Roche Moving Gantenerumab Into Phase 3 Prevention Trial for Early Alzheimer’s

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by Lindsey Shapiro, PhD |

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Roche is launching a Phase 3 clinical trial to evaluate the ability of its investigational antibody therapy, gantenerumab, to slow Alzheimer’s progression in people with early signs of the disease, the company announced.

Called SKYLINE (NCT05256134), the trial is now recruiting 1,200 cognitively unimpaired participants between ages 60 and 80 who show signs of brain amyloid accumulation — an indicator of Alzheimer’s. Recruiting is currently open at two sites in Florida; Roche anticipates opening the trial at sites across 17 countries worldwide.

To advance the trial’s goals, the company will collaborate with scientists from the Alzheimer’s Prevention Initiative at Banner Alzheimer’s Institute at Massachusetts General Hospital and the University of Southern California Alzheimer’s Therapeutic Research Institute.

“My colleagues, collaborators, and I are pleased about the chance to continue working with Roche, helping to inform the study design, endpoints, recruitment options, and promising blood-based biomarker tests used in this important prevention trial,” Eric M. Reiman, MD, one of the study’s lead investigators and a member of the Alzheimer’s Prevention Initiative, said in a press release. “We are eager to help find and support the widespread, appropriate, and affordable use of prevention therapies for people facing Alzheimer’s disease as soon as possible.”

Alzheimer’s is characterized by toxic brain accumulation of beta-amyloid plaques, which are thought to amass before the emergence of symptoms such as cognitive impairment.

Gantenerumab, an antibody developed by Roche and its U.S. affiliate Genentech, is designed to bind to amyloid plaques and facilitate their removal.

Roche hopes the therapy will clear amyloid plaques and slow disease progression in people with early signs of Alzheimer’s before the severe neurological damage and cognitive symptoms that mark later disease stages are observed.

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To that end, SKYLINE will now test the treatment in participants who show amyloid pathology but do not yet have cognitive impairment. Participants will be randomized to receive either subcutaneous (under-the-skin) injections of gantenerumab or a placebo.

Cognition will be monitored for four years using the Preclinical Alzheimer’s Cognitive Composite-5 score, which can detect even small cognitive changes, with the intention that gantenerumab will slow or prevent cognitive decline. Other cognitive function tests and MRIs will also be performed to monitor disease progression.

Some participants will undergo lab testing to monitor for levels of Alzheimer’s biomarkers, namely amyloid, tau, and neurofilament light, in the brain, blood, and cerebrospinal fluid — the fluid surrounding the brain and spinal cord.

Roche plans to enact strategies to encourage participants to stay enrolled in the trial, including options of weekly or biweekly dosing that can be administered at home.

The full study design of SKYLINE will be presented at the international conference on Alzheimer’s and Parkinson’s diseases (AD/PD congress) March 18 in Barcelona.

In October 2021, gantenerumab was granted breakthrough therapy status by the U.S. Food and Drug Administration, a designation intended to accelerate the therapy’s development.

Seven other trials of gantenerumab are also currently underway, including the Phase 3 GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973) trials, which are evaluating the therapy’s safety and efficacy in more than 2,000 people with prodromal (presymptomatic) or mild Alzheimer’s. GRADUATE 1 is still currently recruiting, and results from both trials are expected by the end of 2022.

Gantenerumab is also being evaluated in a primary prevention trial conducted through the Dominantly Inherited Alzheimer Network (DIAN) to evaluate whether the treatment can prevent amyloid buildup and cognitive decline in people at risk of inherited early-onset Alzheimer’s before any symptoms emerge. The trial is recruiting 230 individuals; interested participants can contact trial leaders via email.

Roche is also conducting two open-label studies, the Phase 3 Open RoAD (NCT04374253), for those who participated in the former SCarlet RoAD and Marguerite RoAD studies,  and the Phase 2 GRADUATION trial (NCT04592341), evaluating the pharmacodynamics — the movement of a medicine into, through, and out of the body — of once-weekly administration of gantenerumab in those with early Alzheimer’s.

“As populations continue to age, Alzheimer’s is a looming global health crisis. The possibility to detect this disease at scale more effectively and to intervene even earlier could potentially improve the lives of millions of people and those who care for them,” said Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche. “We are proud to collaborate with key experts in the field and the broader Alzheimer’s community on this study, and we look forward to sharing our learnings in the future.”