AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer’s Disease

Cebers, Gvido; Alexander, Robert; Haeberlein, Samantha Budd; Han, David; Goldwater, Ronald; Ereshefsky, Larry; Olsson, T.; Ye, Naidong; Rosen, Laura; Russell, Muir; Maltby, Justine; Eketjäll, Susanna; Kugler, Alan R.

doi:10.3233/jad-160701

Cited by 71 publications

(93 citation statements)

References 36 publications

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“…This suggests that in rodents, endogenous BACE1 levels are well above the levels necessary for APP processing. These findings demonstrate that the biochemical consequences of BACE1 deletion, at least with respect to APP processing, are consistent between rats and mice42434445 and in alignment with observations in humans following treatment with BACE1 inhibitors46474849, suggesting that this rat model has adequate predictive validity as a translational model in these measures.…”

Section: Discussionsupporting

confidence: 80%

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

Weber¹,

Wu²,

Meilandt³

et al. 2017

Sci Rep

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Assessing BACE1 (β-site APP cleaving enzyme 1) knockout mice for general health and neurological function may be useful in predicting risks associated with prolonged pharmacological BACE1 inhibition, a treatment approach currently being developed for Alzheimer’s disease. To determine whether BACE1 deletion-associated effects in mice generalize to another species, we developed a novel Bace1−/− rat line using zinc-finger nuclease technology and compared Bace1−/− mice and rats with their Bace1+/+ counterparts. Lack of BACE1 was confirmed in Bace1−/− animals from both species. Removal of BACE1 affected startle magnitude, balance beam performance, pain response, and nerve myelination in both species. While both mice and rats lacking BACE1 have shown increased mortality, the increase was smaller and restricted to early developmental stages for rats. Bace1−/− mice and rats further differed in body weight, spontaneous locomotor activity, and prepulse inhibition of startle. While the effects of species and genetic background on these phenotypes remain difficult to distinguish, our findings suggest that BACE1’s role in myelination and some sensorimotor functions is consistent between mice and rats and may be conserved in other species. Other phenotypes differ between these models, suggesting that some effects of BACE1 inhibition vary with the biological context (e.g. species or background strain).

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Section: Discussionsupporting

confidence: 80%

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

Weber¹,

Wu²,

Meilandt³

et al. 2017

Sci Rep

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“…Although phase I and phase II data present exciting benefits on AD models, the preliminary results of phase III trial have failed to meet clinical significance for Verubecestat [324, 325]. Nevertheless, the other oral BACE1 inhibitor Lanabecestat has recently gained support from FDA to further expand its phase III trial, following the data analysis based on early results [326]. On the other hand, PF-03084014, a γ-secretase inhibitor found curative in solid and hematological malignancies, remains in preclinical stage for AD field [327, 328].…”

Section: Discussion and Perspectivementioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

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“…It is among a few small‐molecule BACE1 inhibitors with improved central nervous system exposure and reduced human ether‐a‐go‐go‐related gene activity compared with larger peptidomimetic BACE1 inhibitors, which have progressed into clinical trials. In the first‐in‐man studies conducted in the United States (NCT01739647 and NCT01795339), lanabecestat was generally well tolerated and had a similar pharmacokinetic (PK) profile in healthy subjects and in patients with mild to moderate AD (median time to peak concentration = 1.0 and 1.5 hours, geometric mean [geometric CV%] peak concentration [C max ] = 314 [36.8] and 361 [22.6] ng/mL, and geometric mean [GCV%] area undeer the concentration‐time curve [AUC] = 2820 [32.5] and 3960 [30.5] h·ng/mL for healthy elderly subjects and patients with AD, respectively, at steady state following multiple daily 50‐mg doses of lanabecestat) . Lanabecestat produced potent and prolonged suppression of plasma and cerebrospinal fluid (CSF) Aβ peptides in healthy subjects as well as in patients with AD, confirming the central target engagement and expected mode of action of the drug .…”

mentioning

confidence: 99%

BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides

Sakamoto

Matsuki

Matsuguma

et al. 2017

The Journal of Clinical Pharma

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Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease.

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AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer’s Disease

Cited by 71 publications

References 36 publications

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Aβ Peptides

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