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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.
Still, targeting gamma secretase has promise, Ives says. His company, Satori, has a dog in this hunt. Satori is working on a gamma secretase “modulator”— which is supposed to reduce the production of the neurotoxic amyloid beta peptides while allowing the enzyme to do its other jobs in the cell. Satori’s compound, originating from early discoveries from the Mayo Clinic, is designed to selectively modulate gamma secretase so that it particularly reduces production of a 42-amino-acid long peptide called amyloid-beta 42 that is one of the particularly devilish forms of amyloid beta. The company has raised more than $40 million in venture capital for this concept, and expects its candidate to enter clinical trials in early 2013, Ives says. If all goes well, Satori will be in position to form a partnership with a Big Pharma company for late stage trials.
Satori isn’t the only company in this class, though. Japan-based Eisai Pharmaceuticals has a gamma secretase modulator in development, as does another venture-backed company, Watertown, MA-based EnVivo Pharmaceuticals.
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.
One last compound in the works worth mentioning is from Deerfield, IL-based Baxter International, called Gammagard. This is a protein drug isolated from blood, which is used in patients with insufficient immune systems, and to improve muscle strength in patients with multifocal motor neuropathy. I’m less interested in this one, because it’s an expensive product that is isolated from human blood—which means it’s scarce, and almost certainly can’t meet the demand from a market this big. Plus, as Ives put it, the scientific mechanism of action of this drug against Alzheimer’s isn’t very well understood, other than its anti-inflammatory properties.
Like I said at the beginning, the obstacles in this field are huge. When you start talking about multiple PET scans, MRIs, and spinal fluid draws among thousands and thousands of patients, it’s easy for the R&D tab to run into the tens of millions of dollars per study. Since this is a slow-moving disease, it generally takes two years of follow-up in clinical trials for an effective drug to start showing an advantage over patients on placebo.
There’s no clinical data anywhere yet that says a drug can slow the progression of the disease, much less prevent it. The “bapi” failure certainly was a big disappointment, and entirely predictable, but scientists can sometimes learn some valuable lessons from failure. I think there’s a good chance that scientists have learned a lot in the last couple of years, and the headlines could very well be much more upbeat in another five years.
And one last note: I love to hear comments from readers at the end of these columns, but in this case, I won’t be able to read or respond to them in a timely way. As you read this, I’m on vacation somewhere far away from an Internet connection. See you back here in the online world next week.
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