The Wall Street Journal reports (below) that: “A group of major pharmaceutical companies will share pooled data from failed clinical trials in an attempt to figure out what is going wrong in the studies and what can be done to improve drug development.”

“Companies said they’re running into a stone wall with Alzheimer’s and Parkinson’s,” said Ray Woosley, chief executive of the Critical Path Institute, which oversees the coalition. “We really believe drugs are failing because we honestly don’t understand the disease.”

In the first wave, data from 4,000 patients across 11 failed Alzheimer’s-drug clinical trials will be made publicly available by Johnson & Johnson, GlaxoSmithKline PLC, AstraZeneca PLC, Sanofi-Aventis and Abbott Laboratories.

The Lancet Neurology reports the findings of the Pfizer’s latest failed Alzheimer’s drug, bapineuzumab, which targets attacking plaque.  It follows the failure of Dimbeon, the company’s acquired Russian antihistamine that it was developing for use in Alzheimer’s.

But Dr. Andrew Dillin, of the Salk Institute in California and the Howard Hughes Medical Institute, said the drug, like several others aimed at trying to stop plaques from forming, was destined to fail. “This hypothesis is actually completely wrong, and we need a new way to start looking at this disease. This is actually not a viable therapeutic avenue,” Dillin said.

Alzheimer’s drugs are failing because they are attacking the wrong target, according to new research.  “For more than two decades, the prevailing plan of attack for researchers and drug companies has been to find a way to remove sticky clumps of a protein called amyloid beta from the brain.”

A new study, funded by the National Instites of Health reported in The Annals of Neurology challenges–if not shatters–the prevailing causal theory of Alzheimer’s:

“Recent evidence suggests that high molecular weight soluble oligomeric A (oA) assemblies (also known as A-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in AD.”

Instead of being the chief toxin, several research teams suspect, the sticky  plaques may be the body’s way of trapping and neutralizing oligomers–which are now thought to be the real culprits that are killing brain cells in Alzheimer’s patients.

The new information and the acknowledgment by drug manufacturers of the drugs’ failure overturns the legitimacy of prescribing the FDA-approved Alzheimer’s drugs that are not only useless, but that may contribute toward causing patients more harm.

These developments undermine the credibility of leading neurologists who continue to cling to unsupportable theories and to prescribe and promote drugs they know to be useless.

Vera Hassner Sharav

THE WALL STREET JOURNAL
June 11, 2010
Drug Makers Will Share Data From Failed Alzheimer’s Trials
By SHIRLEY S. WANG

Drug makers’ attempts to find treatments for Alzheimer’s disease have produced scant results and a long string of busts. Now a broad effort is under way to learn something from those failures.

A group of major pharmaceutical companies will share pooled data from failed clinical trials in an attempt to figure out what is going wrong in the studies and what can be done to improve drug development.

In the first wave, data from 4,000 patients across 11 failed Alzheimer’s-drug clinical trials from Johnson & Johnson, GlaxoSmithKline PLC, AstraZeneca PLC, Sanofi-Aventis and Abbott Laboratories will be publicly available as of Friday.

Data from additional drug makers and the National Institutes of Health will be added in the future. The coalition aims to create similar pooled databases for Parkinson’s disease and tuberculosis, said Marc Cantillon, executive director of the Coalition against Major Diseases, which spearheaded the project, funded by the Food and Drug Administration and Science Foundation Arizona.

The data will be available to all the participating drug makers, as well as outside researchers with a valid scientific question, Dr. Cantillon said.

“Companies said they’re running into a stone wall with Alzheimer’s and Parkinson’s,” said Ray Woosley, chief executive of the Critical Path Institute, which oversees the coalition. “We really believe drugs are failing because we honestly don’t understand the disease.”

The hope is that this large database will help answer some questions that individual trials with just a couple of hundred patients can’t answer, such as how the disease progresses and whether there are differences in subgroups in the population.

“Innovation no longer happens solely in one company’s lab,” said Frank Casty, AstraZeneca’s vice president of technical evaluations. “It is happening through constant interaction between scientists in the biopharma industry, patient advocates, academia and government.”

For the FDA, the project is something of a counter to criticism that it has been slowing down drug development because it is too focused on patient safety as opposed to on how well a drug works. Rather than debate whether the benefit-risk calculation for new drugs should be changed, the FDA wanted to help the industry develop better methods for determining if drugs are safe and effective, according to Mark McClellan, a former FDA commissioner who helped develop and support the coalition.

“The whole point of this type of effort is to get out of that debate,” Dr. McClellan said.

FDA Deputy Commissioner Joshua Sharfstein said, “I think the FDA recognizes that one thing that can accelerate drug development is sharing information that is relevant to a disease.”

If the database works as hoped, it may enable drug makers to build more sophisticated computer models to help design more efficient clinical trials that require fewer patients and less money, Dr. Cantillon said.

With current studies, if the results show no difference between patients getting an experimental treatment and those getting a placebo, it often isn’t clear if the drug failed or if there was something wrong in the study design that prevented the effect from being picked up in the statistical analyses.

The most recent example is Pfizer Inc.’s Dimebon, originally a Russian cold medicine that had shown promise in treating Alzheimer’s patients in a small, Russian-based trial several years ago. But, a larger, multinational late-stage study recently showed that the drug had no effect on this new sample of patients.

“People are left wondering why it didn’t work,” said Dr. Cantillon.

If a better model could be developed to predict which patients would respond, “it’s possible” that Pfizer could go back and look at Dimebon’s response in those subgroups, he said.

