Aims

Compared to episodic-memory-focused cognitive tests such as the ADAS-COG, the Clinical Dementia Rating sum-of-boxes (CDR-SB), in addition to also evaluating function, is potentially better suited to evaluate the cognitive deficits seen in DLB. However, there is limited information on its utility in that context. The aim of this abstract is to report CDR-SB results in a phase 2 placebo (PBO)-controlled study of neflamapimod (NFMD) in DLB. The initial results of that study, presented previously at another scientific conference, demonstrated that 40mg TID neflamapimod significantly improves, relative to placebo, both cognition (evaluated by Neuropsychological Test Battery designed to assess attention and executive function) and motor function (evaluated by Timed Up and Go Test).

Methods

Mild-to-moderate DLB, including abnormal DaT-scan, receiving cholinesterase-inhibitor therapy. Randomized to 40mg NFMD capsules or matching PBO capsules for 16 weeks; BID (<80kg participants) or TID (≥ 80 kg participants). Treatment effects evaluated by linear-mixed-effects-model for repeated measures, with baseline as a covariate.

Results

Baseline mean(N,SD) CDR-SB score: 5.1(42,2.9) in placebo and 4.9(41,2.1) in NFMD. In PBO, there was a significant increase (worsening; +0.67 points, 95%CI:0.13 to 1.21) in CDR-SB from baseline to week 16. There were significant differences favoring neflamapimod treatment in comparisons of all NFMD vs. all PBO (p=0.023, difference=-0.45, 95%CI:-0.83 to -0.06), 40mg TID vs. all PBO (p=0.007, difference= 0.56, 95%CI:-0.96 to -0.16), and NFMD 40mg TID vs. PBO TID (p=0.005, difference=-0.63, 95%CI:-1.06 to -0.21).

Conclusions

CDR-SB proved useful to demonstrate beneficial effects, relative to placebo, of neflamapimod treatment on cognition and function in patients with mild-to-moderate DLB.

Aims

Currently, there are no disease-modifying treatments for Synucleinopathies. Increasing the levels of α-Glucocerebrosidase (GCase; gene name GBA) lowers the levels of α-synuclein in cell and animal models and improves Parkinsonian symptoms. Ambroxol is an over the counter expectorant which is a pharmacological chaperone for GCase. This study aims to test the safety, tolerability and efficacy of Ambroxol in individuals with Parkinson’s Disease Dementia.

Methods

Our goal was to randomize 58 individuals with mild to moderate dementia (MoCA <=24, MMSE >=16) to Ambroxol 1050mg/day or placebo for 1 year. Primary outcome measures are the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician’s Global Impression of Change (CGIC). Secondary outcomes include the UPDRS and a battery of cognitive and clinical assessments, and plasma/CSF and neuroimaging biomarkers. Pharmacokinetics and pharmacodynamics will also be examined.

Results

We have screened 70 candidates and 55 have been enrolled (94% of target). Enrollment is closed. So far 46 are at full dose, 34 have passed 6 months and 26 have completed a year. Mean MOCA at baseline was 19 and Mean MMSE was 25. Ambroxol has been well tolerated and there have been no SAE’s judged to be due to Ambroxol. We are achieving blood levels of 10-12 micromolar and CSF levels of about 0.7 μM. GCase levels in white blood cells is increased by 1.6 fold.

Conclusions

We are achieving Plasma and CSF levels predicted to be clinically useful. If found effective, Ambroxol will be the first disease-modifying treatment for PDD.

ClinicalTrial.gov NCT02914366. Funded by the Weston Brain Institute.

Aims

Objectives: NYX-458, a positive allosteric modulator of the N-methyl-D-aspartate receptor (NMDAR), enhances NMDAR-mediated synaptic plasticity and is currently in Phase II clinical development for the treatment of mild dementia in Parkinson’s Disease and Lewy body dementia. NYX-458 enhances attention, working-memory, and cognitive flexibility in a primate model of Parkinson’s disease cognitive-impairment that depends on optimal activity in the prefrontal cortex (PFC) and hippocampus. This study sought to examine the molecular mechanism of action of NYX-458 within the PFC and hippocampus in a rodent model of age-related cognitive decline.

Methods

Methods: Male, 3-4-month-old (young) and 26-27-month-old (aged) F344 rats were assessed for changes in NMDAR-mediated plasticity and performance in the Morris water-maze (MWM) after oral dosing with NYX-458 (0.1-10 mg/kg, PO). Synaptic spine density and NMDAR-relevant protein levels were quantified in the hippocampus and PFC following learning assessments in the MWM.

Results

Results: NYX-458 enhances NMDAR-mediated current and plasticity within the PFC and enhances PFC-dependent learning in a novel object recognition assay. NYX-458 also enhances hippocampal plasticity specifically in aged F344 rats and hippocampal-dependent learning in the MWM. The dose of NYX-458 (1 mg/kg, PO) that improved MWM performance reversed age-related synaptic spine loss and increased CAMKIIβ-mediated signaling and resultant downstream effects on NMDAR2B and AMPAR trafficking in both the hippocampus and PFC of aged rats.

