Abstract Body

There are numerous reports about successful proof of concept testing of new treatments in differnt models of Alzheimer's disease (AD), but so far the translational value of these findings was extremely low. Initially mainly transgenic mice overexpressing 1 or more of the pathogenetically important proteins with at least one, but very often multiple mutations were used. These systems are highly artifical and may not really recapitulate the human disease. But even this speculation needs to be carefully discussed, because there was a high tranlational success if proposed disease mechanisms were addressed, e.g. gamma- or beta-secretase inhibitors decreaed Abeta production in animals and in humans. The most critical issue is the overall clinical efficacy, namely the interpretation and translation of cognitive and behavioral findings in transgenic mice and rats.Over the last few years major efforts were made to better model AD, by switching to knock-in models with normal gene expression, or by creation of mice co expressing "human risk gene" of AD. Now it is important to validate their translational value, but unfortunately so far no drug tested in these models was in clinical trials. Beside the right choice of a modle, the experimantal approach itself needs dicussion and standardisation. This includes all steps like blinding, randomisation, sample size calculation, behavioral tests and suitable positive or negative control groups. This should also allow for a better comparibility of data from different systems and a realistic judgement of the potential clinical usefulness of tested new drugs.

Aims

Aims - Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development.

Methods

Methods - We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality.

Results

Results - We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19,2 %) is even higher than the percentage in clinical development (10,7 %), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development.

Conclusions

Conclusions - Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well.

Abstract Body

The CXCR4/CXCL12 (SDF1) axis is one of the major signal transduction cascades involved in the inflammation process and homing of hematopoietic stem cells (HSCs) within the bone marrow niche. We recently reported that treatment of transgenic mice model of Alzheimer’s disease (AD) with AMD3100, a reversible antagonist of CXCR4, attenuates their pathology by mobilization of endogenous HSCs from the bone marrow to the periphery into the brain and improving the cognitive functions. Notably we have found that AMD3100 increased the Monocarboxylate transporters 1( MCT1)in an AD and ALS animal models. An increase in MCT1 level may enable a better utilization of exogeneous and endogenous lactate as an energy substrate by neurons and oligodendrocytes. .L-lactate is as an active metabolite, capable of moving into or out of cells, acts as a signaling molecule and may have a potential therapeutic role in neurodegenerative diseases. Based on the findings, namely reduced expression of MCT1 and low content of lactate identified in AD patients and animal models, we propose a combined treatment with AMD3100 and exogeneous L-lactate. The combined treatment of acute mice model of AD showed an additional beneficial effect by improving cognitive deficit, shifting of microglia to anti-inflammatory M2 profile and remyelination compared with AMD3100 treatment alone. The combination ameliorates AD pathology increasing BDNF and synaptophysin expression. The therapeutic approach presented here, based on combination of an anti-inflammatory and remyelinating procedures, suggests an innovative path to intervene in AD ,repurposing an existing drug whose pharmacokinetics and pharmacodynamics have already been established.

Aims

Type II diabetes is a risk factor for developing AD. We have previously tested the analogue of glucagon-like peptide 1 (GLP-1) liraglutied in patients with Alzheimer’s disease and showed that it improved cognition and memory and reduces shrinking of the brain. Novel dual GLP-1/GIP receptor agonists have been developed by us that can enter the brain. We tested the protective effects ofdual agonists in comparison with liraglutide in the APP/PS1 model.

Methods

First we tested the dual GLP-1/GIP agonist DA4-JC and compared it with liraglutide at equal doses of 10nmol/kg bw ip. once-daily for 8 weeks in the APP/PS1 transgenic mouse model of AD. DA5-CH was tested separately in the same model. Memory formation in the water maze, synaptic plasticity (LTP) in area CA1 of the hippocampus using in vivo electrophysiology techniques, amyloid plaque load, and chronic inflammation was evaluated.

Results

When comparing DA4-JC with the GLP-1 analogue liraglutide in the APP/PS1 mouse model of AD, DA4-JC was more effective in reversing memory loss in the water maze task, was superior in enhancing synaptic plasticity (LTP) in the hippocampus, in reducing amyloid plaque load in the cortex, and in lowering pro-inflammatory cytokine levels of TNF-alpha and IL-1ß in the brain compared to liraglutide. DA5-CH also reduced memory impairments, amyloid plaque load in the brain, and normalized synaptic plasticity in the hippocampus.

