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Pfizer Inc., Johnson & Johnson, and a half-dozen competitors are committed to a research strategy for Alzheimer’s
disease that has resulted in a string of study failures, the most recent involving Eli Lilly and Co.
A dozen potential products designed to slow or stop clumps of protein from forming in the brain, a condition linked to the
disease since 1906, have failed in mid- to late-stage testing since 2003. The experimental drug from Lilly, semagacestat,
didn’t improve cognition in a study and worsened the ability of patients to perform daily activities, the Indianapolis-based
company said Tueday.
Lilly said it would no longer develop the product, one of the company’s two Alzheimer’s drugs in the final stage
of testing usually required for U.S. regulatory approval. The Lilly failure, on top of seven years of other unsuccessful tests,
calls into question research into similar treatments and leaves patients with little hope for the future.
“This is definitely going to make people a lot more pessimistic about many drugs” already in late-stage development,
P. Murali Doraiswamy, head of the biological psychiatry division at Duke University School of Medicine in Durham, N.C., said.
“This will cast a shadow on those trials as well.”
Lilly shares fell 82 cents, or 2.3 percent, to $34.75 each on Tuesday. The shares have declined 2.7 percent this year before
the start of trading Wednesday..
Current therapies for the disease, including Forest Laboratories Inc.’s Namenda and Pfizer and Eisai Co.’s Aricept,
address only Alzheimer’s symptoms; they don’t cure or even slow it. Alzheimer’s and other dementias will
afflict 35.6 million people in 2010, and will rise to 115.4 million by 2050, according to a report from Alzheimer’s
Disease International.
Researchers have announced setbacks with experimental treatments from GlaxoSmithKline Plc and AstraZeneca Plc, both of London;
Martek Biosciences Corp., of Columbia, Md.; New Brunswick, N.J.-based J&J; Abbott Laboratories of Abbott Park, Ill.; New
York-based Pfizer, Medivation Inc. of San Francisco, and Myriad Genetics Inc. of Salt Lake City, Utah, in the past several
years, many targeting amyloid.
One of the drugs, Pfizer and J&J’s bapineuzumab, reduced the buildup of amyloid plaque in the brains of patients
with Alzheimer’s disease, according to a study published March 1. Patients getting the medicine in the trial, though,
didn’t show a clear improvement in mental function.
On Aug. 9, Dublin-based Elan Corp. and Transition Therapeutics Inc. of Toronto said their experimental Alzheimer’s
disease drug, ELND005, will move into the final stage of human tests, even though the drug failed to meet an interim study’s
main goals of improving patients’ mental status or daily living activities.
The drugs from Pfizer and Elan are in the final stage of testing usually required by the Food and Drug Administration to
approve the marketing of new treatment.
Lilly’s other final-stage drug is an antibody called solanezumab that binds to and removes beta amyloid, the protein
clumps in the brain. Baxter International Inc.’s blood product Gammagard also is in late-stage testing.
“The problem is that amyloid is still not the unanimous choice for what causes Alzheimer’s,” said Les Funtleyder,
an analyst with Miller Tabak & Co. in New York. “If you don’t understand how the disease starts and operates,
it’s going to be hard to find a cure or a treatment. That’s what we are up against.”
Pfizer and J&J’s bapineuzumab, when given at high doses, was linked to a side effect similar to swelling in the
brain. Researchers stopped giving the highest dose of the drug in the last stage of study.
The failed Lilly medicine inhibits an enzyme called gamma secretase that’s tied to the production of amyloid. Attempting
to lower the levels of amyloid is also at the center of action by bapineuzumab, Lilly’s solanezumab, and Elan’s
ELND005.
Lilly CEO John Lechleiter said Tuesday in a telephone interview that the failure of semagacestat “doesn’t in
any way impact our commitment to Alzheimer’s.”
Gwen Fisher, a spokeswoman for Pfizer, said in an e-mail that Pfizer is testing a variety of pathways thought to be implicated
in Alzheimer’s and the failure of a specific compound isn’t enough to dismiss a particular approach given the
complexity of the disease and the methods being studied.
