Brian A. Willis

The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central Aβ Pharmacodynamic Responses in Mice, Dogs, and Humans

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimers disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer's disease

The neuroanatomy of agitation and aggression in Alzheimers disease is not well understood.

Comparison of pharmacokinetics, pharmacodynamics, safety, and tolerability of the amyloid β monoclonal antibody solanezumab in Japanese and white patients with mild to moderate alzheimer disease.

ObjectivesSolanezumab is a humanized anti-amyloid &bgr; monoclonal antibody being developed as a passive immunization treatment to slow the progression of Alzheimer disease (AD). Pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after a single dose of solanezumab were compared between Japanese and white patients with AD. MethodsJapanese and white patients with mild to moderate AD were enrolled in 2 separate studies. In each study, single doses of solanezumab at 0.5, 1.5, 4.0, and 10.0 mg/kg were administered by intravenous infusion. Plasma concentrations of solanezumab and amyloid &bgr; (A&bgr;) were measured. A safety assessment was conducted up to 112 days after a single-dose administration of solanezumab. ResultsThe PK profile was similar between the Japanese and the white patients with AD. In both the Japanese and the white patients, clearance and volume of distribution appeared similar across doses, suggesting that solanezumab exhibited dose-proportional PK within the studied dose range. A marked increase in plasma total A&bgr; was observed; both the magnitude and time to reach maximum concentration tended to increase with increasing doses of solanezumab. Administration of solanezumab was generally well-tolerated in both Japanese and white patients with AD. ConclusionsWhen administered as a per-kilogram single dose of solanezumab, PK and pharmacodynamics (plasma total A&bgr;1-40 concentration) in the Japanese patients with AD were comparable with those in the white patients with AD. In addition, solanezumab was generally well tolerated in both Japanese and white patients at all dose levels.

Enriching Amnestic Mild Cognitive Impairment Populations for Clinical Trials: Optimal Combination of Biomarkers to Predict Conversion to Dementia

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimers disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimers Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimers disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial.

Mibampator (LY451395) randomized clinical trial for agitation/aggression in Alzheimer's disease

BACKGROUND Mibampator, an amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor potentiator, was evaluated for treatment of agitation and aggression (A/A) in Alzheimers disease (AD). METHODS Outpatients (n = 132) with probable AD and A/A randomized to 12 weeks of double-blind treatment with 3-mg po mibampator or placebo were assessed using the 4-domain A/A subscale of the Neuropsychiatric Inventory (NPI-4-A/A) derived from the Neuropsychiatric Inventory. Secondary measures included the Cohen-Mansfield Agitation Inventory, Cornell Scale for Depression in Dementia, Frontal Systems Behavior Inventory (FrSBe), and Alzheimers Disease Assessment Scale-Cognitive. Efficacy was analyzed using mixed-effects model repeated measures from baseline to endpoint. Adverse events (AEs), labs, vital signs, and electrocardiograms were monitored. RESULTS Baseline characteristics were comparable between groups. Both groups improved on the NPI-4-A/A, but without group differences. Among secondaries, mibampator was significantly better (p = 0.007) than placebo only on the FrSBe. AEs were similar between groups. One death occurred in the placebo group. CONCLUSION Possible explanations for no significant group differences include caregiver, drug target engagement, and design issues. This trial is registered on ClinicalTrials.gov; ID: NCT00843518.

Subscale Validation of the Neuropsychiatric Inventory Questionnaire: Comparison of Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center Cohorts

OBJECTIVE Neuropsychiatric symptoms are prevalent in mild cognitive impairment (MCI) and Alzheimer disease (AD) and commonly measured using the Neuropsychiatric Inventory (NPI). Based on existing exploratory literature, we report preliminary validation of three NPI Questionnaire (NPI-Q-10) subscales that measure clinically meaningful symptom clusters. METHODS Cross-sectional results for three subscales (NPI-Q-4-Frontal, NPI-Q-4-Agitation/Aggression, NPI-Q-3-Mood) in amnestic MCI and AD dementia cases from the National Alzheimers Coordinating Center (NACC) and Alzheimers Disease Neuroimaging Initiative (ADNI) databases were analyzed using confirmatory unrotated principal component analysis. RESULTS ADNI contributed 103 MCI, 90 MCI converters, and 112 AD dementia cases, whereas NACC contributed 1,042 MCI, 763 MCI converters, and 3,048 AD dementia cases. NACC had higher baseline mean age (75.7 versus 74.6), and more impaired mean scores (at month 24) on Mini-Mental State Exam (19.5 versus 22.4) and NPI-Q-10 (5.0 versus 4.3), and all NPI-Q subscales than ADNI. Medians were not different between cohorts for NPI-Q-4-Agitation/Aggression, and NPI-Q-3-Mood, however. Each item on all scales/subscales contributed variance in principal component analysis Pareto plots. All items in Factor (F) 1 for each scale/subscale projected in a positive direction on biplots (revealing coherence), whereas F2 and F3 items showed more spatial separation (revealing independence). There were remarkable similarities between cohorts for factor loadings and spatial patterns of item projections, although factor item identities varied somewhat, especially beyond F1. CONCLUSION The similar pattern of results across two cohorts support validity of these subscales, which are worthy of further psychometric evaluation in MCI and AD patients and preliminary application in clinical settings.

