Alzheimer’s R&D: targeted failure

A very interesting article regarding failures with novel drugs against AD.

We know that monoclonal antibodies are sh…t and will not be useful:

The biggest hope for the treatment of Alzheimer’s disease in a long time just went up in smoke. The next high-profile drug candidate will probably be toast in a few weeks, analysts say.

 The easiest thing now would be to write off the whole field of Alzheimer’s R&D, and declare that scientists have to go back to the drawing board.

This is the major category of drug getting most of the negative attention because of the failure of the Pfizer/J&J/Elan drug and expected failure of Lilly’s drug, also an antibody. These drugs are designed to specifically bind to and clear plaques that are piling up in Alzheimer’s patients, causing neurotoxicity that leads to all the tragic symptoms of the disease.

 

Scientists have long been attracted to anti-amyloid beta antibodies for Alzheimer’s, because they can be designed to specifically bind with the amyloid beta peptides while mostly sparing healthy tissues. While the failure of bapineuzumab (or “bapi” for short) is a downer for the field, some people, Ives included, say Pfizer/J&J/Elan may have a better chance using the drug in an Alzheimer’s population that hasn’t yet displayed many symptoms.

Essentially, the argument is that the companies were trying to help patients after it was already too late. “Think about a car wreck,” Ives says. “Bapi is like a tow truck clearing away the wreckage, but there’s already been a wreck. You really want to prevent the accident.”

And to go back to the drawing board will be the best idea. But what will be proposed instead of mAbs? Almost the same “targeted” approaches!

Gamma Secretase inhibitors and modulators:

One other major class in development are drugs that regulate the gamma secretase, Ives says. These drugs are synthetic chemical compounds that can be made into oral pills, which can conveniently be taken by patients on a daily basis at home. They are designed to bind with an enzyme, gamma secretase, which chops up larger amyloid into smaller amyloid beta peptide pieces. In patients with Alzheimer’s, gamma secretase enzymes overproduce longer amyloid beta peptides that pile up to form plaques that are toxic to nerves.

Drugs from the past that sought to inhibit gamma secretase, like Lilly’s semagacestat, looked to have potential for a while, but failed in the third and most expensive phase of clinical trials. Early-generation gamma secretase inhibitors also shut down all kinds of other essential protein processing in cells, which led to toxicity that prompted drug developers to limit their dosing and stop trials, Ives says.

And another one:

BACE Inhibitors:

 Another class of drugs in development can be filed under the header of beta secretase, or BACE, inhibitors. These drugs are also small molecule compounds made to bind with a different kind of enzyme in cells, one that performs its amyloid processing work at an earlier step in the amyloid pathway than gamma secretase, Ives says. Drugmakers have labored for years against these targets, because inhibiting beta secretase can clearly reduce production of amyloid beta peptides in their various lengths, which should reduce the troublesome plaque deposits.

 Companies like Lilly, Merck, and Roche all have drug candidates moving through early-to-mid-stage clinical trials, and they generated a fair bit of buzz at the Alzheimer’s Association meeting in Vancouver, BC in July, Ives says. As Alzheimer Research Forum science writer Esther Landhuis described it recently, drugs in this class have long struggled to get into the brain, to stay there, or to fend off other molecules that would render them inactive. “At long last, drug developers have overcome these and other hurdles, and well over a decade of effort developing beta-secretase (BACE1) inhibitors is starting to pay off,” Landhuis wrote.

 One big question with BACE inhibitors, Ives says, is what happens over time to people who have so much of their amyloid processing shut down. If people take these drugs for three decades to prevent Alzheimer’s, what kind of unforeseen side effects might pop up? “That chapter remains to be written,” Ives says.

I would conclude: It is better not to get AD due to it seems like new efficient treatment will not be developed in the nearest decades…