A Pfizer spokesman said the company “is participating in a number of public-private partnerships with governments, independent medical and scientific groups, companies and advocacy groups. Collaborations such as these can lead to more treatment options and better care for patients and the people who care for them.”

Write to Shirley S. Wang at shirley.wang@wsj.com

Copyright 2009 Dow Jones & Company, Inc. All Rights Reserved

~~~~~~~~~~~~~~~

WALL STREET JOURNAL     
May 12, 2010
New theory of Alzheimer’s explains drug failures
By JULIE STEENHUYSEN

CHICAGO (Reuters) – Brain plaques, long considered the chief killer of brain cells and the cause of Alzheimer’s disease, may actually play a protective role, under a new theory that is changing the way researchers think about the disease.

Instead of sticky plaques, free-floating bits of a toxic protein called amyloid beta may be what’s killing off brain cells in Alzheimer’s patients, U.S. researchers say.
If the theory is right, then drugs that target plaque, including bapineuzumab – being developed by Pfizer, Johnson & Johnson and Elan – may be aiming at the wrong target, they say.

“The plaque is not the main culprit in terms of toxicity,” said Dr. Scott McGinnis of Harvard Medical School and Brigham and Women’s Hospital in Boston, who treats Alzheimer’s patients and runs clinical trials testing new Alzheimer’s drugs.

For more than two decades, the prevailing plan of attack for researchers and drug companies has been to find a way to remove sticky clumps of a protein called amyloid beta from the brain. But several recent studies in mice and rats now suggest that floating pieces of amyloid beta called oligomers are the real bad actors in Alzheimer’s disease. And instead of being the chief toxin, several teams suspect, the plaques may be the body’s way of trapping and neutralizing oligomers.
“If you say Alzheimer’s, everyone immediately thinks that it’s the plaques that actually cause the disease. That couldn’t be further from the truth,” Andrew Dillin, of the Salk Institute in California and the Howard Hughes Medical Institute, told reporters in London this week at a conference on aging.

“The data actually suggest these plaques are a form of protection that the body tries to put on. So this is a sign that your brain was trying to do something very useful and helpful to you, and the remnant was the formation of amyloid plaques,” Dillin said.

A GOOD THING?
Adrian Ivinson, who directs the Harvard NeuroDiscovery Center in Boston, a drug discovery center affiliated with Harvard Medical School working on new Alzheimer’s drugs, said scientists are beginning to think plaque is a good thing.
“It actually sequesters all of that amyloid,” he said, adding that oligomers are “the really toxic substance.”

In the latest study, a team led by Dr. Sam Gandy of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine in New York genetically engineered mice that form only oligomers, but never brain plaques. They found these mice developed the same level of memory and thinking problems as genetically engineered mice that get both plaques and oligomers. And when the team added a gene that converted the oligomers to plaques, the mice got no worse.
“That suggests that plaques were not necessary and the addition of plaque did not make the oligomer-induced memory problems any worse,” said Gandy, whose study appeared last month in the Annals of Neurology.

The findings may help explain the stunning failure of drugs designed to remove plaques from the brain of patients, which do little to improve thinking in Alzheimer’s patients.
Alzheimer’s is the most common form of dementia in which patients progressively lose their ability to think and care for themselves. Current drugs only treat symptoms.

LACK OF EFFECTS
Gandy points to a recent imaging study in Lancet Neurology looking at the drug bapineuzumab – now in late-stage clinical trials.
The team used an imaging agent called Pittsburgh Compound B or PiB that can be used in brain scans to identify amyloid plaques. Using these scans in 28 patients, the team found that bapineuzumab shrank brain plaques by 25 percent, but Gandy said the drug had no effect on patients’ ability to think and reason.
“We don’t know whether bapineuzumab sees oligomers or not,” Gandy said in a telephone interview.

And because PiB can only see amyloid deposits and not floating clumps of oligomers, there is no way to know whether the drug is having any effect.
Gandy said the Lancet Neurology study may simply mean that patients need to be treated longer to benefit from bapineuzumab. Or, it may mean that the drug – an engineered immune-system molecule called a monoclonal antibody – is targeting the wrong thing.

Bapineuzumab has had mixed results in a mid-stage clinical trial, and some researchers were encouraged by the Lancet Neurology study because it reduced plaque levels in patients.  But Dillin said the drug, like several others aimed at trying to stop plaques from forming, is destined to fail.
“This hypothesis is actually completely wrong, and we need a new way to start looking at this disease. This is actually not a viable therapeutic avenue,” Dillin said.

Pfizer this month said results of its U.S. phase 3 trials would be released in mid-2012 and the European phase 3 trials would be done in 2014, a bit later than analysts had expected.
Many investors have already written off bapineuzumab, but since Alzheimer’s afflicts 26 million people worldwide, any success could mean billions of dollars in revenue.

SOURCES: http://www3.interscience.wiley.com/journal/123351444/abstract
Annals of Neurology, online April 14, 2010; http://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2810%2970043-0/abstract The Lancet Neurology, April 2010.

FAIR USE NOTICE: This may contain copyrighted (© ) material the use of which has not always been specifically authorized by the copyright owner. Such material is made available for educational purposes, to advance understanding of human rights, democracy, scientific, moral, ethical, and social justice issues, etc. It is believed that this constitutes a ‘fair use’ of any such copyrighted material as provided for in Title 17 U.S.C. section 107 of the US Copyright Law. This material is distributed without profit.