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team

Abstract Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

Cortisol response to individualised graded insulin infusions: a reproducible biomarker for CNS compounds inhibiting HPA activation

AIM To determine the potential of cortisol secretion, in response to a physiological stressor, as a biomarker for centrally active compounds targeting the hypothalamic-pituitary-adrenocortical (HPA) axis. METHODS Cortisol response to hypoglycaemia was measured in 26 healthy males in two stages: firstly to derive an algorithm for individualized, graded insulin infusion rates to achieve defined hypoglycaemic targets over 3 h and secondly to determine the inter- and intra-subject variability of cortisol response to hypoglycaemia over two identical periods by measuring the maximum (t(max) ), time to maximum (C(max) ) response and cortisol area under the response curve (AUC). RESULTS Hypoglycaemia induced a consistent cortisol response starting at approximately 1 h, corresponding to blood glucose concentrations of approximately 3.3 mmol l⁻¹, and peaking approximately 3 h after the start of infusion. The inter- and intra-subject coefficients of variation (CVs) of cortisol response were approximately 19 and 19% (AUC), 15 and 19 % (C(max) ) and 10 and 14% (t(max) ), respectively. The intra-subject CVs for the ratio of maximum cortisol response to baseline concentration and rate of initial cortisol response between study days were more variable (32.8% and 59.0%, respectively). The blood glucose-cortisol response model derived from the study was predictive of the individual observed cortisol responses, and estimated a blood glucose EC(50) associated with onset of the cortisol response of 3.3 mmol l⁻¹. CONCLUSIONS Gradual hypoglycaemia is an effective, reproducible and well-tolerated method of stimulating a cortisol response and may therefore be useful in assessing the neuroendocrine response to HPA axis inhibitors, such as corticotropin-releasing hormone-1 (CRH-1) antagonists.

Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β Peptides in Cerebrospinal Fluid Specimens from Alzheimer's Disease Studies

The aim of this study was to validate assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF)specimens according to regulatory guidance and demonstrate their utility with measurements in specimens from Alzheimer’s disease (AD) studies. Methods based on INNOTEST(®)β-AMYLOID(1-42) and prototype INNOTEST(®)β-AMYLOID(1-40) ELISAkits were developed involving pre-analytical sample treatment with Tween-20 for reliable analyte recovery.Validation parameters were evaluated by repeated testing of CSF pools collected and stored in the same manner as clinical specimens. Intra- and interassay coefficients of variation were ≤11% and relative accuracy was within ± 10% for both analytes. Dilutional linearity was demonstrated for both analytes from a spiked CSF pool, but not from a non-spiked native CSF pool. Recovery of standard Aβ peptide spikes standard ranged from 77% to 93%. No interference was observed from the investigational drugs LY2811376, LY2886721, LY3002813, or semagacestat. Aβ(1-40) and Aβ(1-42) were stable in CSF for up to 8 hours at room temperature and during 5 f reeze-thaw cycles from ≤−20◦C and ≤−70◦C. In frozen native CSF specimens, Aβ(1-40) was mostly stable up to 3 years at ≤−70◦C, whereas stability of Aβ(1-42) was limited to 221 days. Dose-dependent changes in measured CSF Aβ were observed in healthy volunteers up to 36 hours after treatment with the-site cleavage enzyme inhibitor LY2886721. In conclusion, rigorous validation tests have successfully demonstrated the strengths and operational limitations of these INNOTEST(®)-based assays.They have proved to be robust and reliable tools for pharmacodynamic evaluations of investigational AD therapeutics in clinical trials.

Semagacestat Pharmacokinetics Are Not Significantly Affected by Formulation, Food, or Time of Dosing in Healthy Participants

Semagacestat, a γ‐secretase inhibitor, reduces formation of amyloid beta peptide. Two single‐dose (140 mg), open‐label, randomized, 3‐period, crossover studies evaluated the effect of formulation, food, and time of dosing on the pharmacokinetics and pharmacodynamics of semagacestat in healthy participants. The first study (n = 14) compared tablet to capsules. For all formulations, the median time to maximum plasma concentration (tmax) was generally 1.0 hour. Plasma elimination was rapid, with a half‐life of approximately 2.5 hours. Tablet form II bioavailability (F) relative to capsule was approximately 100% (F = 1.03 [90% confidence interval (CI), 0.96–1.10]). In the second study, participants (n = 27) received semagacestat either fed or fasting in the morning or fasting in the evening. No significant change in exposure (AUC0‐∞ [area under the concentration‐time curve from 0 to infinity] ratio = 1.02, [90% CI, 0.990–1.05]) occurred with food, whereas maximum plasma concentration (Cmax) declined approximately 15%, and median tmax was delayed to 1.5 hours. Time of dosing made no significant difference in AUC0‐∞, Cmax, or tmax (AUC0‐∞ ratio 1.01, [90% CI, 0.975–1.04]). No clinically significant safety concerns occurred in either study. Accordingly, semagacestat may be dosed without regard to formulation, food, or time of administration.