Gene G. Kinney

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis

BACKGROUND Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimers disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patients treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.

First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction

PURPOSE Light chain (AL) amyloidosis is caused by the accumulation of misfolded proteins, which induces the dysfunction of vital organs. NEOD001 is a monoclonal antibody targeting these misfolded proteins. We report interim data from a phase I/II dose-escalation/expansion study of NEOD001 in patients with AL amyloidosis and persistent organ dysfunction (NCT01707264). PATIENTS AND METHODS Patients who had completed at least one previous anti-plasma cell-directed therapy, had partial hematologic response or better, and had persistent organ dysfunction received NEOD001 intravenously every 28 days. Dose levels of 0.5, 1, 2, 4, 8, 16, and 24 mg/kg were evaluated (3 + 3 study design). Primary objectives were to determine the maximum tolerated dose and the recommended dose for future studies and to evaluate safety/tolerability. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and organ responses on the basis of published consensus criteria. RESULTS Twenty-seven patients were enrolled in seven cohorts (dose-escalation component). No drug-related serious adverse events (AEs), discontinuations because of drug-related AEs, dose-limiting toxicities, or antidrug antibodies were reported. The most frequent AEs were fatigue, upper respiratory tract infection, cough, and dyspnea. Recommended dosing was 24 mg/kg. Pharmacokinetics support intravenous dosing every 28 days. Of 14 cardiac-evaluable patients, eight (57%) met the criteria for cardiac response and six (43%) had stable disease. Of 15 renal-evaluable patients, nine (60%) met the criteria for renal response and six (40%) had stable disease. CONCLUSION Monthly infusions of NEOD001 were safe and well tolerated. Recommended future dosing was 24 mg/kg. Organ response rates compared favorably with those reported previously for chemotherapy. A phase II expansion is ongoing. A global phase III study (NCT02312206) has been initiated. Antibody therapy targeting misfolded proteins is a potential new therapy for the management of AL amyloidosis.

Vascular alterations in PDAPP mice after anti-Aβ immunotherapy: Implications for amyloid-related imaging abnormalities

Clinical studies of β‐amyloid (Aβ) immunotherapy in Alzheimers disease (AD) patients have demonstrated reduction of central Aβ plaque by positron emission tomography (PET) imaging and the appearance of amyloid‐related imaging abnormalities (ARIA). To better understand the relationship between ARIA and the pathophysiology of AD, we undertook a series of studies in PDAPP mice evaluating vascular alterations in the context of central Aβ pathology and after anti‐Aβ immunotherapy.

Sustained levels of antibodies against Aβ in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice.

Passive immunization with anti-Aβ antibodies leads to the reduction of AD-like neuropathology in transgenic mice. Previously we showed that anti-Aβ antibodies enter the brain and bind to amyloid plaques. Now using (125)I-labeled 3D6, the mouse parent antibody of the clinical candidate bapineuzumab, we further characterized the pharmacokinetic profile of this antibody in the brain and serum. Our studies demonstrated that following a single intravenous injection, the labeled antibody accumulates and persists in plaque rich regions of the brain in transgenic PDAPP mice. Accumulation was specific to amyloid since it did not occur in non-transgenic animals lacking human APP, could not be measured in transgenic animals prior to plaque deposition, and correlated with the level of plaque burden in aging transgenic mice. After a single intravenous injection, CNS levels of (125)I-labeled 3D6 continued to increase for 14 days even as serum levels of the antibody declined. The calculated half-life of antibody in the circulation was 6 days, while antibody levels in the CNS remained stable for nearly a month. When given at supra-therapeutic levels, unlabeled antibody did not compete with tracer levels of labeled antibody for accumulation in the CNS, indicating that the binding capacity of plaques was very high. Our results demonstrate that even when administered in the periphery at very low (tracer) doses, 3D6 and bapineuzumab cross the blood brain barrier to accumulate in plaque rich regions of the brain. CNS clearance is markedly slower than in the serum and correlates with binding to deposited amyloid in a transgenic model of Alzheimers disease.

