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https://www.science.org/content/blog-post/alzheimer-s-clinical-trial-results-sadly-running-true-form

There have been some interesting failures recently in Alzheimer’s trials. As long-time readers will know, I consider basically all Alzheimer’s drug trials to have failed to one degree or another, and particularly when it comes to clearing the “will improve patient’s lives in the real world without putting them at too much risk” hurdle. But these two are notable because they’re aimed outside the usual amyloid zone.

First off, Novo Nordisk reported that semaglutide (the company’s GLP-1 agonist drug, of course) failed in two Alzheimer’s trials. This was going to be a long shot, but long shots are worth taking in this area if you can afford to try them. Studies of thousands of patients with early cognitive impairment who took an oral form of semaglutide (Rybelsus, currently approved as a diabetes therapy) did not show improvements in mental function as compared to placebo. The company says that the treatment group showed “improvement of Alzheimer’s disease-related biomarkers” in both trials, although it does not (as far as I can see) say what those biomarkers were. And I would wonder how good they are as indicators given that you can show improvements in them and still not beat placebo, personally.

The company’s stock took a hit on the news, which is kind of strange. Surely people weren’t betting on this succeeding? But Novo investors have been a jumpy bunch for a while now as Eli Lilly’s star continues to ascend in this area, so the sight of another possible  life preserver disappearing might have been enough by itself. At any rate, it does appear as if there’s a disease where GLP-1 drugs are not actually beneficial. Novo had some better news today, though, with a once-weekly shot/once-daily pill combination for amycretin, a dual GLP-1/amylin agonist. I see that people are not quite giving up on the GLP-1/Alzheimer’s idea, but it has to be considered an even longer shot than before.

There’s also new in the anti-tau protein area. That’s long been considered a possible Alzheimer’s target, and by “long” I mean decades. But it’s been hard to put that idea to the test in the clinic. Unfortunately, in the last couple of years it has been possible, and the results have not been good so far.  Early last year a Lilly candidate (LY3372689, ceperognastat) failed its own trial. Earlier this year Asceneuron halted work on its own oral anti-tau drug candidate (ASN51), and Biogen stopped BIIB113, another similar effort.

Now all of these are (were) O-GlcNAcase inhibitors, so you could easily make the case that the problem is that might not be a good mechanism to target tau, even if tau itself is a valid idea. But last year Roche bailed on a collaboration for an anti-tau antibody, which went on to fail its trials shortly afterwards. And the latest news is that J&J’s shot at an anti-tau antibody (posdinemab) has also failed its pivotal trial, with no efficacy seen in slowing the disease at the two-year mark. There are other tau programs that are now in the clinic, but they’re clearly going to have to bring something unusual to make you think that they will show interesting levels of efficacy at this point. Good luck, folks. . .

https://www.science.org/content/blog-post/alzheimer-s-clinical-trial-results-sadly-running-true-form