Ellen Rose, a spokeswoman for J&J’s Janssen Alzheimer Immunotherapy R&D LLC, said in an e-mail that Lilly’s
setback doesn’t “disprove the amyloid hypothesis and it does not change our commitment to our development programs.”
Beta amyloid clumps were first identified during autopsies of patients with memory loss by Alois Alzheimer. From the early
1900s, many doctors and scientists believed the protein caused the disease, the most common form of dementia.
The relationship between the protein clumps and the disease was strengthened two decades ago with the discovery of a gene
that inexorably leads to an early form of Alzheimer’s. People who carry it make an abundance of amyloid, and typically
are diagnosed with Alzheimer’s disease in their 40s.
Allen Roses, director of the Deane Drug Discovery Institute at Duke University Medical Center in Durham, isn’t convinced
by the amyloid-based research.
“Alzheimer’s research has overemphasized the amyloid hypothesis for a very long time,” Roses said in a
telephone interview. “When the leading candidates for Alzheimer’s disease appear to fail for one reason or another,
to me it’s simply evidence that the hypothesis is not right.”
The amyloid hypothesis has been tested by a variety of agents for the past decade, and each has raised concerns that derailed
the drugs, said Roses, who discovered a gene that predisposes certain people to the disease.
“The genetics have led me down a different path,” said Roses, who is discussing a large prevention trial with
a major pharmaceutical company he declined to name. “Amyloid may or may not be an accelerator for Alzheimer’s
disease, but it’s not the basic trigger,” he said.
Michael Rafii, co-director of the Memory Disorders Clinic at the University of California, San Diego, said treating patients
with mild to moderate symptoms with these drugs may be akin to treating heart attack patients with the cholesterol drug Lipitor.
Like fat in arteries, amyloid deposits form in the brain for years before patients become forgetful, he said.
“Once you’ve reached a certain level of pathology, you’re never going to come back,” Rafii said.
If so, other trials in patients with mild-to-moderate Alzheimer’s will probably fail, despite the number of drugs under
study, he said.
Rudolph Tanzi, professor of neurology at Harvard Medical School and director of the genetics and aging research unit at Massachusetts
General Hospital’s Institute for Neurodegenerative Disease, said the failure of the Lilly drug may be specific to the
compound being used rather than the entire approach of controlling amyloid.
“Gamma secretase has dozens of proteins it must cleave to have a healthy brain and a healthy body,” Tanzi said
in a telephone interview. “You can’t hit that enzyme with a sledgehammer because it’s vital, and has lot
of different functions.”
Bristol-Myers Squibb Co. is pursuing two different research strategies in attacking Alzheimer’s.
The New York-based drugmaker is developing a medicine that acts like Lilly’s, blocking gamma secretase. It is also
targeting a protein called tau, which is found abundantly in abnormal form in the brains of patients with some dementias including
Alzheimer’s.
“Our gamma secretase inhibitor program is moving forward,” Sonia Choi, a spokeswoman for Bristol-Myers, said.
Results from a phase 2 study will be available this year, she said.
When tau is normal, it supplies nutrients to nerve cells in the brain. When damaged, it becomes tangled and shuts off nutrients.
There’s a clear connection between the amount of aggregated tau in the brain and the state of dementia, said Claude
Wischik, a professor at the University of Aberdeen, Scotland, and chairman of TauRX Pharmaceuticals., a company testing a
compound called Rember that targets tau.
There isn’t a similar connection between cognition and amyloid plaques, he said, noting that amyloid plaques form before
people become forgetful.
If the existing drugs don’t work, advances in genetics are giving researchers a growing list of targets to slow or
prevent Alzheimer’s disease, Harvard’s Tanzi said.
“Four genes account for 30 percent to 50 percent of Alzheimer’s disease, but they are driving most of what we
do in terms of drug development,” he said. “I’m optimistic that some of the existing anti-amyloid drugs
will work, but you have to always prepare for the worst. If everything crashes and burns, we’ll still have something.”
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