Alzheimer’s Conference Offers Cautious Hope for New Treatments

by Aalok Mehta

August 7, 2008

Despite some high-profile setbacks, scientists are offering a note of “cautious optimism” about new drug candidates and diagnostic tests after a recent conference on Alzheimer’s disease.

Several drugs, with widely varying targets, had promising—but preliminary—results in clinical trials, say attendees of the International Conference on Alzheimer's Disease and Related Disorders (ICAD), held July 26-31 in Chicago.

This is the “most drugs in Phases II and III ever reported at any single meeting on Alzheimer’s disease,” says Samuel Gandy, a neurologist at the Mount Sinai Alzheimer’s Disease Research Center in New York City and chairman of the National Medical and Scientific Advisory Council of the Alzheimer's Association, which sponsored the conference.

“I think this conference will end up being a watershed experience in the tau versus amyloid debate. The tide is really shifting towards tau.”—Claude Wischik, professor of mental health at the University of Aberdeen in Scotland and chairman of TauRX Therapeutics

 The wealth of data represents significant progress toward the first drugs that treat the underlying causes of Alzheimer’s—widely believed to be associated with tangles and plaques of protein in the brain—researchers say. The four currently used treatments do not represent a true “cure” but only delay the progress of symptoms.

But attendees reiterated that the results come from early stages of clinical testing and that any potential drugs remain years away from coming to market—if they make it that far at all.

“These results are promising but are still relatively early in human trials (Phase II) and need to be taken into larger Phase III randomized, controlled trials to see how efficacious they are,” says Laurie Ryan of the Dementias of Aging Branch at the National Institute of Aging’s Division of Neuroscience.

Amyloid setbacks

One sobering note from ICAD was disappointing data from a pair of closely watched anti-amyloid drugs, which target the insoluble protein deposits that many experts believe lie at the root of Alzheimer’s.

More data were released, for instance, about the Phase III failure of tarenflurbil, also known as Flurizan. Myriad Genetics had announced in late June that they were abandoning development of the drug, which modulates the activity of gamma secretase, an enzyme known to cleave amyloid precursors.

Meanwhile, researchers expanded upon mixed results from Phase II trials of bapineuzumab, a monoclonal antibody developed jointly by Wyeth and Elan that targets an end domain of amyloid deposits.

The trial failed to achieve its stated end goals, and there were also concerns about 12 incidences of vasogenic edema—a fluid buildup in the brain—that occurred among the study’s 234 participants.

But a post-trial statistical analysis suggested that bapineuzumab can still be highly effective in specific groups of people, and Phase III trials to test this have already started, says Sid Gilman, a neurologist at the University of Michigan and chair of the independent safety monitoring committee for the drug.

Drug results were “very convincing in noncarriers” of the ApoE4 gene, among whom those taking bapineuzumab experienced far less cognitive decline than the group taking a placebo, says Gilman, who presented the trial data at the conference.

There was little difference, however, for carriers of the gene, one of the biggest risk factors for Alzheimer’s. No one is sure why the antibody had no effect on the group, which is known to develop Alzheimer’s earlier on average and in whom the disease often progresses more quickly.

Phase III trials will also commence for LY2062430, a monoclonal antibody that binds to a middle section of amyloid.

Eli Lilly scientists presented Phase II trial results that found that, in people treated with the drug, levels of amyloid in spinal cord fluid went up. The antibody appears to have bound to amyloid in the brain and “dissolved” some of it for eventual breakdown, meeting presenters say. But the clinical trials found no change in cognitive scores, something scientists hope changes in the longer study.

‘Rising tide’ of tau?

The developments may dampen some of the enthusiasm for amyloid as the main cause and best drug target for Alzheimer’s, even as a growing number of researchers are turning toward a competing explanation: tau protein, which makes up neurofibrillary tangles—brain lesions that seem to be associated with onset of the disease.

“I think this conference will end up being a watershed experience in the tau versus amyloid debate,” says Claude Wischik, a professor of mental health at the University of Aberdeen in Scotland and chairman of TauRX Therapeutics. “The tide is really shifting towards tau.”

