domains, reflecting disease-related impairment, while minimizing noise not related to disease progression that may exist within each domain. In AD, disease-modifying therapies (DMTs) are expected to slow the rate of clinical decline, changing the trajectory of disease progression. The overall percent slowing of disease progression with treatment is a more informative outcome of effect than absolute point differences between treatment and placebo groups at any given time point because the latter is influenced by treatment period and disease severity. The TRAILBLAZER-ALZ trial was a phase 2 study designed to evaluate the safety and efficacy of donanemab in participants with early symptomatic AD; the primary outcome measure was the change from baseline to 76 weeks on the iADRS. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months (
= 0.04 vs placebo), demonstrating clinical efficacy. At the patient level, one can assess whether the DMT effect is clinically meaningful by estimating the threshold of change consistent with clinically meaningful worsening; based on the TRAILBLAZER-ALZ findings, treatment with donanemab would delay reaching this threshold by approximately 6 months.
The iADRS is capable of accurately describing clinical changes associated with disease progression and detecting treatment effects and is an effective assessment tool for use in clinical trials of individuals with early symptomatic AD.
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