The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer's disease (AD). Its primary aims are to investigate ...the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers. This review details the unique attributes of DIAN as a model AD biomarker study and how it provides the infrastructure for innovative research projects, including clinical trials. The recent design and launch of the first anti-amyloid-beta secondary prevention trial in AD, led by the related DIAN Trials Unit, also are discussed.
Abstract Introduction The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's ...disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. Methods In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. Results Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. Conclusion These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD.
Background
Alzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited ...AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.
Method
DIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.
Result
The primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.
Conclusion
These results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.
Introduction
While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of ...gantenerumab were increased 5‐fold, and solanezumab was increased 4‐fold. We evaluated to what extent mid‐trial dose increases produced a dose‐dependent treatment effect.
Methods
Using generalized linear mixed effects (LME) models, we estimated the annual low‐ and high‐dose treatment effects in clinical, cognitive, and biomarker outcomes.
Results
Both gantenerumab and solanezumab demonstrated dose‐dependent treatment effects (significant for gantenerumab, non‐significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose‐dependent treatment effects were observed in clinical or cognitive outcomes.
Conclusions
Mid‐trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases.
Highlights
We evaluated the dose‐dependent treatment effect of two different amyloid‐specific immunotherapies.
Dose‐dependent treatment effects were observed in some biomarkers.
No dose‐dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.
Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and ...symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a ...predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease.
In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes.
Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).
Background
Tau pathology is closely associated with the onset and progression of Alzheimer’s disease. Recent advances in drugs that target tau suggest the potential to prevent or attenuate the ...pathophysiology and pathology of tau. Novel CSF and blood tau species including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, increases 10 years or more before tau tangles are detected by tau‐PET. Two stages of AD are identified and studied using soluble p‐tau and MTBR‐tau forms in the asymptomatic stage and Tau PET in the post‐tangle symptomatic stage. E2814, an anti‐tau monoclonal antibody targets MTBR‐tau and decreases tau pathology in animal models.
Method
We designed an anti‐tau trial to target soluble tau species in two cohorts including pre‐tangle asymptomatic and post‐tangle symptomatic participants in dominantly inherited AD (DIAD). We analyzed longitudinal clinical, cognitive, tau PET and CSF measures of tau species including, multiple p‐tau species (e.g., p‐tau217, 231, 181, 205), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in DIAD cohorts from DIAN and DIAN‐TU. Novel trial design and statistical approaches have been developed to address primary and secondary outcomes, magnitude of effect by stage of disease (pre‐tangle vs. post‐tangle), and potential for prevention.
Result
We designed a trial of two cohorts, each powered, with different biomarker outcomes: in the pre‐tangle, tau‐PET negative cohort, CSF ptau217/tau217 is the endpoint; for the post‐tangle tau‐PET positive cohort, tau‐PET is the endpoint. Further, each cohort will measure target engagement by CSF MTBR‐tau and downstream effects on soluble total tau, p‐tau and MTBR tau with common measures of neurodegeneration by CSF and blood NfL, atrophy by MRI, hypometabolism by FDG‐PET, effects on amyloid by abeta42/40 and amyloid‐PET, and cognitive and clinical measures. This design is facilitated by the predictable pattern of biomarker changes observed in DIAD allowing appropriate powering of the study even in this rare condition.
Conclusion
The Tau Next Generation Platform will address disease progression, before and after tangle formation begins, assessing when an anti‐MTBR tau monoclonal antibody will have the largest effects. It is the first anti‐tau trial for DIAD.
Background
Amyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited ...Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.
Method
The DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.
Result
Eleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=1.1,75.9, p‐value<0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR>0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=1.0,30.4, p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=0.34,7.33, p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value<0.05), rate of change (rho=0.78, p‐value<0.01), and baseline PiB‐PET (rho=0.68, p‐value<0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.
Conclusion
In DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.
Solanezumab in‐depth outcomes Farlow, Martin R.; Bateman, Randall J.; Aschenbrenner, Andrew J. ...
Alzheimer's & dementia,
12/2020, Volume:
16, Issue:
S9
Journal Article
Peer reviewed
Abstract
Background
Solanezumab is a monoclonal antibody targeting soluble forms of β‐amyloid protein important in the pathogenesis of Alzheimer’s disease (AD). Three previous 18‐month double‐blind ...placebo‐controlled trials of low‐dose solanezumab in late‐onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly‐inherited mutation‐associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.
Method
Mutation‐carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 – 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double‐blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN‐MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale‐Revised, the Digit Symbol Substitution Test total score from the WAIS‐R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN‐MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β‐amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre‐specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.
Result
The topline efficacy, safety and biomarker results will be reported.
Conclusion
This study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti‐amyloid therapy in sporadic AD.
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