Lilly Alzheimer's drug prospect only the latest to fail

Back to TopCommentsE-mailPrintBookmark and Share

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.”


  • Corporate reaction and The Star's "reporting"
    Gotta see this article in The Star. One source, just spitting back news that Eli Lilly took out a one-page ad. http://www.indystar.com/article/20100818/BUSINESS/308180002/Lilly-CEO-vows-medical-innovations-in-full-page-ad?plckFindCommentKey=CommentKey:21d03841-83d2-4cf3-b451-794a6e217318 According to The Star's retail sales division, a full-page display ad runs more than $25,000, plus another 15 percent for "premium placement" such as inside the front page, or on a section back. The guy who wrote this article is not even The Star's Eli Lilly beat reporter. It says something too about The Star's journalistic "integrity" that they have a guy working there who's beat is Eli Lilly/life sciences, and that's how they list it on their staff list. Their staff list also includes one mention of WellPoint, four mentions of Colts, two mentions of NBA, and one mention each of Butler, IU, Indians, Ice, Fever, Pacers and Olympics. How are readers supposed to believe journalists are objective when their job title includes an institution's name? No, these reporters are not directly working for those institutions, but if those institutions did not exist, they would not have that beat to cover, or at least not that job title. The result creates reporters whose job title depends on the continued existence of those institutions.

Post a comment to this story

We reserve the right to remove any post that we feel is obscene, profane, vulgar, racist, sexually explicit, abusive, or hateful.
You are legally responsible for what you post and your anonymity is not guaranteed.
Posts that insult, defame, threaten, harass or abuse other readers or people mentioned in IBJ editorial content are also subject to removal. Please respect the privacy of individuals and refrain from posting personal information.
No solicitations, spamming or advertisements are allowed. Readers may post links to other informational websites that are relevant to the topic at hand, but please do not link to objectionable material.
We may remove messages that are unrelated to the topic, encourage illegal activity, use all capital letters or are unreadable.

Messages that are flagged by readers as objectionable will be reviewed and may or may not be removed. Please do not flag a post simply because you disagree with it.

Sponsored by

facebook - twitter on Facebook & Twitter

Follow on TwitterFollow IBJ on Facebook:
Follow on TwitterFollow IBJ's Tweets on these topics:
Subscribe to IBJ
  1. The Affordable Care Act is not the reason for the slow recovery and lack of high paying jobs for low skill workers. This is a trend that has been going since the early 80's. The recovery is real in the sense that GDP has been growing steadily at a rate of roughly 2.5% since the recession ended in late 2009 (newsflash, the stimulus worked) and the unemployment has been steadily dropping. The reason issue we are facing deals with a skills gap (not enough workers with the right credentials / experience) and wage stagnation due to corporate America being focused solely on maximizing profits for shareholders and not caring about the American middle class. Why should they? Multi-billion dollar mutlinational companies keep offshoring their profits in order to avoid paying taxes (which makes our deficit worse) they convince Americans to fight amongst themselves. If you want to create jobs and reduce the deficit, raise the minimum wage and change corporate tax laws. Of course, if you want to continue to belive that tax cuts for wealthy create jobs (which they don't) and allow corporations and the wealthy to continue to make you cover more and more of the costs of maintaining infrastructure, funding the military and other government services, then keep voting Republican. Hopefully someday you wake up and realize what's been going on since Reagan took office.

  2. Helloooooo, my name is Kate. I am so joyous to share this wonderful testimony about what Dr. Osoijiakhena, a great spell caster, did for me and my family. I wedded a year and 6 months ago, we were very happy during this whole period, i really love my husband so so much. I started noticing changes when he started coming home late at night, he stop paying attention to me, i later found out that he was having an affair with another lady, i dont know what she did to get to him but she really got a hold on him. He started spending weekends with her, and threaten for divorce. I was so heart broken and devastated, i spent many night thinking on how to get my husband back. A friend took it upon herself to to introduce me to one Dr. Osoijiakhena, a great spell caster, who once helped her with a spell that reunited her family and helped her husband secure a very prolific job. Though i had my doubts and never believed, but i decided to give it a try because i was helpless. I contacted Dr. Osoijiakhena, the Spell caster, to help me reunite my family by bringing back my husband from that other woman and break whatever hold she had on him. He only just told me that it's a minor issue, once i provide and do everything he will ask me to do, then i will have my family back again. I did everything he required. And he did it!!!!! My husband returned back to me and pleaded for forgiveness, and i also secured a well paid job in a big company, just as the great spell caster, Dr. Osoijiakhena said. I am so so happy to share my testimony on this wall. I am using this medium to tell every one that has same or similar problem to try the great Dr. Osoijiakhena through his mail: drosoijiakhenaspell@gmail.com......he is so real!!!!! He can also help you with: (1) IF YOU WANT YOUR EX GIRL/BOYFRIEND TO RETURN BACK TO YOU (2) IF YOU WANT YOUR HUSBAND/WIFE BACK (3) IF YOU WANT TO BE PROMOTED IN YOUR OFFICE (4) IF YOU WANT YOUR MAN OR WOMAN TO LOVE YOU (5) IF YOU WANT A CHILD (BARREN) (6) IF YOU WANT TO BE RICH/WEALTHY (7) IF YOU WANT YOUR HUSBAND/WIFE TO BE YOURS FOREVER (8) IF YOU'VE BEEN SCAMMED AND WANT YOUR MONEY BACK (9) IF YOU ARE HAVING DELAY IN GETTING MARRIED (10) IF YOU HAVE A COURT CASE AND WANT TO WIN (11) IF YOU'RE A DRUG ADDICT AND YOU WANT TO REALLY STOP (12) IF YOU CANNOT IMPREGNATE A WOMAN (STERILE) (13) ALL TYPES OF DISEASES I advise you to contact the great Dr. Osoijiakhena, the spiritualist for solutions via his email: drosoijiakhenaspell@gmail.com

  3. Sergeant McNally is buried in Cathcart Cemetery on a hill known as McNally%u2019 Hill. The Cemetery is in a natural bushland setting and is very well maintained.The emergency department at Ararat Hospital is known as the John McNally Emergency Department. Cathcart is approx. 4.6 km from Ararat and is approx. 345 m above sea level.

  4. My spring chicken of a Mom is turning 75 years young. She is a big fan of Frankie and I think she would get a big kick out of the film. I wanted to take her to the Broadway play but am priced out. Thanks for your time and consideration. Oh yea, Wildwood! Joie

  5. I thought this company would go bankrupt in 2013/2014. I predicted that four years ago. I was wrong. It will take another couple of years, but they will get there.