Clinical Trial Set for Gantenerumab in Early-onset Alzheimer’s Disease

An international clinical trial for gantenerumab aimed at preventing inherited, early-onset Alzheimer’s disease is being launched at the Washington University School of Medicine in St. Louis.

The trial, called the Primary Prevention Trial, is enrolling people with a family history of early-onset Alzheimer’s and its associated genetic mutations up to 25 years before their expected onset of dementia, starting at age 18.

The study will investigate whether gantenerumab — an investigational antibody under development for Alzheimer’s disease by Roche and its U.S. affiliate, Genentech — can prevent and clear amyloid beta buildup.

“We are thrilled to be part of this important clinical trial in one of the earliest stages of Alzheimer’s studied to date,” Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech said in a press release.

“Our vision has always been to detect Alzheimer’s early, before damage in the brain is irreversible, offering tools and treatment all along the journey for people at risk of the disease. Close collaboration between industry, academia and patients is so critical to achieve this and tackle the complex challenge of this disease,” Doody added.

Gantenerumab has been granted breakthrough therapy status by the U.S. Food and Drug Administration (FDA) in order to accelerate its development and treatment of early Alzheimer’s. It has shown potential in clearing beta amyloid, a key protein involved in Alzheimer’s progression due to its aggregation, or clumping, in the brain.

Many scientists hypothesize that amyloid plaque buildup in the brain may start to develop up to two decades before patients display dementia symptoms.

“Overwhelming evidence suggests that the most effective way to slow or stop amyloid beta is to prevent it from building up in the first place, but most of the drugs targeted to this protein have been tested in people who already have at least some early signs of the disease, such as memory loss — when the disease is far enough along that reducing amyloid alone isn’t likely to stop it,” Eric McDade, DO, the trial’s principal investigator, said.

“We now know that changes in the brain can begin a decade or more before symptoms appear, so this trial is designed to provide another piece in the Alzheimer’s prevention puzzle,” Laurie Ryan, PhD, chief of the Clinical Interventions and Diagnostics Branch in National Institute on Aging’s (NIA) Division of Neuroscience said.

This new clinical trial for gantenerumab use is the second international Alzheimer’s prevention trial led by WashU’s School of Medicine.

Both trials are being conducted in association with the Dominantly Inherited Alzheimer Network (DIAN) — a National Institutes of Health-funded international research network led by Washington University and involving nearly 40 research institutes across North America, Australia, Europe, Asia, and South America.

The first trial, started in 2012 and still ongoing, was the Dominantly Inherited Alzheimer Network-Trials Unit-001 (DIAN-TU-001) (NCT01760005), which looked at the effectiveness of treatments, including gantenerumab, in patients likely to develop Alzheimer’s during the trial. Nearly all the participants had some amyloid plaques at the time they entered the study.

Although this Phase 2/3 study did not achieve this main objective — to slow cognitive decline and prevent memory problems — gantenerumab significantly reduced amyloid plaque formation in the brain compared with placebo. It also significantly reduced the number of other disease biomarkers in participants’ cerebral spinal fluid (CSF), the liquid that surrounds the brain and spinal cord.

Trial leaders are offering gantenerumab to participants as part of an open-label extension study to continue to monitor changes in measures of Alzheimer’s disease.

This new trial will be recruiting 230 people from families who carry genetic mutations that lead to early-onset Alzheimer’s. These individuals, with a 50% chance of inheriting a gene associated with Alzheimer’s, are almost guaranteed to develop dementia near the same age as their parent if any of these genes are inherited. Those interested can email the DIAN Expanded Registry.

This genetic predisposition allows researchers the opportunity to evaluate gantenerumab in preventing Alzheimer’s. WashU notes that the trial may also further the overall understanding of Alzheimer’s, as the processes involved in memory loss and cognitive dysfunction are thought to be similar in the inherited forms of the disease, as well as in other forms.

The participants will have few to no amyloid plaques and will be seen in sites on five continents over the course of four years. The goal is to determine whether early treatment targeting amyloid can prevent familial, inherited Alzheimer’s disease.

“Initiating a new prevention trial alongside the DIAN-TU-001 trial gives family members an opportunity to attempt to stop the disease even earlier — 10 years or more before symptoms are likely to arise, which is before or just as the first brain changes begin,” said Randall J. Bateman, MD, the principal investigator and program director of the Knight Family DIAN-TU trial.

This clinical trial for gantenerumab has already gathered support from numerous interested parties. Over $130 million has already been set aside for the trial, including $97.4 million from the NIA, $14 million from the Alzheimer’s Association and the GHR Foundation, and up to $11.5 million from Joanne Knight, a longtime WashU benefactor, and her family.

Additionally, WashU has pledged to raise an additional $6.5 million, and additional funding is being provided by Roche and Genentech, which are closely partnering with the trial.

“We’re thankful for the support from many sources to make this trial possible,” McDade said. “We’re also grateful to the families, for their encouragement and willingness to take part in trials like this one.”

“DIAN-TU is a landmark project and has dramatically accelerated the pace of discovery of treatment and prevention strategies for Alzheimer’s disease, and this innovative new prevention study is no exception,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer.