Alzheimer’s pernicious amyloid-beta plaques and tau tangles, discussed last week, remain important targets for the biotech industry. In the past few years, however, companies have begun to search more broadly for new treatments. This Weekly looks at products in development that use different strategies to fight this heartbreaking illness.



Loss of neurons is Alzheimer’s signature, devastating effect. What if we could jump start the development of new brain cells? Two companies are trying to do just that.

Neurotrope Biosciences (New York, NY) is developing bryostatin, a drug that activates protein kinase C epsilon (PKCꞓ). This protein plays a key role in forming memories. In animal models of stroke, traumatic brain injury, and Alzheimer’s disease, bryostatin appears to restore deficits in synapses (connections between brain cells) and decrease cell death. These results suggest that bryostatin could help to prevent the loss of neurons and restore and generate new synapses.

Phase II clinical studies of late-stage Alzheimer’s patients demonstrated improved cognitive function as measured by the Severe Impairment Battery Scale (SIB), a standard tool for evaluating treatment response in advanced Alzheimer’s. Their improvement was greater than that seen in patients given the placebo, but the difference was not statistically significant. A Neurotrope Biosciences spokesperson says that it considers the Phase II study exploratory, designed to determine correct dosing. The company is planning a larger confirmatory trial in hopes of demonstrating statistically significant efficacy.

Neuronascent (Clarksville, MD) also aims to develop small molecule activators of neurogenesis. By screening large chemical libraries, the company has identified compounds that show promise of sparking neurogenesis from adult neural stem cells in both tissue culture and mouse models.

The company’s lead compound, NNI-362, promoted the growth of new hippocampal neurons in mice. The new cells migrated to the correct location and differentiated. Moreover, they survived long enough to reverse previously observed cognitive declines. The hippocampus is one of the first regions of the brain to show damage in AD and is thought to play a role in memory formation and spatial navigation. Neuronascent is preparing for Phase I trials of NNI-362.



Neuroinflammation is one of the drivers of neurodegeneration in Alzheimer’s disease, multiple sclerosis and other brain disorders. Research conducted at Stanford University (Palo Alto, CA) suggests that the protein c1q is present at higher levels in people with Alzheimer’s disease. C1q accumulates at neuronal synapses, the key points of communication between brain cells. This protein also signals other immune cells, such as macrophages—which then chomp up cellular debris present in affected brains. The accumulation of c1q could account for the loss of synapses and accompanying mental decline.

South San Francisco-based Annexon is working on a promising therapy that centers on controlling inflammation in the brain. ANX005, now in preclinical development, is a monoclonal antibody that mops up excess c1q.

Another company homing in on neuroinflammation is vTv Therapeutics (High Point, NC). Their drug, Azeliragon, now in Phase III clinical development, is a small molecule inhibitor of the receptor for advanced glycation endproducts (RAGE). RAGE is present on many neurological cell types. Its activation may promote amyloid-beta production and transport, tau aggregation, and chronic inflammation. Preventing any of these developments could improve Alzheimer’s symptoms.



Rather than target Aβ plaques directly, Yumanity Therapeutics (Cambridge, MA) is trying to identify the problems they cause. Yumanity scientists have engineered yeast cells to overproduce the Aβ protein and monitor its detrimental effects, such as disrupting the action of other important cellular proteins.

Surprisingly, yeast share many molecular pathways with humans. This similarity means researchers can use the little fungi to screen for potential drugs that address protein disruption. Promising candidates are then tested in Alzheimer’s patient-derived cells. By tackling a completely different disease mechanism, the new compounds may achieve greater success than seen so far with drugs that act directly on amyloid beta or tau. Yumanity is currently in the lead-optimization phase of pre-clinical development.

In partnership with Biogen (Cambridge, MA), Cambridge-based Proteostasis Therapeutics is targeting AD-associated protein aggregates by activating proteasomes. These cellular components get rid of damaged proteins and dysfunctional protein aggregates by dismantling their chemical bonds. The protein USP14 inhibits proteasomes. Proteostasis is working on the preclinical development of a USP14 inhibitor that allows proteasomes to fully activate in AD patients. This makes it more likely that the proteasomes will recognize and destroy amyloid plaques and tau tangles.

Oryzon Genomics (Barcelona, Spain) is taking an epigenetic approach to Alzheimer’s. Epigenetic modifications are chemical changes to gene sequences that don’t change the information content but instead affect how much that content is used – in other words, the amount of a particular protein that the body makes.

Oryzon researchers identified an enzyme, lysine-specific histone demethylase 1 (LSD1), which makes epigenetic modifications to genes that results in “turning them down” so they produce less of the corresponding protein. LSD1 makes these changes to genes that support neuronal survival. Oryzon scientists have designed a drug, ORY-2001, that inhibits LSD1. Inhibiting LSD1 could mean that more neurons survive in AD patients, leading to improved cognitive function. ORY-2001 recently entered Phase II clinical trials.



Finally, the elusive AD treatment may lie in pursuing a well-established target after all—but at a new angle. That’s where Ionis Pharmaceuticals (Carlsbad, CA) is headed in the Phase I/IIA clinical studies of their drug, IONIS-MAPT. This antisense drug targets the source of the tangles associated with AD. Like other antisense drugs, IONIS-MAPT destroys tau mRNA, thereby diminishing tau protein production.

It’s encouraging to know how many therapies are in the Alzheimer’s treatment pipeline. With more hard work and investment, perhaps one of the many introduced above will lead to a cure.

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