Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using ¹¹C-Pittsburgh compound B (¹¹C-PiB)-PET.

Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an ¹¹C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region.

Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in ¹¹C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = −0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = −0.068; p = 0.027; 1.0 mg/kg vs placebo δ = −0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results.

Conclusions: The ¹¹C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.

Published in: Neurology August 25, 2015 vol. 85 no. 8 692-700

Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease

Introduction

CAD106 is designed to stimulate amyloid-β (Aβ)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections.

Methods

Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer’s disease (AD) aged 40 to 85 years. Patients were randomized to receive 150μg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 μg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aβ-specific antibody response in serum and Aβ-specific T-cell response (core only). Comparable Aβ-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments.

Results

Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aβ-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aβ1–6 nor Aβ1–42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier.

Conclusions

No unexpected safety findings or Aβ-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aβ-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD.

Full text: (doi:10.​1186/​s13195-015-0108-3) 

Immunotherapeutic Approaches for Alzheimer’s Disease

Aβ and Tau Conformational Changes in AD

(1–5) (1) APP undergoes normal cleavage by β and γ-secretase (PS is part of the γ-secretase complex) to produce the (2) normal sAβ. sAβ can undergo a conformational change to (3) a β sheet-rich conformer that further aggregates to form (4) soluble, toxic Aβ oligomers. These also may precipitate to form (5) relatively inert fibrils in amyloid plaques and congophilic amyloid angiopathy.

(A–F) (A) Tau is a microtubule-binding protein. Tau can undergo (B) hyperphosphorylation or (C) a conformational change to a β sheet conformer. These species can both further change to (D) hyperphosphorylated tau in a β sheet-rich form that is predisposed to further aggregation into (E) toxic, tau oligomers. These can precipitate to form (F) PHFs in the form of NFTs.

(I and II) The Aβ β sheet conformers and Aβ oligomers may cross-seed, under some circumstances, with intermediate tau species in a β sheet conformation and with tau oligomers, to synergistically exacerbate AD pathology.

The most effective immunotherapeutic approaches for AD will need to be able to concurrently reduce levels of the toxic Aβ and tau oligomeric species.

Different Immunotherapeutic Approaches to Ameliorate AD Pathology

(A) Active immunization can be performed using Aβ peptides, phosphorylated tau (ptau) peptides, or preparations such as pBri as an immunogen. These immunogens are presented to B cells by antigen-presenting cells (APC). Use of Aβ peptides or ptau peptides will give rise to the production by B cells of antibodies to Aβ or ptau epitopes, respectively. Use of pBri (or equivalent preparations of an immunogen that is a non-self peptide, in a stabilized, oligomeric β sheet conformation) will lead to the production of antibodies that recognize both Aβ and tau pathological conformers (but not normal monomeric sAβ or tau proteins).

(B) Passive immunization can be performed by the production of mAbs that bind to Aβ, ptau, or β sheet pathological conformations. These antibodies need to be infused systemically in concentrations sufficient for adequate BBB penetration (typically only ∼0.1% of a systemically injected mAb will cross the BBB).

Once antibodies cross the BBB (using either active or passive immunization), they will act to enhance the clearance and degradation of their targets. Additional or alternative mechanisms may include disaggregation or neutralization of their target (i.e., blocking of toxicity). Antibodies to Aβ will recognize normal sAβ, oligomeric Aβ, and/or deposited fibrillar Aβ (with varying preference depending on the type[s] of antibodies to Aβ). Similarly, antibodies to ptau will recognize monomeric ptau species, oligomeric tau, and/or NFTs, with varying preference depending on the specific anti-ptau antibody(ies). Antibodies to β sheet will simultaneously act to ameliorate both Aβ and tau pathologies by specifically binding pathological conformers, without binding to normal sAβ or tau.

(C) Stimulation of innate immunity also can be used to ameliorate AD pathology by enhancing microglia/macrophage function via TLRs or related pathways. Microglia/macrophages are stimulated similarly by the immune complexes produced using active or passive immunization approaches.

Reference: DOI: http://dx.doi.org/10.1016/j.neuron.2014.12.064

Opportunity to get involved in research to detect early Alzheimer's disease by participating in a registry

Biogen Idec is running a registry for researchers to advance their knowledge of early Alzheimers Disease. If you're having memory problems or are worried you're at risk of early Alzheimer’s, you can play an important role in improving our understanding of the disease. You will have the opportunity to learn about and take part in local studies looking at new treatment options. You will also receive some reimbursement for your time.

