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Wednesday, March 15, 2017

Clinical Trials Need You

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In the April/May 2017 issue, we speak to Marcia Gay Harden about her mother's diagnosis of Alzheimer's disease and how that motivated Harden to become an advocate for people with the disease. In this online exclusive, we describe several of the Alzheimer's disease clinical trials currently underway.

BY LINDA CHILDERS

More than 400 clinical trials are currently studying new treatments for Alzheimer's disease, and many are actively recruiting participants. Here are a few.

Engage and Emerge

Aducanumab, a monoclonal antibody thought to target clumps of beta amyloid, is currently being evaluated in two global phase 3 studies, ENGAGE and EMERGE. Based on preclinical and phase 1b data, aducanumab has been shown to reduce amyloid plaque levels. The phase 3 trials are designed to evaluate the drug's safety and efficacy in slowing cognitive impairment and the progression of disability in people with early Alzheimer's disease. For more information, visit engageandemerge.com.

Anti-Amyloid Treatment in Asymptomatic Alzheimer's

The Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study at Brigham and Women's Hospital in Boston is currently recruiting participants, says lead investigator Reisa A. Sperling, MD. The trial will measure the effectiveness of the experimental therapy solanezumab, an anti-amyloid antibody that may slow memory loss associated with amyloid buildup. The trial is aimed at delaying memory decline in older individuals who have amyloid plaque buildup in their brains but still have normal memory.

In previous studies, solanezumab did not show a beneficial effect in more than 1,000 people who did not exhibit any symptoms of Alzheimer's disease, says Dr. Sperling. But the participants in the A4 study are about 10 years earlier in their disease trajectory than the patients studied in previous solanezumab trials, she says. "This is a very similar prevention approach to what has been successful in diabetes and heart disease, such as using statins in individuals with elevated cholesterol before they have a heart attack or stroke," she says.

Volunteers must be 65 to 85 years of age with normal thinking and memory function and no outward signs of dementia, Dr. Sperling says. The researchers will use a PET scan to determine whether the participants have an elevated level of amyloid plaque in their brains. For more information, visit A4study.org or call 844-A4STUDY.

TOMMORROW

The phase 3 clinical trial known as TOMMORROW, which completed enrollment last year, is one of the largest to look at mild cognitive impairment (MCI) due to Alzheimer's disease. The five-year randomized, double-blind, placebo-controlled, parallel-group trial, funded by Takeda Pharmaceuticals and Zinfandel Pharmaceuticals, involves approximately 3,500 people between the ages of 65 and 83 at centers in the United States, the United Kingdom, Germany, Switzerland, and Australia.

Researchers are investigating whether identifying specific genes is a valid way to assess the risk of MCI due to Alzheimer's disease in people older than 65. One of these genotypes is TOMM40, which inspired the study's name. They are also evaluating the safety and efficacy of pioglitazone, a drug currently used to treat type 2 diabetes, for postponing the onset of MCI in people with normal cognitive function who are considered to be at high risk for Alzheimer's disease. Research suggests that pioglitazone works by increasing the sensitivity of cells to insulin and regulating glucose levels, which are abnormal in both diabetes and Alzheimer's disease, and suppressing inflammation, which is also linked to both conditions.

Dominantly Inherited Alzheimer Network Trials Unit

Formed in 2012 at Washington University in St. Louis, the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) designs and directs trials for people with or at risk for dominantly inherited Alzheimer's disease, a rare form of the condition caused by a gene mutation, which is responsible for less than 1 percent of all cases of the disease. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN-1), or presenilin 2 (PSEN-2) are associated with developing Alzheimer's disease at a young age, usually in the 30s, 40s, or 50s.

A phase 2/3 randomized, double-blind, placebo-controlled trial is currently underway to test the experimental drugs gantenerumab and solanezumab for safety, side effects, and effects on imaging and biomarkers in people who know they have a genetic mutation, as well as those who don't know their genetic status but have a 50 percent chance of having a mutation because a parent or sibling has one. The researchers will evaluate them for subtle changes in cognition, but participants at this early stage are not likely to have more than minimal changes during the study period.

Alzheimer's Prevention Initiative

Last year, the Banner Alzheimer's Institute in Phoenix, AZ, launched the Alzheimer's Prevention Initiative (API), an international, collaborative research team formed to study ways to prevent the disease. The group currently has two five-year trials underway in individuals who are cognitively well but have the highest risk for developing Alzheimer's symptoms.

In the first, the API Autosomal Dominant Alzheimer's Disease (ADAD) trial, researchers are testing the efficacy and safety of crenezumab, a monoclonal antibody that that helps to remove amyloid beta protein from the brain, in members of an extended family in Medellin, Colombia, who carry the PSEN1 E280A autosomal dominant mutation, which makes it a certainty that they will develop the disease at an average age of 44.

In the other trial, the API Generation study, scientists are investigating whether two experimental therapies—an active immunotherapy (CAD106) and a beta-secretase 1 inhibitor (CNP520) can prevent or delay the disease in 1,300 cognitively healthy older adults between the ages of 60 and 75 who are at high risk of developing Alzheimer's disease because they have two copies of the risk gene apolipoprotein 4 (one from each parent).

Learning from Failure

"We have seen several clinical trials across the country that were unsuccessful," Dr Sperling says. "Yet even unsuccessful trials provide us with new clues about the disease." Consider the anti-amyloid therapies solanezumab, crenezumab, and bapineuzumab, for example, . In trials involving people with mild to moderate Alzheimer's disease, none has significantly slowed cognitive decline or improved global functioning. But at higher doses, the drugs have had an effect on those with mild forms of the disease, which supports the theory that to treat the disease, therapy must begin at a much earlier stage, well before symptoms appear.

Both Dr. Aisen and Dr. Sperling emphasize the urgent and ongoing need for clinical trial participants. For information on other Alzheimer's disease clinical trials in your area, visit alz.org or clinicaltrials.gov and type in "Alzheimer's disease."