The reports by Dr. Atwal and Ms. Yu and their colleagues offer encouraging news about the development of selective anti-BACE1 antibodies and anti-TfR antibodies. These reports are encouraging because targeting gamma-secretase with inhibitors has been fraught with systemic complications, including hematologic, GI, and more recently, neoplastic. Complicating matters further for gamma-secretase inhibitors (GSIs) is the report that the GSI semagecestat was halted in phase III clinical trials (
BACE1 antibodies would be desirable because they are more specific to the Alzheimer's disease process and pathophysiology. Still, antibodies are confounded by BBB permeability issues, and so enthusiasm for the reports by Dr. Atwal and Ms. Yu will need to be tempered until we are further along in the drug development process. Enthusiasm for amyloid approaches is waning overall. However, critical consideration should be given to not only whether anti-amyloid approaches are appropriate but also the timing of administration of these approaches. Until now, all GSIs and immunotherapies have been administered to symptomatic individuals who are carrying established and heavy amyloid burdens. One has to wonder whether these agents would be more effective if administered earlier in the disease process.
MARWAN N. SABBAGH, M.D., is director of the Banner Sun Health Research Institute, Sun City, Ariz. He was an investigator in trials for semagacestat. He has received research grants from Lilly, Pfizer, Eisai, Celgene, Bristol-Myers Squibb, Bayer, Baxter, GE Healthcare, Avid, and Janssen, and is a consultant to or is on advisory boards of Takeda, Bristol-Myers Squibb, Amerisciences, Eisai, and Bayer. He has received royalties from Amerisciences.
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