Scot Styren

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

ObjectivePonezumab (PF-04360365) is a humanized anti–amyloid beta (A&bgr;) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid A&bgr;. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. MethodsSubjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. ResultsAll subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of A&bgr;1-x and A&bgr;1-40 increased dose-dependently. ConclusionsAdministration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma A&bgr; species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Safety, efficacy, pharmacokinetics and pharmacodynamics of multiple doses of Ponezumab in subjects with mild-to-moderate Alzheimer's disease

ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a “Go-No-Go” decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab

The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimers disease assessment scale‐cognitive 11‐item [ADAS‐cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status.

Biomarker Exposure-Response Analysis in Mild-To-Moderate Alzheimer’s Disease Trials of Bapineuzumab

BACKGROUND Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimers disease (AD) patients. OBJECTIVE To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. METHODS Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. RESULTS Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. CONCLUSIONS Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

Alzheimer's disease progression model using disability assessment for dementia scores from bapineuzumab trials

Disability assessment for dementia (DAD) measurements from two phase‐3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimers disease (AD) patients were integrated to develop a disease progression model.

A PROSPECTIVE, SYSTEMATIC LITERATURE REVIEW AND META-ANALYSES TO EVALUATE GLOBAL AND REGIONAL BRAIN VOLUMES BY STRUCTURAL MRI AS BIOMARKERS OF ALZHEIMER'S DISEASE (AD) PROGRESSION

and MMSE was found in the occipital lobes for the combined AD+MCI+HC (Pearson 0.82, p1⁄40.0465) and AD (Pearson 0.99, p1⁄40.01) groups. Conclusions:Based on relatively small number of studies, no apparent relationship between change on brain amyloid burden and cognition in AD was found. In contrast, the negative correlation seen in MCI suggests that PiB PET changes may be a useful biomarker in earlier disease phases. The significant finding in the correlation between changes in amyloid deposition in the occipital lobe and MMSE warrants further study. Limitation included the paucity of studies having longitudinal data on both brain amyloid burden and clinical measures and heterogeneity amongst studies.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy

Multiple intravenous doses of ponezumab, an anti‐amyloid antibody, were evaluated in subjects with mild‐to‐moderate Alzheimers disease (AD).

POOLED AMYLOID PET BASELINE DATA FROM THE BAPINEUZUMAB IV PHASE III TRIALS

mL (n1⁄4516), 5.86 (1.10) mL (n1⁄4518) and 50.56 (22.89) mL (n1⁄4517), respectively. The left hippocampus volume (LHV) was 0.117 mL (95% CI: 0.088-0.145) smaller than the right hippocampus volume (RHV) with volumes of 2.87 (0.56) mL (n1⁄4518) and 2.99 (0.59) mL (n1⁄4518), respectively. Mild AD subjects (MMSE 21) had a larger brain volume (95% CI: 16.392-51.390) and LHV (95% CI: 0.012-0.206) than moderate AD patients (MMSE 20). In contrast significant differences were not observed between mild and moderate AD subjects in the RHVand total hippocampus volume or ventricular volume. Whole brain and ventricles volume were not impacted by APOE4 status of subjects whereas a difference was found for LHV (95% CI:0.074-0.278), RHV (95% CI:0.064-0.283) and total (95% CI:0.148-0.553) hippocampus volume with APOE4-carriers presenting with more atrophied structures. Conclusions: These data from a partial sample of EPOCH trial participants showed differences in whole brain atrophy stage between mild and moderate AD patients and a higher hippocampal atrophy in APOE4-carriers They also suggest that the left hippocampus is more vulnerable to atrophy than the right hippocampus. A comparison of our study brain parameters to ADNI data will also be presented.