Randy Slemmon

Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study of the Oral γ-Secretase Inhibitor BMS-708163 (Avagacestat): Tolerability Profile, Pharmacokinetic Parameters, and Pharmacodynamic Markers

BACKGROUND γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-β (Aβ) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound. OBJECTIVE The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Aβ, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers. METHODS This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Aβ (Aβ(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing. RESULTS Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Aβ(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg. CONCLUSIONS Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development.

Pharmacodynamics of Selective Inhibition of γ -Secretase by Avagacestat

A hallmark of Alzheimer’s disease (AD) pathology is the accumulation of brain amyloid β-peptide (Aβ), generated by γ-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, γ-secretase inhibitors (GSIs) may lower brain Aβ and offer a potential new approach to treat AD. As γ-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of Aβ and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) Aβ levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF Aβ40 and Aβ42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending–dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF Aβ40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF Aβ levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.

A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat

AIM To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. METHODS All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)(1-40) concentratios and exploration of Notch biomarkers. RESULTS Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t(max) between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ(1-40) serum concentrations showed a pattern of decreasing concentrations over the first 4-6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. CONCLUSIONS The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimers disease.

The safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of BMS-708163 in young and elderly subjects

improved cognitive function in a mouse model of AD (APP/PS1). Methods: To track BMDCs, bone marrow harvested from the mice carrying green fluorescent protein (GFP) was transplanted to the APP/PS1 mice. Thereafter, SCF+G-CSF were subcutaneous administered for 12 days, beginning at the age of 8 months when Ab plaques had appeared in the brain. To evaluate special learning and memory, water maze test was performed before and 9 months after treatment. Results: We observed that SCF+G-CSF-treated mice showed significantly shorter escape latency and that the number of senile plaques was significantly reduced by SCF+G-CSF treatment. In addition, a significant high number of GFP+/Iba1+ cells surrounding Ab plaques was seen in SCF+G-CSF-treated mice. Conclusions: These data suggest that SCF+G-CSF treatment may delay AD progress by enhancing clearance of Ab deposits via BM-derived microglial cells. These data would help in developing an effective treatment to improve health of AD.

An assessment of variability in CSF biomarkers in clinical experimental models: a meta-analysis

all biomarkers considered for this review. Six percent of studies included more than 500 patients. It was unclear whether scan/test interpretation was conducted blind to knowledge of conversion to dementia in 62% of reports. Similarly, it was unclear whether decisions about conversion to dementia were made without knowledge of scan/test results in 63% of reports. Uninterpretable or intermediate test results were either not reported, or reported unclearly in 79% of cases. It was rarely possible to make an assessment, on the basis of the report, that the spectrum of patients in the cohort was representative of the patients whowould receive the test in practice. 21 studies of CSF or plasma Abeta reported conversion in 1128 patients. 26 studies of CSF tau reported conversion in 1054 patients. 22 structural MRI studies reported conversion in 1343 patients. 11 studies of FDG-PET reported conversion in 270 patients. 5 studies of PET based amyloid imaging reported conversion in 27 patients.Conclusions: The quality of reporting of longitudinal studies of biomarkers raises the possibility that substantial biases may be present. Multiple publication is commonplace in studies of diagnostic accuracy in dementia. Whilst this reflects developing techniques and continuing monitoring of subjects for outcomes, greater transparency is required so as to allow easier compilation of these data. A more formal process with cohort registration, reporting of ’intention to diagnose’ data, and clear independence of clinical and test evaluations is required. PET-based tests have the smallest evidence base. The small sample size of most studies limits their overall generalizeabilty. Funders, including those seeking licences for new products, should support large-scale, representative evaluations in that part of the population who would be most likely to utilize the test. Critical evaluation of the evidence base for diagnostic biomarkers is of major importance to the field of dementia. Without it, there is a risk that future clinical care and research will be built on assumptions about diagnostic validity that are wrong.

The Gamma Secretase Inhibitor, BMS-708163 Increases Alpha Secretase Abeta Peptide Cleavage Fragments and Decreases the Gamma Secretase Abeta Peptide 1-34 Fragment in Cerebrospinal Fluid

to investigate the role of the innate immune system inAlzheimer’s disease (AD) bymeasuring complement factors in cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI), AD and other dementias (oDem).Methods: We selected healthy controls (n1⁄4 19, age1⁄4 63, MMSE1⁄4 29.1), subjects with MCI (n 1⁄4 56, age 1⁄4 70, MMSE 1⁄4 26.9), AD (n 1⁄4 45, age 1⁄4 72, MMSE 1⁄4 22.9) and oDem (n 1⁄4 31, age 1⁄4 69 MMSE 1⁄4 24.1) from the EDAR study (www.edarstudy.eu). We measured C3a, central to the classical, alternative and lectin complement pathways, C5a involved in the lytic complement pathway, and the soluble C5b-9 terminal complement complex (TCC). We also measured in CSF abeta 1-42, total tau, and serum amyloid P (SAP, an acute response protein which activates complement). We compared groups and correlated complement markers with other biomarkers, neuropsychological markers, andmarkers of functional impairment using non-parametric tests.Results: Complement data are shown in the table. C3a was decreased by 50-60% in subjects with MCI, AD, and oDem relative to controls (p < 0.003 all comparisons). C5a was increased 3-6 fold in AD relative to controls (p 1⁄4 0.077), MCI (p1⁄4 0.016), and oDem(p1⁄4 0.07). TCCdid not differ between the groups, although subjects with AD had higher concentrations than the other groups. In the combined sample of subjects with MCI, AD, and oDem, higher levels of C3a correlated with higher levels of TCC (r 1⁄4 0.51, p < 0.001), SAP (r 1⁄4 0.40, p< 0.001), and tau (r1⁄4 0.18, p1⁄4 0.048). Higher levels of C5a correlated with more impairment on memory, executive functioning, and the MMSE (r1⁄4 0.22-0.30, p 1⁄4 0.05-0.002). Higher levels of TCC correlated with higher SAP levels (r 1⁄4 0.41, p < 0.001) and more functional impairment (r 1⁄4 0.25, p 1⁄4 0.018).Conclusions: The innate immune system is actively involved in neurodegeneration and may provide diagnostic and prognostic information for AD. The large reduction of C3a in subjects with MCI, AD and oDem, suggests increased use of this factor, regardless of the cause of neurodegeneration. Alternatively, increased C3a levels may protect against neurodegeneration. The increase of C5a in AD suggests a disease specific activation of the lytic complement pathway. Since this measure correlated with clinical measures of severity, C5a activation may be a relatively late event in the disease process.