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Initial promise of immunotherapeutics targeting amyloid-β strengthens the possibility of early intervention in Alzheimer’s disease

Clinical studies of immunotherapies show initial promise for early intervention in Alzheimer’s disease. There are 2 amyloid-β-targeted immunotherapies approaches being studied: immunotherapy via administering Aβ antibodies (passive immunotherapy) and immunotherapy via induction of a humoral immune response (active immunotherapy).1

Amyloid plaque reduction with immunotherapy targeted at Aβ aggregates is seen in individuals with prodromal and mild Alzheimer’s disease, accompanied by a slowing of cognitive decline. The eagerly-awaited results of ongoing phase III clinical trials will ultimately determine whether amyloid-targeted immunotherapies will deliver benefits to patients.

In her keynote presentation, Dr Samantha Budd Haeberlein, Biogen, Boston, USA identified that while animal models and early clinical studies of immunotherapies show initial promise for early intervention in Alzheimer’s disease, results of ongoing phase III clinical trials will ultimately answer the question of whether amyloid-targeted immunotherapies will result in positive outcomes for Alzheimer’s disease patients.

Ongoing and future late-phase clinical trials will ultimately answer the question of whether amyloid-targeted immunotherapies can bring benefit to Alzheimer’s disease patients

Intervening at an early stage of Alzheimer’s disease is a goal of developmental therapies.2 The accumulation of amyloid-β (Aβ) plaques in the brain occurs early in Alzheimer’s disease, decades before manifest Alzheimer’s dementia, and represents a key therapeutic target.

The amyloid hypothesis suggests that Alzheimer’s disease is caused by a chronic imbalance between the production and clearance of Aβ, leading to the accumulation of cytotoxic species of amyloid in brain areas including those serving memory, sense of smell, and cognition.3 The aggregation of Aβ is thought to trigger a cascade of disease-causing processes such as inflammation, tau-tangle formation, synapse dysfunction and cell death, which ultimately leads to dementia.

Although the relevant pathological form of Aβ remains elusive, aggregated amyloid in the form of soluble oligomers and/or insoluble fibrils may play an important role in the disease process, and are causative in Alzheimer’s disease.3,4 There are currently several amyloid-targeted immunotherapies in development which bind to different targets, e.g. fibrillary and oligomeric Aβ, or soluble monomeric Aβ, and differences in binding patterns are likely to relate to clinical effect.

Immunotherapies that are selective for Aβ aggregates demonstrate a reduction in amyloid plaque deposits in mouse models that correlate with change in brain cell functionality, including benefits in cognition: restoration of neurite calcium levels, recruitment of microglial cells and induction of phagocytosis-mediated clearance of amyloid plaques.5,6

Targeting Aβ has been the focus of research for many years, although clinical trials to date have not yet furnished new medicines in the clinic. The failure of many trials may be due in part to the inclusion of patients without a certain AD diagnosis and too late in the disease progression, for whom reversal of the damage is not possible. Hence the focus of recent and upcoming trials is to both ensure a biomarker-based diagnosis of AD.

Amyloid plaque reduction with immunotherapy has been seen in patients with prodromal Alzheimer’s disease and in mild Alzheimer’s disease dementia, which is accompanied by a slowing of cognitive decline.7,8 The validation of these preliminary results in two large-scale phase III clinical studies is currently being performed.

This article provides highlights from Biogen’s keynote presentation at CTAD

Further reading:

https://progress.im/en/content/β-amyloid-remains-compelling-target

References
  1. Winblad B et al. Alzheimer's Research & Therapy. 2014; 6:7
  2. Jack CR Jr et al. Lancet Neurol. 2010;9:119-28.
  3. Selkoe DJ & Hardy J. EMBO Mol Med. 2016;8:595-608.
  4. Wang ZX et al. Mol Neurobiol. 2016;53:1905-24.
  5. Savigny J et al. Nature. 2016;537:50-6.
  6. Kastenaka KV et al. Neurobiol Dis. 2016;536:12549-58.
  7. von Rosensteil P et al. CTAD 2018; October 24-27: Poster LBP19.
  8. von Rosensteil P et al. CTAD 2018; October 24-27: Poster P80.
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