Wischik presented Phase II data on TauRX’s drug Rember, or methylthioninium chloride, which is currently used to conduct various chemical tests and as a medical dye.

He had previously found that abnormal tau acts like a prion, causing regular proteins to alter their structure and begin binding to one another. He says that Rember seems to selectively inhibit tau proteins from completing this clumping process.

Both cognition-decline tests and brain-scan images showed “highly significant” results in patients who took Rember, Gilman says, and TauRX scientists have already started seeking approvals for Phase III testing.

“This is the real deal,” Wischik says. “These are the best results so far on a disease-modifying drug [for Alzheimer’s].”

Allon Therapeutics also presented data on AL-108, a nasal spray that targets tau-related tangles. A Phase II clinical trial of 144 people found a significant improvement in tests of short-term memory, and further testing is likely, scientists announced at the meeting.

Dimebon makes progress

ICAD attendees also presented expanded data on an extended study of the closely watched drug Dimebon. Positive results from the tests had first been reported prior to the meeting in a July Lancet article.

The results of six months of additional drug treatments—though this time with no placebo group as a control—suggested that Dimebon can slow the progress of Alzheimer’s and has increasing effects the longer it is taken, according to the presenters.

How the drug works remains unclear, but the developer, Medivation, says it appears to act in a manner distinct from other Alzheimer’s drugs by improving mitochondrial function, which has been implicated in neuronal cell death. Further Phase III trials are now being conducted.

“Dimebon is closer to approval than any drug has come since Namenda was approved in 2003,” Gandy says. “It needs only six months in a repeat Phase III to be approved.”

Other results reported at the conference included Phase II trial data on Prana Biotechnology’s PBT2, which prevents copper and zinc ions from interacting with beta- amyloid. Scientists believe these metals play a vital role in the aggregation of beta- amyloid proteins.

Gilman says the data showed little effect on cognitive decline tests but caused enough of a reduction in spinal beta-amyloid levels to progress to further testing.

Elsewhere, Baxter International presented data on IVIg, a broad-spectrum cocktail of antibodies currently used to treat immune deficiencies and autoimmune disorders. IVIg is known to contain antibodies that bind to beta-amyloid aggregates in the brain.

The small trial, of 24 people, offered enough signs of improvement in cognitive decline rates to warrant a full Phase III trial, Baxter scientists say.

Scientists also presented early results from several new diagnostic tests for Alzheimer’s.

One test measured a cell-cycle defect in white blood cells called lymphocytes that appears to mirror a similar defect in Alzheimer’s-affected neurons. A second looked at a particular type of beta-amyloid in spinal fluid that appears to vary inversely with the amount of amyloid in the brain.

Another test explored measuring spinal fluid levels of BACE1, an enzyme involved in the processing of amyloid precursor proteins. Scientists also presented data on a new amyloid imaging agent for positron emission tomography scans.

“BACE1 elevation in [cerebrospinal fluid] is important, because we know that BACE1 goes up in the brain,” Gandy says. It’s “probably the most promising new fluid marker.”

Growing interest in Alzheimer’s

The boom of findings at ICAD is no accident. Alzheimer’s research has taken off in recent years as companies and governments race for solutions to the costly condition in the face of aging demographics.

A 2007 report by researchers from Johns Hopkins University estimated that by 2050 the worldwide prevalence of Alzheimer’s disease will have quadrupled from its 2006 level of 26.6 million, coming to affect 1 in every 85 people.

“The number of interesting findings is simply reflective of the growth of research in the field,” says Constantine Lyketsos, a neuropsychiatrist at the Johns Hopkins School of Medicine.

According to the U.S. National Institutes of Health, there are now 511 clinical trials in various stages looking at Alzheimer’s disease.

That’s a trend that has not escaped the notice of the Alzheimer’s Association. The group is now planning on holding ICAD every year, instead of biennially as it has been previously, though the change has elicited mixed reactions.

“Other, smaller meetings are being affected that are very important. We’ll have to see—I’m not sure there is enough data to support this level of meeting every year,” Lyketsos says.

“We probably won’t see as many developments next year,” he adds. “It takes a while to get Phase III results.”