INTRODUCTION:TRAILBLAZER-ALZ 3 is investigating donanemab in preclinical Alzheimer's disease (AD). METHODS:This double-blind, placebo-controlled trial used a plasma phosphorylated tau-217 (p-tau217) assay to detect AD pathology for eligibility and a decentralized design to enhance screening and enrollment. After nine monthly infusions, clinical assessments continue every 6 months with a time-to-event primary outcome. A sub-study will evaluate longitudinal changes in amyloid and tau positron emission tomography (PET). RESULTS:Participants 55-80 years of age were screened (N = 63,124). Plasma p-tau217-eligible participants were enrolled (N = 2196), with Clinical Dementia Rating (CDR) scale-Global score (CDR-GS) of 0 (n = 1202) and 0.5 (n = 664). Plasma p-tau217 eligibility increased with age, differing across races and ethnicities. Mean baseline amyloid levels were 63.2 (CDR-GS: 0) and 70.7 Centiloids (CDR-GS: 0.5). Elevated global tau signal (standardized uptake value ratio ≥1.10) was observed in 15.1% and 26.3% of CDR-GS 0 and 0.5 subgroups, respectively. DISCUSSION:Utilizing a unique decentralized design, the trial showed baseline data consistent with preclinical AD. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05026866, TRAILBLAZER-ALZ 3 HIGHLIGHTS: TRAILBLAZER-ALZ 3 screened 63,124 participants in the United States and Japan Plasma phosphorylated tau-217 (p-tau217) was used to determine Alzheimer's disease pathology for eligibility A decentralized model was used, including remote raters for clinical testing Randomized participants had Clinical Dementia Rating scale-Global scores of 0 and 0.5.

Alzheimer's disease is the most common form of cognitive impairment. With increasing longevity, its prevalence continues to grow, and treatments that prevent its clinical onset would have a profound effect. Characterised by amyloid plaques, tau tangles, and neuronal loss, Alzheimer's pathology is already extensive and hard to stop by the time cognitive impairment is detected. Secondary prevention therapies have the potential to avert further disease progression and to stop or delay cognitive impairment in people with biomarker evidence of the disease.

Background: TOMM40 ‘523 has been associated with cognitive performance and risk for developing Alzheimer’s disease independent of the effect of APOE genotype. Few studies have considered the longitudinal effect of this genotype on change in cognition over time. Objective: Our objective was to evaluate the relationship between TOMM40 genotype status and change in cognitive performance in the TOMMORROW study, which was designed to prospectively evaluate an algorithm that includes TOMM40 ‘523 for genetic risk for conversion to mild cognitive impairment. Methods: We used latent growth curve models to estimate the effect of TOMM40 allele carrier (short, very long) status on the intercept and slope of change in cognitive performance in four broad cognitive domains (attention, memory, executive function, and language) and a combined overall cognitive score over 30 months. Results: TOMM40 very long allele carriers had significantly lower baseline performance for the combined overall cognitive function score (B = –0.088, p = 0.034) and for the executive function domain score (B = –0.143, p = 0.013). Slopes for TOMM40 very long carriers had significantly greater increases over time for the executive function domain score only. In sensitivity analyses, the results for executive function were observed in participants who remained clinically stable, but not in those who progressed clinically over the study duration. Conclusions: Our results add to the growing body of evidence that TOMM40, in the absence of APOE ɛ4, may contribute to cognitive changes with aging and dementia and support the view that mitochondrial function is an important contributor to Alzheimer’s disease risk.

Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson's disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg(-1), and p < 0.001 at 1 mg kg(-1) and 10 mg kg(-1)) and cynomolgus monkeys (p <= 0.05 at 1 mg kg(-1) and 3 mg kg(-1)). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants ( identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.

We previously examined the impact of using a cerebellar, pons, or cerebral white matter (WM) reference region (RR) on the ability of each to distinguish cortical measures of fibrillar amyloid-(Aβ) deposition with baseline data in unimpaired presenilin (PSEN1) E280A mutation carriers and non-carriers (NC) from the Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease (API ADAD) Colombia Trial (NCT01998841). In this study, we extend our findings by comparing these RRs on their ability to distinguish longitudinal changes in cortical measures of serial Aβ-PET scans from the completed clinical trial. We estimated template-based (SPM12) cortical mean change using baseline, 2, and 5-year florbetapir PET standard-uptake value ratios (SUVRs) with three different RRs (whole cerebellum, pons, and WM) and compared carriers on placebo (placebo-carriers, n = 82) with NC all on placebo (NC, n = 83). We calculated Cohen’s D with [95% CI] and standard deviation of NC as effect-sizes for 2 and 5-year cortical changes. Additionally, we characterized cerebellar Aβ burden in carriers on crenezumab (treatment-carriers, n = 81), placebo-carriers, and NC, using our previously reported method targeting the whole cerebellum region-of-interest (ROI) with pons as RR to estimate cerebellar-to-pons-SUVRs and compare using a mixed-model repeated-measures ANOVA adjusted for age but not multiple comparisons. As expected, placebo-carriers had significantly greater SUVR change compared with NC for all three RRs. However, the pons RR was best at detecting 2-year changes ( d = 1.75[1.39-2.11]), and WM and pons were best at detecting 5-year changes in cortical-Aβ levels between placebo-carriers and NC (pons d = 2.01[1.64-2.39], WM d = 2.51[2.10-2.92]). Additionally, treatment-carriers had higher cerebellar-to-pons-SUVRs compared with placebo-carriers at baseline and 2-years, but not 5-years (p = .034, p = .027,& p = .06,respectively), both carrier groups had higher cerebellar-to-pons-SUVRs compared to NC at each interval(p<.001). Cerebellar-to-pons-SUVRs continued to increase within carrier groups at each interval(5-year>2-year>baseline,p<.05) and remained constant within the NC-group(p>.05). Use of pons for 2-year and WM or pons RRs for 5-year changes may improve the power to track longitudinal increases and evaluate Aβ-modifying treatments in 2 and 5-year studies, in this ADAD population. A cerebellar RR may be confounded by early Aβ deposition in the cerebellum which can artificially reduce average cortical Aβ-PET SUVRs even in preclinical stages of ADAD.

