Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic ...interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid‐ß (Aß) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The Aß peptide is central to the pathogenesis, and immunotherapy against Aß has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti‐amyloid immunotherapy remains one of the most promising emerging strategies for developing disease‐modifying treatments for AD. In this review, we examine the presently ongoing Aß‐directed immunotherapies that have passed clinical development Phase IIa.
LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 ...weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.
Treatments that are designed to reduce Alzheimer’s disease (AD) pathology may be most useful when given to subjects prior to a diagnosis of AD using current diagnostic criteria. These earlier ...patients may have early cognitive losses consistent with mild cognitive impairment (MCI) or may be completely asymptomatic. Screening and treatment programs for other disease states have been explored previously; these include cholesterol screening for cardiovascular disease, genetic screening for Huntington’s disease and screening for some types of cancer. Cancer screening and treatment programs have been developed for colon cancer, breast cancer and prostate cancer. Screening programs for these other disease states are briefly reviewed and are compared to preliminary modeling data describing a hypothetical screening and treatment program for AD. While primary prevention based on screening of asymptomatic individuals using biomarkers has broad appeal, secondary prevention employing treatment of patients with MCI may be more easily implemented.
Accurate understanding of practice characteristics, performance stability, and error on neuropsychological tests is essential to both valid clinical assessment and maximization of signal detection ...for clinical trials of cognitive enhancing drugs. We examined practice effects in 28 healthy adults. As part of a larger study using donepezil and simulating a Phase I trial, participants were randomized into: placebo, no-treatment and donepezil. Donepezil results are presented elsewhere. Neuropsychological tests were administered in a fixed order for 6 weeks, with alternate forms available for most tests. Despite alternate forms, ANOVAs revealed significant improvements for the pooled control group (placebo and no-treatment) on all tests except Letter Number Sequencing and Trails B. Learning occurred principally in the first three to four sessions. PASAT and Stroop interference showed the greatest learning. Thus, serial assessment with alternate forms may attenuate retest effects on some tests, but continued learning occurs on novel tests or those in which an advantageous test-taking strategy can be identified. Alternate forms and baseline practice sessions may help control early, rapid improvements in clinical trials.
The Ups and Downs of Amyloid in Alzheimer's Siemers, E; Aisen, P S; Carrillo, M C
The journal of prevention of Alzheimer's disease,
01/2022, Letnik:
9, Številka:
1
Journal Article
Alzheimer's disease is a large and growing unmet medical need. Clinical trial designs need to assess disease-related outcomes earlier to accelerate the development of better treatments for ...Alzheimer's disease. ACU193 is a monoclonal antibody that selectively targets amyloid β oligomers, thought to be the most toxic species of Aβ that accumulates early in AD and contributes to downstream pathological effects. Nonclinical data indicate that ACU193 can reduce the toxic effects of amyloid β oligomers. ACU193 is currently being investigated in a phase 1 clinical trial designed with the properties described in this report. This phase 1 trial is designed to provide data to enable a go/no-go decision regarding the initiation of a subsequent phase 2/3 study.
To design a phase 1 study that assesses target engagement and incorporates novel measures to support more rapid development of a potential disease-modifying treatment for Alzheimer's disease.
The INTERCEPT-AD trial for ACU193 is an ongoing randomized, placebo-controlled phase 1a/b study that assesses safety, tolerability, pharmacokinetics, target engagement, clinical measures, and several Alzheimer's disease biomarkers, including novel digital and imaging biomarkers.
For INTERCEPT-AD, brief inpatient stays for patients in the single ascending dose portion of the study, with the remainder of the evaluations being performed as outpatients at multiple clinical trial sites in the U.S.
Patients with early Alzheimer's disease (mild cognitive impairment or mild dementia with a positive florbetapir positron emission tomography scan).
ACU193 administered intravenously at doses of 2- 60 mg/kg.
Safety assessments including magnetic resonance imaging for the presence of amyloid-related imaging abnormalities, clinical assessments for Alzheimer's disease including the Alzheimer's Disease Rating Scale-cognition and Clinical Dementia Rating scale, pharmacokinetics, a measure of target engagement, and digital and imaging biomarkers, including a computerized cognitive test battery and a measure of cerebral blood flow using arterial spin labelling magnetic resonance imaging.
A phase 1 study design was developed for ACU193 that allows collection of data that will enable a go/no-go decision for initiation of a subsequent adaptive phase 2/3 study.
A phase 1a/b trial and an overall clinical development plan for an Alzheimer's disease treatment can be designed that maintains patient safety, allows informed decision-making, and achieves an accelerated timeline by using novel biomarkers and adaptive study designs.
Alzheimer's disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of ...soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.
We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).
A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.
Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665 .).
The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - ...instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.
Current treatment options for Alzheimer's disease (AD) are limited to medications that reduce dementia symptoms. Given the rapidly ageing populations in most areas of the world, new therapeutic ...interventions for AD are urgently needed. In recent years, a number of drug candidates targeting the amyloid-ss (A ss) peptide have advanced into clinical trials; however, most have failed because of safety issues or lack of efficacy. The A ss peptide is central to the pathogenesis, and immunotherapy against A ss has attracted considerable interest. It offers the possibility to reach the target with highly specific drugs. Active immunization and passive immunization have been the most widely studied approaches to immunotherapy of AD. A favourable aspect of active immunization is the capacity for a small number of vaccinations to generate a prolonged antibody response. A potential disadvantage is the variability in the antibody response across patients. The potential advantages of passive immunotherapy include the reproducible delivery of a known amount of therapeutic antibodies to the patient and rapid clearance of those antibodies if side effects develop. A disadvantage is the requirement for repeated infusions of antibodies over time. After more than a decade of research, anti-amyloid immunotherapy remains one of the most promising emerging strategies for developing disease-modifying treatments for AD. In this review, we examine the presently ongoing A ss-directed immunotherapies that have passed clinical development Phase IIa.
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