Wednesday, May 27, 2015

A randomized, placebo-controlled, double-blind, phase 2 trial of Etanercept in Alzheimer disease

Objectives: To determine whether the tumor necrosis factor α inhibitor etanercept is well tolerated and obtain preliminary data on its safety in Alzheimer disease dementia. Methods: In a double-blind study, patients with mild to moderate Alzheimer disease dementia were randomized (1:1) to subcutaneous etanercept (50 mg) once weekly or identical placebo over a 24-week period. Tolerability and safety of this medication was recorded including secondary outcomes of cognition, global function, behavior, and systemic cytokine levels at baseline, 12 weeks, 24 weeks, and following a 4-week washout period. This trial is registered with EudraCT (2009-013400-31) and (NCT01068353). 
Results: Forty-one participants (mean age 72.4 years; 61% men) were randomized to etanercept (n = 20) or placebo (n = 21). Etanercept was well tolerated; 90% of participants (18/20) completed the study compared with 71% (15/21) in the placebo group. Although infections were more common in the etanercept group, there were no serious adverse events or new safety concerns. While there were some interesting trends that favored etanercept, there were no statistically significant changes in cognition, behavior, or global function. 
Conclusions: This study showed that subcutaneous etanercept (50 mg/wk) was well tolerated in this small group of patients with Alzheimer disease dementia, but a larger more heterogeneous group needs to be tested before recommending its use for broader groups of patients. Classification of evidence: This study shows Class I evidence that weekly subcutaneous etanercept is well tolerated in Alzheimer disease dementia. 

Reference: Neurology May 26, 2015 vol. 84 no. 21 2161-2168

Monday, March 30, 2015

Aducanumab Buoyed by Phase 1 Data and Hungry Investors

Last week in Nice, France, a single story took the 12th International Conference on Alzheimer’s and Parkinsons’s Diseases by storm. Everyone who was not on Mars on March 20 probably heard from their local radio or TV station, Twitter, or favorite online source that BIIB37, aka aducanumab, the anti-Aβ antibody developed by the company Biogen in Cambridge, Massachusetts, improved Alzheimer’s symptoms in a large Phase 1 trial. Expectations had been high ever since a Biogen executive told investors at a bank conference in Boston last December that aducanumab was showing a dose-dependent benefit on both amyloid removal and cognition.

Sunday, March 22, 2015

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: