Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain.

BACKGROUND: Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain. The clinical trial described in this manuscript is a phase 2, randomized, double-blind, placebo-controlled study investigating the safety and efficacy of tanezumab - a humanized monoclonal antibody that inhibits nerve growth factor - for treatment of SWN-related pain. As the first therapeutic trial for SWN-related pain, it also aims to evaluate trial endpoints, understand recruitment patterns, and improve clinical trial design in this rare disease. AIMS: The primary objective of this trial is to assess the analgesic efficacy of subcutaneous tanezumab 10 mg in subjects with SWN who continue pre-existing pain therapy (excluding non-steroidal anti-inflammatory drugs). The secondary objective is to assess safety in this population. Exploratory objectives include assessment of pain features, quality of life, and predictive biomarkers. METHODS: The study is comprised of four periods (pre-treatment, double-blind treatment, single-arm treatment, safety follow-up) across 10 months with a delayed-start trial design to allow all participants to receive tanezumab. Forty-six participants will be enrolled and randomized 1:1 to receive either tanezumab or placebo subcutaneously in the double-blind treatment period; all participants receive tanezumab during the single-arm treatment period. CONCLUSIONS: This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases. CLINICAL TRIAL REGISTRATION: NCT04163419 on ClinicalTrials.gov.

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

INTRODUCTION: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). METHODS: In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. RESULTS: Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aß1-x and Aß1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. CONCLUSIONS: Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

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 Alzheimer's 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.

Long-term safety and tolerability of bapineuzumab in patients with Alzheimer's disease in two phase 3 extension studies.

BACKGROUND: Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer's disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols. METHODS: The long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses. RESULTS: Because of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7% of the patients who originally received placebo and 66.9% of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1% and 67.6% of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7% and 64.3% of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11% of placebo + bapineuzumab and 4% of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study. CONCLUSIONS: In these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials. TRIAL REGISTRATION: Noncarriers (Study 3002): ClinicalTrials.gov NCT00996918 . Registered 14 October 2009. Carriers (Study 3003): ClinicalTrials.gov NCT00998764 . Registered 16 October 2009.

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

OBJECTIVE: Disability assessment for dementia (DAD) measurements from two phase-3 studies of bapineuzumab in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients were integrated to develop a disease progression model. METHODS: We evaluated longitudinal changes in DAD scores, baseline factors affecting disease progression, and bapineuzumab effect on disease progression. RESULTS: A beta regression model best described DAD disease progression. The estimated treatment effect of bapineuzumab was not significant, consistent with lack of clinical efficacy observed in the primary analysis. The model suggested that progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was similar regardless of APOE ε4 status but more pronounced in patients with mild AD. Baseline disease status, age, memantine use, and years since onset (YSO) had significant effects on baseline DAD scores. AD concomitant medication use, baseline disease status, and YSO had significant effects on disease progression rate, measured by DAD score. CONCLUSIONS: The beta regression model is a sensible modeling approach to characterize functional decline in AD patients. This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further evaluation may be warranted in future studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.

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

INTRODUCTION: The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimer's 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. METHODS: A population-based disease progression model was developed using pooled placebo and bapineuzumab data from two phase-3 studies in APOE ε4 noncarrier and carrier Alzheimer's disease (AD) patients. RESULTS: A beta regression model with the Richard's function as the structural component best described ADAS-cog/11 disease progression for mild-to-moderate AD population. This analysis confirmed no effect of bapineuzumab exposure on ADAS-cog/11 progression rate, consistent with the lack of clinical efficacy observed in the statistical analysis of ADAS-cog/11 data in both studies. Assessment of covariates affecting baseline severity revealed that men had a 6% lower baseline ADAS-cog/11 score than women; patients who took two AD concomitant medications had a 19% higher (worse) baseline score; APOE ε4 noncarriers had a 5% lower baseline score; and patients who had AD for a longer duration had a higher baseline score. Furthermore, shorter AD duration, younger age, APOE ε4 carrier status, and use of two AD concomitant medications were associated with faster disease progression rates. Patients who had an ADAS-cog/11 score progression rate that was not statistically significantly different from 0 typically took no AD concomitant medications. DISCUSSION: The beta regression model is a sensible modeling approach to characterize cognitive decline in AD patients. The influence of bapineuzumab exposure on disease progression measured by ADAS-cog/11 was not significant. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.

Preservation of brain nerve growth factor in mild cognitive impairment and Alzheimer disease.

BACKGROUND: The status of nerve growth factor (NGF) levels during the prodromal phase of Alzheimer disease (AD), characterized by mild cognitive impairment (MCI), remains unknown. OBJECTIVE: To investigate whether cortical and/or hippocampal NGF levels are altered in subjects with MCI or different levels of AD severity. DESIGN AND MAIN OUTCOME MEASURES: An NGF enzyme-linked immunosorbent assay determined protein levels in the hippocampus and 5 cortical areas in people clinically diagnosed as having no cognitive impairment, MCI, mild AD, or severe AD. SETTING AND PATIENTS: Subjects were from the Rush Religious Orders Study and the University of Pittsburgh Alzheimer's Disease Research Center (Pittsburgh, Pa). RESULTS: We found no changes in cortical or hippocampal NGF levels across groups; in MCI, levels did not correlate with an increase in choline acetyltransferase activity in these regions. CONCLUSION: Brain NGF levels appear sufficient to support the cholinergic plasticity changes seen in MCI and remain stable throughout the disease course.

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

OBJECTIVE: Ponezumab (PF-04360365) is a humanized anti-amyloid beta (Aß) 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 Aß. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. METHODS: Subjects 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. RESULTS: All 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 Aß(1-x) and Aß(1-40) increased dose-dependently. CONCLUSIONS: Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma Aß species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.

In Alzheimer's disease (AD), loss of cortical and hippocampal choline acetyltransferase (ChAT) activity has been correlated with dementia severity and disease duration, and it forms the basis for current therapies. However, the extent to which reductions in ChAT activity are associated with early cognitive decline has not been well established. We quantified ChAT activity in the hippocampus and four cortical regions (superior frontal, inferior parietal, superior temporal, and anterior cingulate) of 58 individuals diagnosed with no cognitive impairment (NCI; n = 26; mean age 81.4 +/- 7.3 years), mild cognitive impairment (MCI; n = 18; mean age 84.5 +/- 5.7), or mild AD (n =14; mean age 86.3 +/- 6.6). Inferior parietal cortex ChAT activity was also assessed in 12 subjects with end-stage AD (mean age 81.4 +/- 4.3 years) and compared to inferior parietal cortex ChAT levels of the other three groups. Only the end-stage AD group had ChAT levels reduced below normal. In individuals with MCI and mild AD, ChAT activity was unchanged in the inferior parietal, superior temporal, and anterior cingulate cortices compared to NCI. In contrast, ChAT activity in the superior frontal cortex was significantly elevated above normal controls in MCI subjects, whereas the mild AD group was not different from NCI or MCI. Hippocampal ChAT activity was significantly higher in MCI subjects than in either NCI or AD. Our results suggest that cognitive deficits in MCI and early AD are not associated with the loss of ChAT and occur despite regionally specific upregulation. Thus, the earliest cognitive deficits in AD involve brain changes other than simply cholinergic system loss. Of importance, the cholinergic system is capable of compensatory responses during the early stage of dementia. The upregulation in frontal cortex and hippocampal ChAT activity could be an important factor in preventing the transition of MCI subjects to AD.