Trontinemab: Roche Announces Phase 3 Development Program for the mAb in Adults with Early Alzheimer Disease

Trontinemab, an investigational monoclonal antibody for treatment of early Alzheimer disease (AD), demonstrated dose-dependent, rapid and significant reduction of amyloid plaques in the brain, according to new data from the phase Ib/IIa Brainshuttle AD study.¹ The findings were presented by trontinemab developer Roche at the AD/PD 2025 International Conference on Alzheimer's and Parkinson's Diseases in Vienna, Austria.

Preliminary results from 114 participants in the ongoing Brainshuttle AD study showed that trontinemab reduced amyloid levels below the 24 centiloid threshold in 81% of participants (n=21/26) in the higher 3.6 mg/kg dose group after just 28 weeks of treatment, the data revealed by amyloid positron emission tomography (PET), Roche said in a news release.¹ Existing evidence suggests that both speed of decline in amyloid deposits and the ability to reduce measured amyloid below the positivity threshold early on are essential for a medication to achieve clinically meaningful benefit in management of early AD, according to the company.¹

Beyond amyloid reduction, trontinemab was associated with early and significant reductions in fluid biomarkers of Alzheimer's disease, including total tau, phosphorylated Tau (pTau)181, pTau217, and neurogranin measured in both cerebrospinal fluid (CSF) and plasma, Roche stated. The reduction in AD-specific biomarkers augments confidence in the drug's biological activity to address pathological hallmarks of AD.¹

"We are pleased with the progress across our Alzheimer's portfolio as we move ahead with a Phase III trontinemab programme and continue to expand our diagnostic solutions," Levi Garraway, MD, PhD, Roche chief medical officer and head of global product development, said in the news release.¹ According to Alzheimer's Disease International, more than 55 million people worldwide currently live with dementia, and approximately 70% of them have AD.² "Moreover, up to three-quarters of people experiencing symptoms of Alzheimer's remain undiagnosed," Garraway added. "This growing population needs more accurate, less invasive diagnostic approaches paired with effective disease-modifying treatments to slow neurodegeneration as early as possible."¹

Favorable safety, tolerability. Trontinemab also demonstrated a favorable safety and tolerability profile. Amyloid-related imaging abnormalities-edema/effusion (ARIA-E), a common side effect with amyloid-targeting therapies, were observed in less than 5% of participants according to blinded data. Roche described the cases as radiographically mild, with only one case associated with mild symptoms. This safety profile has the potential to differentiate trontinemab from other amyloid-targeting treatments that have shown higher rates of ARIA, Roche stated.¹

Novel Delivery Mechanism

Trontinemab is an investigational Brainshuttle™ bispecific 2+1 amyloid-beta (Aβ) antibody engineered to enhance delivery across the blood-brain barrier and permit rapid reduction of the toxic amyloid plaques that characterize AD. Tronetinemab is designed to target and clear aggregated forms of Aβ within the brain.

Trontinemab uses the proprietary Brainshuttle technology developed by Roche, which combines an Aβ-binding monoclonal antibody with a transferrin receptor shuttle module that facilitates efficient transport into the central nervous system (CNS). The combination facilitates high CNS trontinemab exposure at low doses, the mechanism responsible for the rapid and profound clearance of toxic aggregated amyloid, according to Roche. The improved cerebral penetration has the potential to "unlock the full potential of disease-modifying monoclonal antibodies" and to effect a slowing of AD progression.¹

Diagnostic Advances

In conjunction with its therapeutic developments, Roche also presented data on its Elecsys pTau181 plasma test, which demonstrated potential to accurately rule out amyloid pathology in people with cognitive impairment. The minimally invasive approach could allow patients to bypass more invasive testing using CSF or PET scans. Roche anticipates the test will be available in Europe by late 2025, with US availability to follow.¹

References
1. Roche presents novel therapeutic and diagnostic advancements in Alzheimer’s at AD/PD 2025. News release. Roche. April 2, 2025. Accessed April 7, 2025. https://www.roche.com/media/releases/med-cor-2025-04-03
2. Dementia statistics. Alzheimer's Disease International. Accessed April 7, 2025. https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/