Roche Alzheimer's Disease New Compound Patent

Alzheimer's disease (AD) is a neurodegenerative disease, clinically characterized by memory impairment, aphasia, agnosia, and other comprehensive dementia, commonly known as Alzheimer's disease, with nearly 500 in the United States alone.million patients. With the aging of our population, Alzheimer's disease will become a major threat to public health.

The Dilemma of Drug Development

"If two III'sAll phase trials have achieved positive results, and we will 2019This is vTv Therapeutics CEO Stephen Holcomb's statement on the azeliragon of Alzheimer's drugs in an interview in early January this year. It is precisely because the failure rate of new drug development for Alzheimer's disease is high enough that azeliragon has attracted enough attention. However, as the saying goes, the greater the hope, the greater the disappointment. When the efficacy data of azeliragon in a Phase III clinical trial were not equal to placebo on April 10, the stock price of vTv Therapeutics also fell hard enough, and the 78% drop at the close directly fixed its stock price at 0.71 US dollars.

Similar tragic incidents have not happened rarely to pharmaceutical giants. 2016Year 11Lilly's share price fell 10.5 percent after news of another failure in the third large Phase III EXPEDITION3 study solanezumab on March 23. Axovant spent US $5 million to find a drug intepirdine from GSK that had failed four trials but seemed to have good safety and tolerance. On September 27, 2017, it was announced that Phase III MINDSET study had failed to reach the end point and had no improvement effect on patients' cognitive function and activity patterns at 24 weeks. As a result, Axovant's stock price fell from a high of US $27.98 to US $5.54.

Alzheimer's disease is simply a "living burial ground" for new drug research and development. if you want to have a deeper understanding of this sentence, you may as well look at a chart from the global new drug library of the medical rubik's cube (click on the picture to enlarge it), only aBeta has 8 for one target.A project failed or died, not to mention AChE, BACE... This failure rate can be said to be quite shocking.

pathogenesis

Whether it's Solanezumab，还是IntepirdineOr other drugs, after a clinical trial fails, we can always find some seemingly reasonable explanations for the failure and propose improvement strategies. The uncertainty of these clinical trial decisions is caused by the lack of understanding of the disease. This is not only because we lack reasonable animal models and research methods, but also because of the complexity of our brains. Today, more than 100 years after the term Alzheimer's was proposed, we still have no clear understanding of the pathogenesis. There are three main hypotheses for how to develop Alzheimer's disease: the amyloid cascade hypothesis, the APOE4 hypothesis and the Tau protein hypothesis.

Patent Application for Novel Compounds of Roche Alzheimer's Disease

2017Pharmaceutical giant Roche (Roche) filed patent applications for novel compounds (WO2018007331A1, fused pyrimidine derivatives) relates to the field of anti-Alzheimer's disease and is an anti-amyloid candidate. Studies have shown that Alzheimer's disease is closely related to the brain "senile plaques" and the cerebral cortex and subcortical neurofibrillary tangles. The brain "senile plaques" are caused by beta amyloid plaques, which is considered A nerve agent, which is formed by the Aβ42 protein, aβ42 protein is produced by the orderly cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, so β-secretase and γ-secretase are targets for inhibiting the formation of β-amyloid plaques.

The patent describes a class that can inhibit γ-The compound of the secretase enzyme (see the figure below) exhibited excellent activity in the in vitro assay.

Summary

All development projects in the field of Alzheimer's can be called a gamble, and it is clear that starting this project is a costly gamble for Roche, as entering IIIAll amyloid-targeting drugs in the phase of the trial have failed, and the voice of not optimistic about the amyloid hypothesis is getting louder and louder. But the greater the risk, the greater the possible reward, especially with the aging of the world, Alzheimer's disease has become increasingly common, and now the disease has become the sixth leading cause of death in the United States. Even with limited efficacy, some commonly used Alzheimer's drugs, such as donepezil, galantamine and rivastigmine, have huge sales, and Pfizer's donepezil peak sales even reached 24Billions of dollars.

At present, the compound is still in the early stage of research and development, whether it can really become a new drug still needs to see further research, but its published novel compound structure and mechanism of action still have great reference value.