It’s not a secret that a very large phase 3 clinical trial was recently relegated to the trash heap of failed, expensive anti-amyloid monoclonal antibodies. It is thus doubly disappointing that modifying a different therapeutic target not only doesn’t have clinical benefits but also causes unacceptable side effects.

This strategy is inhibition of BACE, an enzyme that cleaves the amyloid precursor protein (APP). Three different BACE-1 inhibitors show no benefit in prodromal, mild, or moderate dementia. In fact, they seem to worsen cognitive function and cause side effects of rash, insomnia, weight loss, and cough. One also caused a change in hair color in up to 5% of the subjects.

But giving up altogether is not an option. The winter of the Alzheimer’s epidemic is already upon us and will only get worse. More anti-amyloid and anti-tau antibodies are in phase 3 trials.

See the three articles in the NEJM, 2019, by Egan et al, Henley et al, and Knopman et al.

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