Evaluating Thrombin Inhibition in Alzheimer’s Disease (The BEACON Trial): Protocol for a Pilot Study (Preprint)

BACKGROUND The precise mechanisms whereby cardiovascular risk factors increase the risk of Alzheimer’s disease (AD) have not been delineated. We reported that microvessels isolated from AD brains overexpress a diverse array of neurotoxic and inflammatory proteins, which is consistent with the process of vascular activation. In pre-clinical studies using AD animal models we showed that a vascular activation inhibitor reduced vascular-derived neuroinflammation and improved cognitive performance. Thrombin is a key mediator of cerebrovascular activation in AD. OBJECTIVE This study aims to investigate the safety and potential efficacy of the direct thrombin inhibitor dabigatran, in patients with mild cognitive impairment (MCI) or mild AD to decrease vascular-derived neuroinflammation and improve cognitive performance. METHODS Participants will be enrolled then evaluated quarterly throughout the 24-month study. This is a 24-month randomized-control, double-blind, placebo-controlled, multicenter, delayed-start, pilot study evaluating thrombin inhibition in people with biomarker-confirmed MCI probably due to AD or mild AD. 40 - 60 participants will be recruited between 50 - 85 years old. In the initial 9-months of study, either dabigatran or placebo will be orally administered to patients at a dose of 150 mg per day. After 9 months of the placebo-control (Phase I), the placebo arm will cross-over to an active, open-label (Phase II) where all patients will be treated with a 150 mg daily dose of dabigatran orally for an additional 12 months. A 3-month non-treatment follow-up period will assess duration of effects. RESULTS Beginning in July 2019, and concluding in August 2022, this study is expected to publish final results in January 2023. CONCLUSIONS BEACON is a first-in-kind randomized clinical trial targeting thrombin activation in AD therapeutics. This trial will stimulate translational investigations of an FDA-approved drugs in a newly defined therapeutic areas. CLINICALTRIAL Clinicaltrials.gov NCT03752294

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Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: A randomized, double-blind, placebo-controlled study and a two-period extension study

10.21203/rs.2.22841/v1 ◽

2020 ◽

Author(s):

Gerald Novak ◽

Johannes Rolf Streffer ◽

Maarten Timmers ◽

David Henley ◽

H Robert Brashear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Oral Treatment ◽

Controlled Study ◽

Open Label ◽

Two Phase ◽

Double Blind ◽

Open Label Phase

Abstract Background Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer’s disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. Methods In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once-daily (later reduced to 5 and 25 mg) for six months. Participants entered ALZ2004, a 12-month-treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. Results Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to open-label phase. CSF Aβ fragments and sAPPβ were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD, but without apparent relation to treatment. In ALZ2004, change from baseline in RBANS suggested a trend toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST >3X ULN; total bilirubin >2X ULN (Hy’s law). Conclusion Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes.

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Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: A randomized, double-blind, placebo-controlled study and a two-period extension study

10.21203/rs.2.22841/v2 ◽

2020 ◽

Author(s):

Gerald Novak ◽

Johannes Rolf Streffer ◽

Maarten Timmers ◽

David Henley ◽

H Robert Brashear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Performance ◽

Oral Treatment ◽

Controlled Study ◽

Open Label ◽

Double Blind ◽

Preclinical Ad ◽

Open Label Phase

Abstract Background Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer’s disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. Methods In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once-daily (later reduced to 5 and 25 mg) for six months. Participants entered ALZ2004, a 12-month-treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. Results Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to open-label phase. CSF Aβ fragments and sAPPβ were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST >3X ULN; total bilirubin >2X ULN (Hy’s law). Conclusion Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes.

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A pilot study of clinical cell therapies in Alzheimer’s disease

Journal of Neurorestoratology ◽

10.26599/jnr.2021.9040023 ◽

2021 ◽

Vol 9 (4) ◽

pp. 269-284

Author(s):

Xiaoling Guo ◽

Yunliang Wang ◽

Yan Li ◽

Yanqiu Liu ◽

Ying Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pilot Study ◽

Cell Therapy ◽

Cell Types ◽

Placebo Control ◽

Clinical Dementia Rating ◽

Olfactory Ensheathing Cell ◽

Double Blind ◽

Cell Therapies

Alzheimer’s disease (AD) is a neurodegenerative disease dominated by progressive cognitive dysfunction causing significant social, economic, and medical crises. Cell therapy has demonstrated favorable effects for AD. This pilot study examined the safety and neurorestorative effects of the olfactory ensheathing cell (OEC), olfactory neuron (ON), and Schwann cell (SC) on patients with AD. Seven patients with AD were enrolled in this two-center, randomized, double-blind, and placebo- controlled cell therapy study with a subsequent 12-month follow-up. We randomly assigned one or two participants in OEC, ON, and SC therapy or OEC combined with ON and placebo control. All enrolled patients were injected cells or medium into the olfactory sub-mucosa. They got an assessment of Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating before treatment and 1, 3, 6, 12 months after treatment. We performed MRI or CT scans before treatment and 12 months after treatment. After integrating the results from the three evaluation methods, all cell types showed better results than a placebo control. ON and SC seem to exhibit more vital potential neurorestorative ability to enhance or convert the neurological functions of patients with AD, and OEC may help AD patients keep neurological functions stable. In this pilot study, there was no adverse or side-effect event. The results of this study strongly suggest conducting a phase II clinical trial of ON, SC, and OEC therapy to prove their neurorestorative effect on patients with AD.

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