The first part of 2018 has not seen positive developments in the search for new treatments for Alzheimer’s Disease. Merck recently announced the discontinuation of the verubecestat Phase III APECS trial when an interim analysis failed to demonstrate a benefit in patients with prodromal Alzheimer's Disease. The EPOCH trial was also terminated early when verubecestat failed to demonstrate a benefit in patients with mild to moderate disease. In both large trials, verubecestat lowered levels of beta-amyloid, but failed to improve symptoms or prevent progression of Alzheimer’s Disease.
Two other drug in development for the treatment of Alzheimer’s Disease were also recently in the news. Biogen announced that enrollment in two Phase III studies of aducanumab (ENGAGE and EMERGE) will be increased by 255 patients each due to variability of the primary endpoint. Earlier this month Boehringer discontinued development of BI 409306 after the drug failed to demonstrate a benefit in two Phase II trials.
These three drugs work by different mechanisms. Verubecestat inhibits Beta-secretase (BACE), which prevents the formation of beta amyloid. Aducanumab is a monoclonal antibody that reduces amyloid beta by binding to the protein. BI 409306 blocks phosphodiesterase 9A (PDE 9A), which improves signaling in the glutamatergic circuit of the brain. So do we need to look at different targets to prevent to treat Alzheimer’s Disease or do we need a new strategy?
It has been debated whether potential treatments would be more effective if used before development of symptoms in Alzheimer's Disease. Studies in early stages of the disease have not been successful, so the drugs may need to be tested in patients at risk of developing the disease. To address this issue, the FDA has proposed that if reliable biomarkers can be developed to diagnose Alzheimer’s before the onset of subtle cognitive or functional changes, these biomarkers could be used as surrogate endpoints for the approval of a new drug. Since there are no accepted biomarkers for Alzheimer’s Disease, the FDA has encouraged researchers to develop them.
There are two drugs being studied in trials with patient populations without any cognitive or functional changes. Amgen and Novartis are developing CNP520 and J&J is developing JNJ-54861911. Both drugs are Beta Secretase (BACE) Inhibitors. They are being studied in long term trials of patients without symptoms that carry the APOE4 gene. Both studies are currently forecast to be completed in 2024 and have patient populations of over 1,500 patients. The APOE4 gene is being used as a biomarker to predict patients at risk of developing Alzheimer’s. Additional biomarkers are needed to predict the actual development or progression of disease.
I reviewed drugs in development for the treatment of Alzheimer’s Disease in the December issue of Hospital Pharmacy last year.
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