|·||Crenezumab is currently being evaluated in a Phase 2 clinical prevention trial in Colombia in 300 cognitively healthy individuals
of whom 200 are genetically predisposed to develop early AD. As of January 2019, two Phase 3 clinical trials, CREAD 1 and CREAD
2, in prodromal to mild AD patients were discontinued after an interim analysis conducted by our collaboration partner Genentech.|
Figure 8: Crenezumab overview
Ref: (1) Amyloid related imaging abnormality-edema; (2) Lin
et al, CTAD 2017; (3) Budd-Heaberlein, JPAD 2017; (4) Andelkovic, CTAD 2017; (5) Siemers et al, Alzheimer’s & Dementia
(6) Logovinsky et al, Alzheimer's Research & Therapy 2016; (7) Swanson et al, AAIC 2018 (8) Salloway et al, New Engl J Med
Figure 8 above summarizes crenezumab’s
multiple neuroprotective mechanisms of action, in particular direct binding and inhibition of toxic Abeta oligomers which may demonstrate
crenezumab's clinical benefit.
Results from pre-clinical studies
Abeta is produced by the breakdown of a
larger protein called amyloid precursor protein, or APP. The Abeta fragment containing 42 amino acids, or Abeta 1–42,
is believed to be associated with the highest toxicity of the Abeta fragments. Misfolded Abeta subunits combine to form oligomers
and fibrils that are found in amyloid plaques. Data resulting from preclinical and clinical studies show that crenezumab binds
with high affinity to amino acids 12–24 of Abeta 1–42, as well as multiple forms of Abeta, including monomers,
oligomers, and fibrils, which reduces Abeta 1–42 induced cytotoxicity. Furthermore, these data indicate that crenezumab
enhances the uptake of neurotoxic Abeta oligomers by microglial cells, the resident immune cells of the brain, which normally respond
to neuronal damage and remove the damaged cells for subsequent disposal and clearance from the brain.
A challenge with agents acting to remove
Abeta is the potential to induce inflammation leading to vasogenic edema, which is accumulation of fluid in the brain that can
lead to headaches, loss of coordination and disorientation. The fluid can be seen clearly on MRI scans and is referred to as ARIA-E.
Crenezumab is engineered on an IgG4 backbone, which was selected because IgG4 antibodies are associated with a greatly reduced
risk of causing inflammation. As a result, crenezumab’s IgG4 structure activates microglial cells to clear Abeta without
producing inflammation and associated vasogenic edema, as demonstrated in the Phase 2 clinical studies. In contrast, ARIA-E and
other inflammation-related side effects have been observed in other antibodies with an IgG1 backbone.
Positioning of crenezumab’s
The formation of neurotoxic Abeta pathology
in AD is caused by misfolding, oligomerization and aggregation of Abeta. This process leads to the formation of smaller oligomeric
species and larger extracellular plaques. To reduce or reverse disease progression, the therapeutic anti-Abeta strategy focuses
on targeting all Abeta species that mediate neurotoxicity in the CNS of patients.