A bifunctional peptide, “peptope”, for pre-targeting antibody 7D8 to systemic amyloid deposits

At present, there are two amyloid fibril-reactive antibodies in clinical trial for the treatment of patients with systemic light chain-associated (AL) amyloidosis [1,2]. In an effort to potentially enhance the utility of these antibodies, we have developed a system that would allow these reagents to be used as immunotherapies for patients with other kinds of systemic amyloidosis, notably patients with transthyretin-associated (ATTR) amyloidosis. We have synthesized a bi-functional peptide (peptope) that comprises the pan-amyloid reactive peptide, p5, with a linear epitope recognized by the 7D8 monoclonal antibody (mAb), which specifically targets AA and light-chain amyloid (Figure 1(A)). The peptope was designed to facilitate the binding of mAb 7D8 with amyloid deposits for which it did not display a natural reactivity, e.g., ATTR. The use of a bifunctional peptope may provide enhanced binding and expand the utility of mAbs already present in the clinical space for the treatment and removal of diverse amyloid deposits, regardless of the precursor protein from which they are comprised.

Microvascular changes associated with passive immunotherapy in PDAPP mice: Potential implication for the etiology of vasogenic edema

ated protein tau. Clinically AD is characterized by the loss of memory and cognitive decline that can be associated with other symptoms including olfactory alterations. We have produced a transgenic mouse model that develops a tau aggregation similar to that observed in human tauopathies, such as AD. This transgenic mouse line expresses human P301Smutant tau under the control of the Thy 1 promoter. In this mouse line we have investigated the presence of olfactory dysfunction and how this correlates with the presence of tau pathology and cell death in areas of the mouse brain involved in olfaction. Methods: Tau pathology was characterized in P301S tau mouse brain tissue using immunohistochemistry with phosphorylation-independent and phosphorylation-dependent anti-tau antibodies. Neuronal cell death was investigated by immunohistochemistry with anti-neuronal nuclei antibody (NeuN) followed by stereology. Olfactory sensitivity was tested by an ascending staircase method using Butanol-1 or Vanilla extract. Results: A progressive tauopathy was found in the olfactory bulb and piriform cortex of transgenic human P301S tau mice. This was associated with progressive neuronal loss in the anterior and posterior piriform cortex. Furthermore, the human P301S tau mice displayed a significant reduction in olfactory sensitivity over time.Conclusions:We have observed progressive tau pathology, neuronal cell death and abnormal olfactory behavior in the human P301S tau transgenic mice. The olfactory alteration in this transgenic mouse line provides an in vivo system where to test mechanism-based therapies for the common and yet untreatable tauopathies.

NEOD001 DEMONSTRATES CARDIAC BIOMARKER RESPONSES IN PATIENTS WITH LIGHT CHAIN AMYLOIDOSIS: RESULTS FROM THE PHASE 1/2 STUDY

Background: Current therapies used to treat AL amyloidosis limit light chain (LC) production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits

Translational Research in Alzheimer’s Disease for Development of Antibody-Based Therapeutics

Clinical and non-clinical biomarkers play a critical role in translational research in Alzheimer’s Disease (AD). Validation of such biomarkers provides the necessary tools to predict target engagement and efficacy in non-clinical and clinical studies. For therapies that target amyloid-beta (Aβ), it is desirable for a compound that decreases brain Aβ in non-clinical studies to correlate with a clinical decrease in brain amyloid load as measured by PET scan of an amyloid binding ligand. Such results provide a set of non-clinical and clinical biomarkers to test potential compounds before moving into large Phase 3 clinical trials. CSF phospho-tau and total tau are also promising biomarkers for therapies that target either Aβ or tau. Volumetric MRI and FDG–PET require further studies before they can be considered biomarkers indicative of response to AD disease modifiers.

Amyloid-related imaging abnormalities (ARIA) in Alzheimer’sdisease patients treated with bapineuzumab: A retrospective analysis

BACKGROUND Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimers disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patients treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.

Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab

BACKGROUND Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimers disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. METHODS Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patients treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. FINDINGS 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). INTERPRETATION ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. FUNDING Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.