Neuro-Bio Ltd. has published animal data it says confirms its hypothesis about an underlying cause of Alzheimer's and showing its lead molecule NBP-14 decreases levels of brain amyloid and restores memory in a mouse model of the disease.

That is said to validate the theory of its founding scientist Susan Greenfield, which holds that in the context of neurodegeneration in the adult brain, a peptide derived from the enzyme acetylcholinesterase (AChE) acts as a toxin and initiates a cycle of cell death.

The presence of AChE is a characteristic feature of the hub cells in the basal forebrain where neurodegeneration is initiated. Here, AChE occurs in the absence of its normal substrate and instead of its normal enzymatic function, it acts as a signaling molecule.

Specifically, a 14mer peptide, called T14, is cleaved from the C-terminus of AChE and binds to an allosteric site on alpha-7 nicotinic receptors, which are involved in various aspects of cognition. Neuro-Bio has shown this promotes production of amyloid-beta and tau phosphorylation.

Importantly, this pathology is initiated well before the formation of amyloid plaques or tau tangles that are the anatomical hallmarks of Alzheimer's disease, raising the prospect of early intervention. T14 can be detected in cerebrospinal fluid and Neuro-Bio believes that detection and measurement of T14 could be developed as a blood test or skin biopsy to identify the occurrence of the degenerative process during the window of 10 to 20 years that typically occurs before symptoms start.

"If you could do that, then you could possibly even get the therapy before the symptoms appear. And that would mean they would never appear. And that's our goal," Susan Greenfield, CEO and founder of Neuro-Bio told reporters at a press briefing in London on April 5.

NBP-14 is still two years away from the clinic. However, it has been granted an innovation passport, the U.K. Medicines and Healthcare product Agency's recently introduced new licensing pathway that aims to reduce the time to market for innovative drugs.

Greenfield has been pursuing this avenue of research for more than 40 years, as an academic at Oxford University and as CEO of Synaptica Ltd., which she set up in 1997, and since 2013 at Neuro-Bio. She previously reported changes in the mode of action of AChE in rat brain ex vivo, which impacts on neurons in the hub cells.

While AChE signaling via T14 plays a key role in fetal development, Greenfield has shown it can turn neurotoxic in mature brains, in response to a blow to the head, ischemia or a decline in cellular scavenging mechanisms. Levels of T14 are doubled in human Alzheimer's brain samples and postmortem cerebrospinal fluid.

"[If] there is damage, then these hub cells, unlike other cells in the brain, will mobilize the developmental mechanism, but now it's not in the fetal brain, it's in an aged brain," Greenfield said. "That will be toxic. The very attempt to compensate for damage, which these cells can do, will actually be the very worst they can do and you'll have a snowball effect."

The only approved small molecule for treating Alzheimer's disease, galantamine, works by inhibiting the hydrolyzing action of AChE on the neurotransmitter acetylcholine, increasing the availability of synaptic acetylcholine, a mechanism of action that Oxford-based Neuro-Bio says supports its theory.

NBP-14, a cyclic form of T14, is designed to engage the alpha-7 nicotinic receptor, but not activate it. By occupying this target, the drug displaces its naturally occurring, potentially toxic counterpart.

In the latest research, published in Translational Research and Clinical Intervention on April 6, 2022, Alzheimer's disease model mice were given intranasally administered NBP-14 or control twice weekly for up to 14 weeks. The treatment started at 7-10 weeks of age, said to be sufficiently early to allow the drug to interact with its target before the neuropathological processes commenced.

Cognitive performance was assessed with the Novel Object Recognition test, which is widely used in assessing drug effects on recognition memory. It is based on the innate preference of the animals to explore a novel over a familiar object, requiring a memory of the object presented in the previous trial.

It was shown NBP-14 displaced T14 binding to the alpha receptor, with a clear dose response.

While there was no difference at baseline, at week 6 (when the mice were 13-16 weeks of age), impaired performance was observed in Alzheimer's mice but the wild-type mice continued to discriminate between familiar and novel objects.

However, by week 14 Alzheimer's mice treated with NBP-14 showed a significant increase in the time spent exploring the novel vs. the familiar object, an effect said to reflect a reversal of cognitive impairment.

Similarly, brain amyloid levels initially rose in the Alzheimer's mice, but after 14 weeks of treatment there was a significant reduction of 50% in the hippocampus, 38% in the frontal cortex and 42% in the basal forebrain.

This positive proof of concept in an animal model with NBP-14 is consistent with "the whole hypothesis" that Greenfield has painstakingly put together over many years, said Paul Herrling, former global head of research and before that, head of neuroscience research, at Novartis Pharma and now a nonexecutive director of Neuro-Bio.

Herrling said he followed Greenfield's research while in the thick of discovery, development and failure of drugs targeting amyloid and tau. "The results consistently indicate that NBP-14 might interfere with the neurotoxic process that leads to neuronal degeneration in Alzheimer's," he said. "This work has very exciting implications for treating Alzheimer's because it is based on a strong scientific theory that hasn't yet been applied to treatment of the disease."