Conclusions

The results show that the dual GLP-1/GIP receptor agonists DA4-JC and DA5-CH are effective in treating AD and show great promise to be a superior treatment for AD than liraglutide.

Aims

The sigma 1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. Agonists of S1R demonstrated neuroprotective effects in preclinical models and there are several on-going clinical trials of S1R agonists in neurodegenerative disorders. However, signaling functions of S1R are poorly understood. We set out to test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol

Methods

Biophysical experiemnts with in vitro reconstitution systems, experiments with neuronal and cellular cultures

Results

By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. Further, we found that S1R agonists cause disruption of S1R clusters. Based on these results we propose that S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners which we performed using the APEX technology

Conclusions

We proposed that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This mechanism may explain neuroprotective and synaptoprotective effects of S1R agonists in Alzheimer's disease and other neurodegenerative disorders.

Aims

Assess the primary outcome of safety; along with exploratory biomarker and clinical assessment in a phase 2a trial in mild-moderate Alzheimer’s disease (AD) for LM11A-31, a first-in-class small molecule modulating p75 neurotrophin receptor signaling. Presented on behalf of the NeuroScios Trial Site Principal Investigators.

Methods

Three study arms were included: placebo, low-dose (200mg) and high-dose (400mg) administered by oral capsules twice daily for 6 months. Inclusion criteria included CSF amyloid beta analysis. Safety assessments included clinical laboratory studies, MRI and EKGs. Exploratory outcome assessments included: AD core and other CSF biomarkers; structural MRI, ADAS-Cog-13, a Neuropsychological Testing Battery and other cognitive tests; and statistical region of interest and voxel-based FDG-PET.

Results

A total of 241 subjects were randomized and initiated on therapy with similar populations distributed across the three study arms. 221(91%) subjects completed the trial with 211 (87%) per protocol. Safety analysis demonstrated that 20 subjects discontinued the study; 16 with adverse events, 4 of these serious, and 4 (2 placebo and 2 drug) with withdrawal of consent. One death occurred in the placebo group. Initial exploratory outcome analyses suggested drug-associated effects on multiple CSF and imaging biomarkers. Follow up analyses will assess dose and sub-group effects including age, ApoE status, sex and disease stage.

Conclusions

Conclusions. These findings indicate an overall satisfactory safety profile. Exploratory outcome analysis suggests that LM11A-31 engages mechanisms relevant to p75 receptor signaling and AD progression. Overall, this study suggests that LM11A-31 is suitable for subsequent larger-scale trials.

Aims

Methods

Results

Conclusions

Aims

Donanemab is an antibody that targets N3pG, a modified form of amyloid-β (Aβ). TRAILBLAZER-ALZ (NCT03367403) was a phase 2 study of 272 individuals with early symptomatic Alzheimer’s disease (AD) with elevated amyloid plaque levels and intermediate tau levels on positron-emission tomography (PET). In TRAILBLAZER-ALZ, donanemab resulted in a 32% slowing of disease progression at 76 weeks on the Integrated Alzheimer’s Disease Rating Scale (iADRS, composite measure of cognition and function) with a reduction of 85 centiloids in amyloid plaque level. We present baseline characteristics of TRAILBLAZER-ALZ 2 (NCT04437511), a global phase 3 study designed to assess the treatment effects of donanemab on disease progression in individuals with early symptomatic AD.

Methods

TRAILBLAZER-ALZ 2 is a randomized, placebo-controlled, double-blind study with a planned enrolment of ~1500 participants. The study population comprises individuals 60-85 years of age, with mild cognitive impairment or mild dementia due to AD, and the presence of both brain amyloid plaque and tau pathology (intermediate or high level). The primary analysis will test the intermediate tau pathology population. Participants were randomized 1:1 to placebo every 4 weeks (Q4W) or to donanemab 700mg IV Q4W for 3 doses and then 1400mg IV Q4W, with a potential blinded dose reduction to placebo based on amyloid plaque clearance at 24 and 52 weeks. The primary endpoint is change from baseline to 76 weeks on the iADRS; secondary endpoints include changes in other cognitive assessments, amyloid PET, tau PET, and volumetric MRI.

Results

Enrollment/baseline findings will be presented.

Conclusions

Enrollment/baseline findings will be presented.