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Fifteen Years of Publication
Then and Now
Alzheimer's Disease Immunotherapy
New Lessons, New Approaches, New Hope

ARTICLE IN BRIEF

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What has happened since the first report in Neurology Today that an Alzheimer's vaccine was moving into clinical trials? Three of the investigators involved in early immunotherapy research initiatives reflect on what has happened in 15 years and predict what likes ahead.

“Alzheimer Vaccine Moves to Human Trials” announced the headline of the cover story of Neurology Today's inaugural May/June 2001 issue. In preclinical studies with mice, the amyloid-beta-42 vaccine, referred to as AN-1792, had cleared amyloid plaques by as much as 78 percent and, experts told Neurology Today then, there was reason to be hopeful that the vaccine, which improved spatial memory in mice, would be promising in an early safety trial in patients with mild-to-moderate Alzheimer's disease (AD).

Did that vaccine deliver on the promise? Some 15 years later, Neurology Today spoke with three experts in the field who were involved in early studies testing immunotherapy approaches to AD to understand what lessons the past decade and a half have offered for AD immunotherapy, and what they expect to see in the next decade and a half.

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DR. DAVID M. HOLTZMAN: “I think in the next three years, there will be an effect shown with something that targets Abeta, either with one of the antibodies or a beta-secretase inhibitor. Treatment isnt going to reverse symptoms, but it will cause a significant slowing of disease progression. That will be the beginning of a new era, one that will lead to new trials targeting tau accumulation and focusing on presymptomatic treatment.”

SIDE EFFECTS WITH ACTIVE IMMUNOTHERAPY

“There was a lot of justifiable excitement about vaccination in the late 1990s, when animal models showed that provoking an immune response by vaccinating with amyloid-beta [Abeta] peptide could decrease amyloid-beta levels in the brain, mitigate toxicity, and improve cognition,” David M. Holtzman, MD, FAAN, a professor of neurology at the Washington University School of Medicine in Saint Louis, told Neurology Today.

“But when active immunotherapy moved into [a clinical trial with] people, the first thing we learned was that you could get side effects we didn't know about until then. The adverse events were related to a cellular immune response from the active vaccination.”

The 2001 trial of the AN-1792 vaccine, which administered Abeta peptide with an adjuvant to stimulate immunity, was stopped in January 2002 when 6 percent of the recipients developed meningoencephalitis due to a T-cell response against brain Abeta. This unexpected and serious side effect dealt a blow to the immunotherapy field.

That blow, however, was only temporary, said Dennis J. Selkoe, MD, FAAN, a professor of neurologic diseases at Harvard Medical School in Boston and an investigator of a trial of an intranasal amyloid beta vaccine. Even as the trial was going on, researchers were investigating passive immunotherapy, in which monoclonal antibodies are infused to bind Abeta in order to prevent its toxic effects.

“Despite the results of the vaccine trial, the idea of using the immune system as a therapeutic for AD has only gained strength in the past 15 years,” Dr. Selkoe said. “Passive immunotherapy, which does not provoke a T-cell response, has gripped the field, and is now moving forward quickly.”

Multiple antibodies have been developed and tested, each designed to bind to a specific form of Abeta. But unlike the goals of treatment in 2001, plaques are not the prime target.

“Fifteen years ago, the thinking was that if you removed the plaques, the patient would improve,” said Thomas M. Wisniewski, MD, a professor of neurology, pathology and psychiatry at New York University School of Medicine. “Now it is clear that once the amyloid cascade is initiated, the damage has been done.”

That cascade is triggered mainly by the oligomeric species of Abeta, rather than the plaques. But neither plaques nor oligomers are thought to be the main culprits in cognitive decline — that role is played by the neurofibrillary tangles of tau protein, a downstream consequence of the amyloid cascade.

“It has become clear over a number of years that Abeta aggregation is probably a trigger,” said Dr. Holtzman. “It causes some injury, but the main cause of injury is tau build-up and accumulation.”

IMAGING AND EARLIER TREATMENT

Another crucial realization over the past 15 years, and especially over the past several years, is the importance of neuroimaging in clinical trials, a point brought home by the recent discovery that about a quarter of patients enrolled in trials of bapineuzumab and solanezumab, two monoclonal antibodies against Abeta, did not have Abeta pathology.

“They couldn't have gotten any better with treatment for something they didn't have, and they were at risk for side effects,” Dr. Selkoe said. “We now recognize that we shouldn't save money by avoiding imaging in trials.”

Finally, all three neurologists agreed, the intervening years have shown the central importance of the earliest possible treatment. “The realization that Abeta pathology builds up over 20 years or more before the onset of mild cognitive impairment or Alzheimer's disease has dramatically changed the field,” Dr. Wisniewski said.

