The biotech world is still aiming to stop Alzheimer’s disease despite many recent drug attempts missing the mark in late phase clinical trials. While the effects of Alzheimer’s are well known (the degeneration of the brain over time due to nerve cell death), the cause of the disease remains a mystery.
As people live longer worldwide, the incidence of Alzheimer’s continues to increase, and the current approach only manages symptoms. With new hope from Biogen Idec (Cambridge, MA) alongside other encouraging pathways in drug development, the quest for a cure remains strong.
In this issue, we will touch upon what is known about Alzheimer’s and circle in on the current state of drug discovery and development.
CIRCLING IN ON THE AMYLOID HYPOTHESIS
Amongst a sea of alternative theories, the current consensus points to Alzheimer’s disease being associated with the buildup of beta-amyloid plaques (Aβ) in patients’ brains. What exactly are Aβ plaques?
To begin, the amyloid precursor protein (APP) is characterized as transmembrane—spanning the entire membrane—and is found in the synapses of neurons. APP is thought to play a role in the formation of synapses, or the gaps between neurons through which chemical messages pass.
Aβ plaques derive from the cleavage of APPs. Aβ is released by the cleavage of the extracellular portion of APP via the enzyme beta-secretase 1 (BACE 1). Then, the individual Aβ molecules subsequently clump together to form the plaques associated with Alzheimer’s.
Last year researchers at Stanford School of Medicine (Stanford, CA) demonstrated that Aβ binding to a receptor on nerve cells disrupted the function of the synapse. This may be the mechanism by which the Aβ plaques cause Alzheimer’s. The ability to interrupt this interaction could potentially preserve functioning nerve cells and points the way to potential drug targets.
Another approach to Alzheimer’s drug development involves the inhibition of Aβ production in the first place. Several big players—such as Lilly (Indianapolis, IN), AstraZeneca (London, England), and Biogen Idec—are sharpening their arrows with hopes of making it on the board.
TARGETING TAU PROTIENS
Currently, most Alzheimer’s therapies in development target Aβ plaques; however, some researchers have their eye on another brain protein called tau.
Tau is concentrated in the neurons and is primarily understood as a component in stabilizing nerve cell structure. Abnormal aggregates of tau form tangles within nerve cells; they are correlated with the onset of Alzheimer’s along with the characteristic plaque formations.
Naturally, a tau-aggregation inhibitor seems like a good therapeutic to test, and Singapore-based TauRx is amidst late stage clinical trials with a developmental drug targeting the tau pathway.
MONOCLONAL ANTIBODIES MAKE THEIR MARK
Last week Biogen Idec announced positive results in early stage clinical trials of developmental drug BIIB037, a monoclonal antibody (mAb) targeting Aβ and sights are set on Phase III.
Investigators reported time-dependent and dose-dependent reductions in Aβ levels. The more of the drug given to the patients and the longer they were exposed, the greater the reduction in Aβ—the gold standard for Alzheimer’s drug efficacy studies. BIIB037 demonstrating time and dose dependency makes it much less likely that the reduction of study subject’s Aβ levels is caused by other factors.
Other companies have attempted to develop mAb therapies for Aβ and ended up abandoning ship. Why is Aβ still being pursued as a drug target? Different mAbs attach to different parts of Aβ and the outcome of one mAb trial does not necessarily predict the outcome of another.
GENETICS PLAYS A ROLE
About 70% of Alzheimer’s cases are thought to have at least some genetic association, with different genes being implicated depending on the type of Alzheimer’s.
A gene found on chromosome 19 called the apolipoprotein E gene (APOE) influences the development of late-onset Alzheimer’s. Individuals with different variants of the APOE gene have different risk profiles:
- Variant ε2 (APOE2) is rare and possibly lessens or delays Alzheimer’s onset.
- Variant ε3 (APOE3) is neutral.
- Variant ε4 (APOE4) is associated with a significantly increased risk of Alzheimer’s.
The APOE proteins plays a role in clearing Aβ from the brain, with APOE4 carrying out this function less efficiently than the other variants. There is also some evidence that APOE4 contributes to the breakdown of the blood-brain barrier seen in patients, resulting in increased brain inflammation—another marker of Alzheimer’s. A better understanding of APOE4’s role in Alzheimer’s onset may lead to the development of a whole new class of drug.