Alzheimer’s R&D Isn’t Doomed, it’s Learning From Failure

8/20/12Follow @xconomy

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. It’s just tough luck for the millions of people who have—and fear getting—this disease of aging which gradually strips away people’s ability to think, reason, and remember.

I have to confess I’m no expert in Alzheimer’s. I haven’t covered the high-profile failure of Pfizer/Johnson & Johnson/Elan’s bapineuzumab in Phase III clinical trials, or the widely anticipated failure to come with Eli Lilly’s solanezumab. My first experience covering Alzheimer’s was a sour one. Five years ago, I wrote about San Francisco’s Medivation (NASDAQ: MDVN) and its odd little allergy medication from the 1980s that showed in a mid-stage clinical trial that it helped Alzheimer’s patients when compared with a placebo. Pfizer wrote them a big check, the two companies charged ahead to confirm the finding with an expensive pivotal trial, then the drug flopped.

Not much has come along in R&D since then to change that first impression of mine that Alzheimer’s researchers are shooting blanks in the dark.

Ah, yes, skepticism is a healthy thing in biotech, but so is periodically challenging one’s own assumptions. So I sought to get updated on what’s new in Alzheimer’s from Jeff Ives, who knows as much about the state of the art in this field as anyone. He’s a Ph.D chemist, a former senior vice president of research at Pfizer, and now the CEO of a startup Alzheimer’s drug developer in Cambridge, MA called Satori Pharmaceuticals.

He shakes his head at the pessimism he sees in much public discussion of Alzheimer’s R&D.

Jeff Ives, CEO of Satori Pharmaceuticals

“It’s not all doom and gloom, like we’re in the dark ages, or that it’s going to be 20 years before something makes it,” Ives says. “We’ve gotten much smarter about how to design trials, and there are many more interesting drugs in development.”

Like everything in biotech, the proof will be in the data, and nobody has produced the data yet for a drug that can slow the progression of the disease, or prevent it.

Alzheimer’s affects more than 5 million elderly Americans, millions more who have to take care of them, and millions more baby boomers who fear it will happen to them. The challenges in fighting this disease are immense. It’s hard to diagnose with certainty. It’s difficult to reliably measure improvements or declines in cognition. The disease takes many years to fully manifest itself. The clinical trials are super-expensive because they require a lot of labor, sophisticated imaging tests, and must enroll thousands of patients followed over many years. And since this is a disease that affects millions of people with a chronic condition, drug developers pretty much have to invent drugs that are as safe as a placebo.

While the market opportunity is “gigantic,” as Ives put it, only about a dozen or so Big Pharma companies have the money and manpower to even attempt to take a new drug all the way to FDA approval for Alzheimer’s. Biotech startups often have some of the best ideas, and they can take a stab at the early stages of development, but it is basically financially impossible for a startup to go all the way in Alzheimer’s.

Jim Healy, a general partner with Sofinnova Ventures, put it succinctly in an email: “Sofinnova is an active investor in the CNS (central nervous system) field including Huntington’s disease, multiple sclerosis and epilepsy. Although the clinical need is high for Alzheimer’s, the capital requirements for the Phase 3 trials and the risks are both substantial. As a result, we are inclined to look more favorably on other markets with shorter timelines, lower risk and better capital efficiency.”

OK, this is no simple puzzle we’re talking about. But here’s a basic rundown of the major categories of experimental Alzheimer’s drugs that are worth watching, based largely on input from Ives and some scanning of the recent scientific literature and conferences.

Antibody drugs against amyloid beta peptides

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.”

Although antibodies have their drawbacks—they’re injectable and expensive—they also can be very specific to a target and can last a long time in the bloodstream to provide long-lasting protection. Besides the antibodies from the companies listed above, Roche has an anti-amyloid beta antibody called gantenerumab in early clinical trials, and so does its Genentech unit, with another antibody called crenezumab.

That latter antibody, licensed from Switzerland-based AC Immune, is being tested in a fascinating clinical trial that was featured recently in The New York Times. The Genentech antibody will be tested in Medillin, Colombia in a well-defined patient population that has a genetic form of early onset Alzheimer’s.

This particular type of Alzheimer’s typically starts showing symptoms when patients enter their mid-40s, and causes full-blown dementia by the time they’re in their early 50s. This anti-amyloid beta drug is going to be given to patients before they are expected to display symptoms, and researchers will be watching to see if it can prevent Alzheimer’s. It will take a few years to get this answer, but it won’t take forever. It’s an elegant study design, supported by the National Institutes of Health and the Banner Alzheimer’s Institute.

Trials like this one, and others in the future, will have the benefit of carefully selecting patients for clinical trials and monitoring how they will benefit. Advances in MRI and PET imaging, along with measurements of amyloid beta peptides in spinal fluid, are giving researchers a clearer idea of what kind of disease they are up against with patients entering studies, and a quantifiable way of measuring progress over time, Ives said.

The scientific understanding of amyloid beta’s role in Alzheimer’s has only gotten stronger with recent published research into a rare gene mutation that slows amyloid beta production and helps people avoid getting the disease. This finding, among others, has helped establish that amyloid beta is the central actor in Alzheimer’s, Ives says. Another substance, known as Tau, comes later in the progression of Alzheimer’s, he adds.

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.

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.

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.

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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  • Jimbo

    a gamma secretase “modulator” is the same as an inhibitor. Modulator is just a buzz word for a more selective inhibitor. The modulator described by Satori seem eerily similar to the one tested by Elan that was Discontinued due to toxicity.

  • Biotech Enthusiast

    In order to “save” on clinical trials , you need better diagnostics/ companion diagnotics to monitor disease progression. if there was blood test for Alzheimer’s, would be easier to budget the drug development…

  • Brian Pan

    “There’s no clinical data anywhere yet that says a drug can slow the progression of the disease, much less prevent it”…. looks like recent LLY data shows its sola ab can slow progression in subset of early AD patients.

  • Richard T Whalley

    There are some other interesting therapeutic approaches in development that are based on a different outlook: Some people believe that soluble forms of amyloid-beta drive disease pathology (inflammation, cell death), rather than insoluble plaques which are now seen mostly as a downstream symptom. Therefore, proteins that are involved in promoting soluble forms are also potential targets. This view intuitively makes sense to me as a chemist, because soluble forms of molecules are generally more reactive and biologically influential than insoluble forms of molecules. Some argue that compounds that break up plaques may actually promote disease progression.

    Other problems in need of solutions: The upstream mechanism is, for the most part, poorly understood. More basic research is needed, as well as longitudinal studies. There is a lack of quantitative molecular-imaging biomarkers for clinical and animal trials. Measuring Tau in the CSF seems to be an unreliable and indirect way to measure disease progression. The standard animal models are not physiologically relevant (compared to Parkinson’s, for example). And, of course, the blood-brain-barrier has never been drug development’s or antibodies’ best friend.