Conclusions

Conclusions: NYX-458 enhances synaptic plasticity mechanisms associated with hippocampal-dependent learning and memory and induces changes within the PFC as part of an interconnected network. These data support the development of NYX-458 for the treatment of cognitive decline.

Aims

Research in the last decade strongly suggests the use and development of neuroprotective/disease-modifying strategies as an absolute need for PD translational research. Under this concept of modality, is N-acetylcysteine (NAC), which has already demonstrated promising therapeutical effects in CNS applications. NAC, a natural compound with strong antioxidant effects, displays a pharmacological profile that implies potential benefits for PD, including neuroprotection and antiparkinsonian properties. Bearing this in mind, the aim of the present work was to explore the impact of NAC disease-modifying effects in a striatal 6-OHDA PD pre-clinical model of PD.

Methods

NAC (1200mg/kg) was given by oral gavage to 6-OHDA-induced striatal lesions. Dopaminergic neuronal survival/transmission, and motor performance were then accessed by histological and animal behaviour analysis.

Results

From the results, we have successfully established the striatal model of PD, producing a retrograde degeneration of the DA neurons. After treatment intervention, we observed that NAC potentiated the increase of TH-positive neurons and fibers both in the SNpc and striatum, thereby supporting the positive recovery observed in the motor performance outcomes. Similar observations were also found to DAT fluorescence intensity analysis, denoting that our strategy could also play a role on dopaminergic transmission.

Conclusions

Collectively, this work has provided an important proof-of-concept milestone regarding the therapeutical application of NAC. Nevertheless, based on the present results, understanding the complexity of NAC potentialities, and how its therapeutical properties interact with the cellular and molecular PD mechanisms may lead to a rational design of new therapeutic strategies for its functional modeling and repair.

Aims

Aim- To investigated the safety, biomarkers effects and determine the lowest effective dose of Bosutinib in Dementia with Lewy Bodies (DLB)

Methods

A single center, Phase 2, randomized, double-blind, placebo-controlled study primarily investigated the safety and pharmacokinetics of 12-week oral treatment of bosutinib,100mg. Biomarkers and clinical outcomes were exploratory.

Results

Approximately 120 subjects were approached, 39 were screened, 13 did not meet inclusion criteria and 26 were randomized and included male and female (12:1) in bosutinib and male (13) in placebo with average age 72.94±8.8 (year±SD). There was no serious adverse events (SAEs) and no difference in AEs and no dropouts. Bosutinib, 100mg, was detected in the cerebrospinal fluid (CSF) and inhibited both Abl and Src in plasma. Bosutinib significantly reduced CSF alpha-synuclein (p=0.023) and the ratio of oligomeric/total alpha-synuclein (p=0.045) compared to placebo. There was also significant decrease in plasma oligomeric alpha-synuclein (p=0.04) and ptau181/Aβ42 (p=0.03). Bosutinib significantly (p=0.034) improved activities of daily living (ADCS-ADL-MCI) compared to placebo.

Conclusions

Bosutinib is safe and enters the brain. Bosutinib, 100mg, inhibited Abl/Src indicting dual target engagement, reduced brain alpha-synuclein and improved activities of daily living, suggesting that this is lowest effective dose (100mg) in DLB. This study is underpowered (by design) but the data will guide adequately powered future studies of a higher dose range of bosutinib over longer time (6 months) in DLB.

Aims

Istradefylline, a selective adenosine A_2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa-containing medication in adults with Parkinson’s disease (PD) experiencing OFF-time. This four-trial analysis evaluated impact of istradefylline dosage on UPDRS-III-ON score.

Methods

Data from four randomized, phase 2b/3 trials (6002-US-018, 6002-009, 6002-0608, and 6002-014) were analyzed to determine the difference in impact of 20 vs 40mg/day istradefylline on UPDRS-III-ON scores in patients with PD experiencing OFF-time. For each study, difference in least-squares (LS) mean change from baseline in UPDRS-III-ON scores for the two dosages was assessed by mixed-model repeated-measures analyses; results were combined using a random-effect meta-analysis.

Results

The LS mean change from baseline to week 12 in UPDRS-III-ON score was greater with istradefylline than placebo; in three studies, this effect was greater at the 40mg/day dose vs 20mg/day (Figure). In the random-effect meta-analysis, there was a significant difference in LS mean change from baseline between 20 and 40mg/day treatment arms (-0.80 [95%CI, -1.55, -0.04], nominal p=0.038). The rates of treatment-emergent adverse events (TEAEs) from each of the four studies were comparable between the 20 (59-82%) and 40mg/day (59-84%) dosages; the most common TEAE was dyskinesia in three studies (20mg/day, 11-17% vs 40mg/day, 12-26%) and nasopharyngitis in one (6% vs 9%). Impact of baseline UPDRS-III-ON score on improvements at both dosages will be presented.

Conclusions

Regarding motor improvement, these data suggest that 40mg/day istradefylline has greater benefit than 20mg/day. Safety was comparable between the two istradefylline treatment groups.