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doi: 10.1097/01.NT.0000446542.26657.36
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THEN AND NOW: First Human Trials for Alzheimer's Disease What's Happened Since?

Robinson, Richard

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“Alzheimer Vaccine Moves to Human Trials” was the front-page cover headline in the inaugural May/June 2001 issue of Neurology Today. It told the story of the quest for what was, and continues to be, among the most important unmet goals in neurology, a treatment to slow or halt Alzheimer's disease.

As reported, an active vaccine against amyloid-beta (Abeta) called AN-1792, had just completed a phase 1 safety trial, and was headed for a phase 2 trial. The goal was to determine whether this combination of Abeta and an adjuvant could stimulate production of antibodies against Abeta, leading to clearance from the brain, an effect seen in mice.

Extensive animal studies had showed that immunization with Abeta-42 peptide could prevent or reverse the development of the neuropathological hallmarks of Alzheimer's disease, including amyloid plaque formation, neuritic dystrophy, and synaptic loss.

The developer of the AN-1792 vaccine, Dale Schenk, PhD, then the vice president of discovery research at Elan Pharmaceuticals, which was sponsoring the trial, told Neurology Today in 2001: “Less than 1 percent of antibodies cross the blood-brain barrier in mice, but fortunately, that seems to be enough. Our measurements in mice shows the amount of antibody that move in to the brain is exactly the amount you would predict in animals, and that happens to be very similar to what you see in humans, about 0.1 to 0.3 percent.”

[Dr. Schenk is now chief executive officer of Prothena Biosciences, based in South San Francisco, a company focused on developing novel antibodies that target diseases that involve protein misfolding or cell adhesion. Elan Pharmaceuticals was acquired by Perrigo Company in 2013.]

There were high hopes for the clinical trials of the vaccine, but they were cut short in 2002, when several patients developed an autoimmune meningoencephalitis, which ultimately affected 6 percent of those receiving the treatment. Since then, trials have relied on passive immunotherapy, through administration of monoclonal antibodies against Abeta.

“The Abeta peptide with adjuvant caused the proliferation of pro-inflammatory Th1 cells, which trafficked though the patient's brain and caused a cytotoxic inflammation with loss of neurons, infarction and demyelination,” explained Roger Rosenberg, MD, FAAN, professor of neurology and neurotherapeutics and physiology at the University of Texas Southwestern Medical Center in Dallas, who first commented on the early report in Neurology Today. “That is the negative aspect of this landmark study. The benefit was that the vaccination did reduce significantly the amyloid levels in brain plaques,” as shown on autopsy of treated patients.

Another critical lesson learned over the past 14 years from AN-1792 and trials of the monoclonal antibodies bapineuzumab and solanezumab “is that it is not possible to treat moderate or advanced Alzheimer's disease, as the brain is too advanced in the neuropathology of the disease, with neuronal loss, plaques, tangles, and other downstream secondary pathologies,” and patients continue to decline cognitively and pathologically, Dr. Rosenberg said.

The alternative, treating asymptomatic individuals who are accumulating amyloid as shown by PET scans, is the basis of three passive immunotherapy clinical trials that are now under way. “This early intervention is intended to reverse the amyloid burden at a time before the secondary later pathologies begin,” Dr. Rosenberg said. The results of those trials, which are not expected for several years, could have major implications for the prevention of this most common neurodegenerative disease.

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TIMELINE OF KEY DEVELOPMENTS IN ABETA IMMUNOTHERAPY

1999: Investigators report that immunization with amyloid-beta reduced the severity of Alzheimer's disease pathology in a mouse model.

Citation: Schenk D, Barbour R, Dunn W, et al. lmmunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400(6740):173–177.

2002: Of 298 patients receiving vaccination with AN1792, 18 (6 percent) developed meningoencephalitis, leading to discontinuation of the drug development program.

Citation: Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 2003;61(1):46–54.

2005: Among patients receiving AN1792, 20 percent developed the intended antibody response. However, no significant differences were found between antibody responder and placebo groups on several measures of cognitive function.

Citation: Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 2005;64(9):1553–1562.

2009: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. The data, the investigators concluded, support the hypothesis that Abeta immunotherapy may have long-term functional benefits.

Citation: Vellas B, Black R, Thal LJ, et al. Long-term follow-up of patients immunized with AN1792: Reduced functional decline in antibody responders. Curr Alzheimer Res 2009;6(2):144–151.

2012: A phase 1, double-blind trial of the Abeta vaccine CAD106 suggests the treatment is able to provoke an immune response without triggering meningoencephalitis, raising the possibility that active vaccination may yet be feasible in Alzheimer's disease.

Citation: Winblad B, Andreasen N, Minthon L, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: Randomized, double-blind, placebo-controlled, first-in-human study. Lancet Neurol 2012;11(7):597–604.

2014: Multiple phase 3 trials of two different monoclonal antibodies show that this form of treatment can safely reduce the brain burden of Abeta. However, neither treatment led to clinical improvement or slowing of decline, suggesting that immunotherapy started after dementia develops will not affect disease progression.

Citation: Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370(4):322–333.

Citation: Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370(4):311–321.

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NEUROLOGY TODAY: THEN AND NOW

Neurology Today first debuted its inaugural issue at the AAN Annual Meeting in 2001 in Philadelphia. As the AAN Annual Meeting returns to the city later this month, some 13 years later, we wanted to take a look back at some of the stories we first reported that first year — one, on the launch of clinical trials of an Alzheimer's vaccine, and the other two from reports at the 2001 AAN Annual Meeting — on gene profiling and the identification of a paraneoplastic disorder. Look for Neurology Today: Then and Now as a recurring feature, as we go back to the prominent stories from the archives and explore how those stories have developed in the ensuing years.

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LINK UP FOR MORE INFORMATION:

•. Neurology Today:Alzheimer vaccine moves to human trials. http://bit.ly/1hiG8Bq

•. Neurology Todayarchives on Alzheimer's vaccine: http://bit.ly/1hKjDlf

•. Mathews PM, Nixon RA. Editorials: Setback for an Alzheimer's disease vaccine: Lesson's learned. Neurology. 2003; 61:(1):7–8.

•. Neurologyarchive on AN-1792 vaccine: http://bit.ly/QrTlhX

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