Abstract Digital health technologies can provide continuous monitoring and objective, real world measures of Parkinson’s disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials.

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.

Background The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. Results Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. Conclusions The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Saturday, April 17April 13, 2021Free AccessSafety and efficacy of TAK-925 in adults with obstructive sleep apnea who experience excessive daytime sleepiness despite adequate use of CPAP (4278)Robert Rubens, Tina Olsson, Rachel Neuwirth, Sandy Bialek, Richard Bogan, James Maynard, Howard Schwartz, and Robert AlexanderAuthors Info & AffiliationsApril 13, 2021 issue96 (15_supplement)https://doi.org/10.1212/WNL.96.15_supplement.4278 Letters to the Editor

Background The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0.8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo ( for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0.01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3.3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1.0%) of 402 participants at low risk given placebo (hazard ratio 3.26, 99% CI 0.85-12.45; p=0.023). 39 (2.7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3.3%) of 1406 participants at high risk given placebo (hazard ratio 0.80, 99% CI 0.45-1.40; p=0.307). In the safety analysis set, seven (0.5%) of 1531 participants at high risk given pioglitazone died versus 21 (1.4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

As knowledge of Alzheimer's disease (AD) progression improves, the field has recognized the need to diversify the pipeline, broaden strategies and approaches to therapies, as well as delivery mechanisms. A better understanding of the earliest biological processes of AD/dementia would help inform drug target selection. Currently there are a number of programs exploring these alternate avenues. This meeting will allow experts in the field (academia, industry, government) to provide perspectives and experiences that can help elucidate what the pipeline looks like today and what avenues hold promise in developing new therapies across the stages of AD. The focus here is on Active Immunotherapies and Alternative Therapeutic Modalities. This topic includes active vaccines, antisense oligomers, and cell-based therapy among others, and highlights new clinical developments that utilize these modalities.

AbstractBackgroundA challenge with AD prevention is the timely identification of subjects at risk of cognitive symptom onset, mitigating prohibitive costs associated with the trial size and duration. A biomarker risk assignment algorithm (BRAA) consisting of genotypes at the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) rs10524523 loci (‘523) and current age was developed to enrich the TOMMORROW delay of AD onset clinical study. ‘523 is a poly‐T homopolymer of 14 to 50 residues. For the BRAA, the alleles were categorized by T length as “short” (S: <21), “long” (L: 21‐29), or “very long” (VL: >29).MethodThe TOMMORROW study (NCT 01931566) provided a large dataset to assess APOE‐‘523 haplotypes to improve the performance of the BRAA. The original BRAA used phased genetic information to determine risk categories (developed in 150 individuals, verified in 1018 individuals). Because phased haplotype data were not available from the samples genotyped in the TOMMORROW study, an optimized calibration was performed using APOE 3/3 and 4/4 homozygous individuals (n=1625). By maximizing the genetic congruency between the APOE and ‘523 genotypes, the calibration of the ‘523 categorical boundaries was optimized.ResultFrom these haplotype data, the ’523 categorical assignments were optimized to S: <19; L: 19‐31; and VL: >31. When these optimized categorical assignments were applied retrospectively to the TOMMORROW study cohort (n=1803), the hazard ratio for the time‐to‐event comparison between the high and low risk placebo groups improved from 3.3 (95% confidence interval [CI] 1.2‐9.0, P=0.023) to 4.3 (95%CI 1.3‐13.7, P=0.015). Applying the refined BRAA to a future delay of AD onset clinical trial would reduce enrollment by 26% for a 5‐year interventional study versus an all‐comers enrollment strategy. Furthermore, a streamlined, kit‐based genotyping assay for APOE and TOMM40 ‘523 was evaluated and found to yield congruent results with the sequencing‐based method used for genotyping in the TOMMORROW clinical trial.ConclusionUsing phase 3 clinical trial data, the TOMMORROW BRAA demonstrated the ability to enrich delay of onset/prevention of AD studies for subjects more likely to develop cognitive symptom onset during an acceptable timeframe with significant clinical trial cost savings.

OBJECTIVES:In this study, patients with painful diabetic neuropathy were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments.METHODS:AZD5213, a novel histamine H3 receptor inverse agonist+pregabalin, pregabalin, and placebo were then tested in a 3-period cross-over.RESULTS:The study did not provide any evidence of clinical efficacy for AZD5213 when combined with pregabalin in the treatment of painful diabetic neuropathy.DISCUSSION:The training of study patients in pain reporting and subsequent enrichment with good pain reporters also did not enable the robust detection of the efficacy of pregabalin relative to placebo in a small sample size. Further work is required before recommending the use of "connoisseur" patients in future neuropathic pain studies.

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson’s Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.