That realization may explain why the earliest antibody trials, which enrolled patients with mild-to-moderate AD, failed to have an effect on cognition. “We were treating the disease much too late,” Dr. Selkoe said.

The lessons learned have informed the design of a spate of new trials, some nearing completion and others getting underway. Subgroup analysis of results from two phase 3 trials of solanezumab suggested that treatment slowed cognitive decline in patients with mild disease, which has led to a new phase 3 trial (EXPEDITION-3) of mild AD patients with imaging-confirmed amyloid. Results are expected later this year.

Solanezumab is also being studied in the A4 trial of individuals with demonstrated evidence of amyloid burden but with little or no cognitive impairment.

Even more encouraging than the solanezumab results, Dr. Selkoe said, are early results from treatment with another monoclonal antibody, aducanumab, showing dose-dependent reduction in brain amyloid after 12 months — “much more than I would have expected,” he said — and a dose-dependent slowing of cognitive decline compared to placebo. The results, which have been announced in meetings but have not yet been published, led to commencement of a phase 3 trial, which is now enrolling.

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DR. THOMAS M. WISNIEWSKI: “The realization that Abeta pathology builds up over 20 years or more before the onset of mild cognitive impairment or Alzheimers disease has dramatically changed the field.”

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DR. DENNIS J. SELKOE: “Despite the results of the vaccine trial, the idea of using the immune system as a therapeutic for AD has only gained strength in the past 15 years. Passive immunotherapy, which does not provoke a T-cell response, has gripped the field, and is now moving forward quickly.”

Preventive treatment is the focus of a trial by the Dominantly Inherited Alzheimer's Network (DIAN), which is testing the ability to slow amyloid accumulation and cognitive decline in individuals at high risk for possessing an autosomal dominant AD gene.

Solanezumab and another monoclonal antibody, gantenerumab, will each be tested against placebo for up to four years. Yet another monoclonal, crenezumab, is the focus of a trial with a similar strategy in presymptomatic carriers of autosomal dominant presenilin mutations.

The various monoclonal antibodies differ in their exact targets, some binding to oligomers, others to aggregates, others to monomeric forms. They also differ in their likelihood of causing amyloid-related imaging abnormalities (ARIAs), first identified in the bapineuzumab trial, and now seen to varying extent on treatment with other antibodies. The production of ARIAs is part of the mechanism of action of the more aggressive antibodies, Dr. Wisniewski said. Solanezumab doesn't produce ARIAs, Dr. Selkoe noted, but it is also less potent. “They go hand in hand.”

WHAT LIES AHEAD FOR TREATMENT?

As for what is in store for the next 15 years, Dr. Selkoe predicted, “I think we are going to see more than one FDA-approved drug for disease modification, probably an antibody to Abeta. That could happen in the next two to four years. If it does, it will open the floodgates for further research to limit Abeta production, including revisiting the vaccination approach. If it can be made safe, a true vaccine could be far more practical than monthly antibody infusion, which is expensive and “a logistical nightmare,” he said.

Dr. Holtzman concurred: “I think in the next three years, there will be an effect shown with something that targets Abeta, either with one of the antibodies or a beta-secretase inhibitor. Treatment isn't going to reverse symptoms, but it will cause a significant slowing of disease progression. That will be the beginning of a new era, one that will lead to new trials targeting tau accumulation and focusing on presymptomatic treatment.”

“Fifteen years from now,” Dr. Holtzman said, “I predict we will have approved treatments for more than one target, and be able to delay onset of disease.”

“Other developments likely to radically change the Alzheimer's landscape include cheaper PET imaging,” Dr. Wisniewski said. “I can envisage in the next few years, that, just as we now get a colonoscopy at age 50, we would get an amyloid scan, to determine whether and when to begin treatment.”

But antibodies themselves are not likely to be the final word on preventive treatment, he said, “because there are still upstream events that are driving the accumulation of amyloid. The cure lies further upstream.”

NEUROLOGY TODAY' S ‘THEN AND NOW’ SERIES

As part of Neurology Today's celebration of 15 years of publication, the editors have chosen to look back at some of the important stories and advances that were reported in the inaugural year —with an eye toward ensuing developments since then. Look for our “Fifteen Years of Publication: Then and Now” series of articles in upcoming issues throughout the year.

LINK UP FOR MORE INFORMATION:

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•. Salloway S, Sperling R, Fox NC, et al.for the Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease http://www.nejm.org/doi/full/10.1056/NEJMoa1304839. N Engl J Med 2014;370(4):322–333.
•. Doody RS, Thomas RG, Farlow M, et al.for the Alzheimer's Disease Cooperative Study Steering Committee; Solanezumab Study Group. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease http://www.nejm.org/doi/full/10.1056/NEJMoa1312889. N Engl J Med 2014 Jan 23;370(4):311–21.
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