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Alzheimer's Prevention Study in Genetically Defined High-Risk Patients Includes Roche, Lilly Drugs

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Researchers at the Washington University School of Medicine have picked two Alzheimer's drugs under development at Roche and Eli Lilly to take through a clinical trial that will test how well these agents prevent the disease in those genetically predisposed to get it.

The Dominantly Inherited Alzheimer's Network Trials Unit will launch this trial next year, and enroll 160 people who have inherited mutations that place them at heightened risk for getting the disease early, typically during their 30s, 40s or 50s. The trial also will monitor the health of 80 study participants who did not inherit the Alzheimer's mutations.

Study participants with inherited forms of Alzheimer's will be randomly assigned to one of the investigational drugs – Roche's gantenerumab or Lilly's solanezumab – or placebo. Study participants without mutations also will receive a placebo. A beta-secretase inhibitor being developed by Lilly is also being considered for the trial.

According to a statement from Wash U, researchers involved in the trial selected the drugs from more than a dozen submissions by the DIAN Pharma Consortium, 10 drug developers that have been advising study investigators on the design of the study. The selected drugs have "a unique approach to counter the toxic effects of amyloid beta, the main ingredient of brain plaques found in Alzheimer's patients," Wash U said in a statement. Additionally, the chosen drugs have successfully completed clinical trials evaluating their safety and efficacy and have reached their targets in patients.

Roche's gantenerumab binds to aggregated amyloid beta and helps remove it from the brain. The drug is undergoing a Phase III trial, called Scarlet Road, that will investigate whether the treatment can prevent Alzheimer's before it causes dementia.

Lilly's monoclonal antibody solanezumab is also in Phase III studies, and binds to soluble forms of amyloid beta to clear it before it can form plaques. Meanwhile, Lilly is currently developing a BACE inhibitor that limits amyloid beta production and slows plaque accumulation. This drug is in Phase II studies and is being considered for inclusion in the Wash U study.

The Dominantly Inherited Alzheimer's Network Trials Unit at Wash U is funded by DIAN, a National Institutes of Health -funded consortium of Alzheimer’s research centers; the Alzheimer's Association, and the DIAN Pharma Consortium. Additionally, Roche and Lilly will donate the drugs for the Wash U trial for free and provide additional grants. The Alzheimer's Association will provide $4.2 million in grants. Researchers participating in the project have also applied for NIH grants.

The move to prevent Alzheimer's disease using molecular targets to identify patients at high risk of developing the disease is a newly emerging strategy.

In the 770-patient Scarlet Road trial, researchers will measure Tau/Aβ levels in study participants' spinal fluid to identify early onset or prodormal Alzheimer's patients and treat them with gantenerumab. Roche is developing a companion test to gauge Tau/Aβ levels in trial participants. Results from Scarlet Road are expected in 2015 (PGx Reporter 9/12/2012).

Additionally, Roche is testing another compound, crenezumab, to see if it can prevent Alzheimer's in a population genetically predisposed to getting the disease. Genentech, in collaboration with Banner Alzheimer's Institute and the National Institutes of Health, is conducting a Phase II trial investigating crenezumab in the residents of Medellin, Colombia, where people share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50 (PGx Reporter 5/23/2012).

These targeted prevention strategies are emerging as there have been a number of high-profile late-stage drug failures in the Alzheimer's space. For example, Pfizer's bapineuzumab, a monoclonal antibody designed to bind to and clear beta amyloid, failed late-stage clinical trials. The drug was being studied as a treatment for mild to moderate Alzheimer's disease in APOE4 carriers, which raises a person's risk of getting Alzheimer's.

Meanwhile, Allen Roses, director of Duke University's Dean Drug Discovery Institute and CEO at Zinfandel Pharmaceuticals, has long held that beta amyloid is not the right target for Alzheimer's drug development. Roses' laboratory at Duke discovered in 1993 that carriers of the APOE4 allele have up to a 30 times greater risk of developing late-onset Alzheimer's than non-carriers.

In recent years, Roses and his research team have discovered that varying lengths of the TOMM40 rs10524523 poly-T polymorphism are associated with age of Alzheimer's disease onset and have developed a three-allele risk prediction system for gauging those who are likely to develop early-onset or late-onset Alzheimer's disease (PGx Reporter 7/14/2010).

Zinfandel and Takeda Pharmaceutical are collaborating on a study investigating whether Takeda's diabetes drug Actos can delay Alzheimer's onset in people with a high risk of the disease based on age and genetic factors (PGx Reporter 1/12/2011).

Investigators in this study will test patients with a TOMM40 assay to gauge their risk of getting Alzheimer's in the next five years, and based on their risk, randomize patients to receiving either Actos or a placebo. Actos is an inhibitor of peroxisome proliferator-activated receptor gamma, or PPARg, a receptor that controls genes involved in the metabolism of glucose and lipid in the body, levels of which are abnormal in Alzheimer's patients.

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