New Strategy for Clinical Trial Success in Alzheimer Disease

A shift to focusing on prevention, early intervention

There’s no sugarcoating it: Alzheimer disease (AD) researchers have been unsuccessful in the quest for new therapies to prevent the disease or delay its onset, slow its progression or improve its symptoms.

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That’s the inescapable conclusion of a comprehensive review published in July 2014 by researchers at Cleveland Clinic Lou Ruvo Center for Brain Health. The analysis (Alzheimers Res Ther. 2014;6[4]:37) found that between 2002 and 2012, 99.6 percent of AD drugs that entered the clinical trial pipeline failed.

“Traditionally, most clinical trials have studied drugs to treat AD once an individual has signs of dementia,” says the study’s lead author, Jeffrey L. Cummings, MD, ScD, Director of the Lou Ruvo Center for Brain Health. “By that point, it may be too late to make a significant impact.”

Focusing on the ‘Right Stuff’

Armed with that insight, Dr. Cummings and his colleagues are shaping the Lou Ruvo Center for Brain Health’s clinical trial program for AD ‒ one of the largest programs in the nation ‒ to help change the trajectory of success in AD trials.

The multisite program (with four locations ‒ in Las Vegas; Weston, Florida; and Cleveland and Lakewood, Ohio) is pursuing a bold three-pronged mission of developing strategies to transform the clinical trial process, improve the quality of trials and develop therapies for AD.

Central to the program is a commitment to improve the track record of investigational therapies for AD by doggedly focusing on the “right” things, including:

  • The right patients
  • The right drugs (or other interventions)
  • The right outcomes and biology

Alz-table

The Right Patients ‒ at the Right Time

Although AD trials historically have focused on patients with Alzheimer dementia, researchers have come to realize that AD has a long existence in the brain before signs of dementia manifest.

“We now believe that treating patients in the dementia phase is too late because the neuropathological changes are already well established,” Dr. Cummings explains.

Therefore, much of the center’s current AD research is focused on:

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  • Prevention in individuals who are overtly normal but at high risk of developing AD
  • Earlier intervention in patients who are symptomatic for mild disease but do not yet meet the criteria for Alzheimer dementia

The table profiles a sampling of prevention and early-intervention studies now underway at the center. Two of the major prevention studies are outlined below.

TOMMORROW. The largest worldwide AD prevention study to date, TOMMORROW focuses on age and genetics to determine AD risk among 65- to 83-year-olds who are still cognitively normal. It is recruiting more than 5,000 healthy participants across three continents. Individuals at high risk for AD are assigned randomly to placebo or pioglitazone (currently FDA-approved to treat type 2 diabetes) to determine if the latter therapy can delay or prevent AD.

The study also is investigating whether gene-based biomarkers can determine the risk of developing mild cognitive impairment due to AD within five years. One of the genetic biomarkers being studied is TOMM40, a protein encoded by the TOMM40 gene, which inspired the study name.

Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Study. In this three-year investigation, cognitively normal 65- to 85-year olds with evidence of amyloid plaque in the brain are receiving placebo or the experimental monoclonal antibody solanezumab, which attacks the abnormal protein. The center is participating in the trial through the Alzheimer’s Disease Cooperative Study, a cohort of 40 top U.S. academic medical centers.

“This is the most advanced neuroscience trial in AD currently being conducted,” Dr. Cummings notes.

Along with the priority given to prevention, other studies in patients with diagnosed AD are trending toward an increased focus on mild to moderate disease, where early interventions may have a more significant impact. For example, a randomized trial is evaluating transcranial magnetic stimulation to improve cognitive functioning in patients with early-stage disease (see table and photo). The therapy stimulates targeted brain areas affected by AD to make them more receptive to cognitive training.

The Right Drugs

Current treatments for AD, which include cholinesterase inhibitors and memantine, do not modify the underlying disease process. There is an urgent need to identify therapies that slow disease progression as well as drugs that further improve AD symptoms.

The Lou Ruvo Center for Brain Health is studying novel drug therapies, including antibodies given intravenously or subcutaneously, oral medications to improve mitochondrial function and other agents that impact AD pathology.

The center’s researchers also are embracing a “multiple shots on goal” strategy. For example, a rasagiline study is testing this multifunctional molecule (currently FDA-approved for Parkinson disease) to determine its potential to affect several aspects of neurobiology in AD.

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“This approach promises to be very important in identifying therapies that eventually will be effective,” Dr. Cummings says.

Additionally, immunotherapy studies at the center are looking at ways in which the body’s immune response can be stimulated or antibodies can be developed artificially to potentially reduce AD’s effects on the brain.

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A patient with mild AD undergoes transcranial magnetic stimulation in a clinical trial of the therapy at Lou Ruvo Center for Brain Health in Las Vegas.

The Right Outcomes and Biology

Measuring the success of therapies hinges on measuring the right clinical outcomes, including cognitive-behavioral assessments and biomarkers.

Lou Ruvo Center for Brain Health researchers are collaborating with the FDA’s Coalition Against Major Diseases to develop cognitive-behavioral assessments to measure outcomes in patients with very mild AD.

“Just as we need to move to studying and treating patients with more mild disease, we also need to adjust the instrumentation so we can capture changes induced by the drugs,” Dr. Cummings says. “If the FDA accepts the recommendations, they could become new standard outcome assessments for clinical trials.”

Thinking also is evolving around which biomarkers provide the most useful information in AD research. For the first time, two studies at the center are focusing on pathologies reflected by tangles of tau protein on brain scans, rather than plaques shown by amyloid imaging. “We are finding that tau may be more closely related to cognition than plaques are,” Dr. Cummings notes.

 Hope for a New Era

“Collectively, these clinical trials and studies represent an exciting new era in AD research,” Dr. Cummings says. “We are helping transform the approach to clinical trials through innovation, with an ultimate goal of finding more ‒ and more-effective ‒ options for patients with AD.”