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Alzstatin

Our disease-modifying research platform, Alzstatin, consisting of disease-modifying and preventive drug candidates, focuses on reducing the production of toxic amyloid beta (Aβ) in the brain. Aβ plays a key pathological role in Alzheimer’s and begins to accumulate in the brain years before clear symptoms develop.

The project originated in AstraZeneca’s CNS research, and AlzeCure estimates AstraZeneca’s total investment in Alzstatin to be around SEK 200 million before AlzeCure took over the project. The assessment is based on estimated time spent in the form of working hours in the project and project-related material costs. The drug is based on small molecules, which enables oral administration (tablets), low production costs and good BBB penetration. The target molecule is the genetically supported Aβ molecule.

The drug candidates in the Alzstatin platform are known as gamma secretase modulators (GSMs) which modulate the function of a specific enzyme, gamma secretase. Gamma secretase gives rise to the formation of Aβ42 peptide, which over time forms clumps of so-called oligomers and fibrils that ultimately form the amyloid plaques in the brain so characteristic of the disease. These various Aβ aggregates cause nerve cell fibers to degenerate and ultimately die. Mutations in gamma secretase that lead to a relative increase in Aβ42 peptide is the cause of hereditary Alzheimer’s disease. This demonstrates the role of Aβ42 in the progression of the disease and is, together with mutations in the Aβ-peptide itself, the strongest known genetic link to Alzheimer’s disease.

Aβ42 slowly accumulates to form an aggregate growing from monomers to oligomers, fibrills and ultimately plaques. Research has not yet identified what in these processes, or which molecular form, is most harmful to nerve cells and causes the disease to progress. Thus we consider the best treatment alternative is to reduce the production of Aβ42 as this will reduce all forms of amyloid and is therefore likely to affect and hinder the progression of the disease. GSM has a directly opposite effect on Aβ compared to the mutations that cause the disease in the hereditary forms of Alzheimer’s.

We have shown in preclinical tests that the modulation of gamma secretase leads to a reduction of up to 50 percent in the production of Alzheimer-related Aβ42 without affecting other signaling important for cells. The project is further substantiated by positive findings made in the recently published clinical patient studies with BAN2401, which we believe validate the amyloid hypothesis as a treatable and clinically relevant pathological mechanism.

Major advances have also been made in the field of diagnostics with new blood-based tests, which should provide a cost-effective means of screening high-risk populations and thus identifying the right patients in the presymptomatic phase of the disease for upcoming clinical studies and future treatments.

The video below briefly shows how a compound from the Alzstatin program acts in the brain.

The drug candidates in the Alzstatin platfrom modulate the function of the enzyme gamma secretase. Gamma secretase acts like a pair of scissors and cuts Aβ42 out from a longer protein known as APP. The sticky Aβ42 clumps together giving rise to the amyloid plaque so typical of Alzheimer’s disease. The candidates in the Alzstatin platform affect enzyme function so that it instead cuts out shorter forms of the Aβ peptide, Aβ37 and Aβ38, which in addition to them not being sticky and not forming aggregates, also have a restrictive effects on Aβ42 aggregates already formed. This means the drug candidates in the Alzstatin platform have two separate but synergistic effects that together contribute to a stronger anti-amyloidogenic – and thus more potent – disease-modifyning effect.