More about the registry:

• There will be 14000 participants in this registry
• This registry will take place over two years requiring no visits or overnight stays
• This registry is taking place nationwide and you can complete it from the comfort of you own home.

If you are interested, the full study details and eligibility criteria are listedhere.

Eligibility Criteria:

Participants must:

• be between 50 – 85 years old
• be willing to answer questionnaires periodically over a 2 year block of time
• be concerned that you are at risk for developing early Alzheimers have difficulty with memory or thinking skills

Participants must not:

• already be diagnosed with Alzheimers Disease
• have had events of stroke, epilepsy, or Parkinson's Disease Please complete the online questionnaire to check if you’re eligible for the trial.

ADDITIONAL INFO ON THE REGISTRY

If you agree to participate in the registry, you will be asked to complete an online questionnaire to assess how you understand, remember, and communicate information. This questionnaire will be repeated every 3 – 6 months. You will also be asked to take a brief 10 – 15 telephone call, which will be repeated every 6 months. The registry team may use your answers to see if you may qualify for another clinical research study. If you are interested in participating, we will ask for your permission to send your contact details to the study center. After you speak with someone at the study center, you can decide whether or not you want to participate in the study.

Please complete the online questionnaire to check if you’re eligible for the registry.

Learn why I’m talking about Clinical Trials

Worried you are at risk of developing Alzheimer's disease?

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ_1-42, total tau and p-tau₁₈₁ levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. 

Fig. 1  Chronological relationship among pathology, clinical symptoms and biomarkers. Based on biomarker studies, Ab accumulation appears to start more than 20 years before the onset of dementia. Amyloid positron emission tomography (PET) or a decrease in CSF Aβ1-42 levels may indicate Ab accumulation in the brain, even in preclinical stage of AD. Neocortical tau pathology correlates with the timing of symptom onset and start approximately 10 years before the onset of dementia. However, these findings need to be reconciled with reports that tau pathology is observed in the prior to Ab pathology. FDG, 2-[18F]-fluoro-2-deoxy-D-glucose; MCI, mild cognitive impairment. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

Fig. 2  Sequential process of amyloid precursor protein (APP) metabolism and production of amyloid beta species. Transmembrane APP is cleaved by α-secretase followed by γ-secretase to produce non-toxic amyloid species (non-amyloidogenic pathway, left blue thick arrow), while, through the amyloidogenic pathway (right red thick arrow), toxic Aβ species are generated by β-and γ-secretase. The toxic Aβ species including Aβ1-42and Aβ1-40 are easily aggregated and produce highly toxic Aβ oligomers. Both processes produce soluble ectodomains [soluble APPα (sAPPα) and sAPPβ] and identical intracellular C-terminal fragment of APP (AICD). RAGE and LRP-1 located in bloodbrain barrier (BBB) are involved in the transport of the Ab between the brain and peripheral blood.

Fig. 3  Schematic presentation of tau mediated neurodegeneration. Phosphorylation and dephosphorylation of tau control the stability of microtubule. Hyperphosphorylation of tau induces disassembly of mitrotubules, causing axonal transport failure. Unbound tau produces oligomers or aggregates which congest axonal transport, and the tau pathology is synaptically transmitted. Reproduced from [Therapeutic strategies for tau mediated neurodegneration, Yoshiyama Y, Lee VM and Trojanowski JQ, J Neruol Neurosurg Psychiatry 84:784-795, 2013] with permission from BMJ Publishing Group Ltd.

BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the β-secretase enzyme required for the production of the neurotoxic β-amyloid (Aβ) peptide that is widely considered to have a crucial early role in the etiology of Alzheimer?s disease (AD). As a result, BACE1 has emerged as a prime drug target for reducing the levels of Aβ in the AD brain, and the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. It has proven difficult for the pharmaceutical industry to design BACE1 inhibitor drugs that pass the blood?brain barrier, however this challenge has recently been met and BACE1 inhibitors are now in human clinical trials to test for safety and efficacy in AD patients and individuals with pre-symptomatic AD. Initial results suggest that some of these BACE1 inhibitor drugs are well tolerated, although others have dropped out because of toxicity and it is still too early to know whether any will be effective for the prevention or treatment of AD. Additionally, based on newly identified BACE1 substrates and phenotypes of mice that lack BACE1, concerns have emerged about potential mechanism-based side effects of BACE1 inhibitor drugs with chronic administration. It is hoped that a therapeutic window can be achieved that balances safety and efficacy. This review summarizes the current state of progress in the development of BACE1 inhibitor drugs and the evaluation of their therapeutic potential for AD.

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