Roche's trontinemab, an anti-amyloid antibody equipped with a brain shuttle, is showing promise in early clinical trials for Alzheimer's disease. The drug rapidly removes amyloid plaques and has demonstrated few cases of mild ARIA (amyloid-related imaging abnormalities). However, a recent macrohemorrhage-related death in a trial participant has prompted increased safety scrutiny and stricter exclusion criteria.
Trontinemab's Efficacy and Safety Profile
At the Clinical Trial on Alzheimer’s Disease (CTAD) conference, Roche presented data from an ongoing dose-finding study of trontinemab. The study reported only three mild, asymptomatic ARIA cases. Data showed that at the two highest doses tested (1.8 mg and 3.6 mg), the antibody rapidly reduced Aβ plaques. By week 28, most participants in both dose groups were below the amyloid negativity cutoff, with average reductions of 84 and 107 CL, respectively, from a baseline of approximately 120 centiloids.
Luka Kulic from Roche also presented preliminary CSF biomarker data, showing dose-dependent reductions in total tau, p-tau181, and neurogranin at week 25, with concentrations of each falling by around 30 percent in the 3.6 mg dose group. However, these results were not statistically significant due to the small sample size.
Safety Concerns and Exclusion Criteria
Despite the promising efficacy data, a 78-year-old woman in the 1.8 mg dose group experienced a fatal right frontal lobar macrohemorrhage three weeks after her second dose of trontinemab. Post-mortem analysis of her initial screening MRI revealed superficial siderosis in her occipital cortex and other lesions indicative of probable cerebral amyloid angiopathy (CAA). She also carried an ApoE2 allele, a known risk factor for CAA.
In response to this event, Roche has amended the protocol for ongoing and future trontinemab trials to exclude individuals with superficial siderosis, aligning with recommendations for lecanemab and donanemab.
Addressing Anemia and ARIA Risks
TfR-targeted drugs carry a risk of anemia due to high TfR expression by reticulocytes. Trontinemab mitigates this risk through steric hindrance, temporarily blocking access to the antibody’s effector domain upon TfR engagement. Kulic reported that 13 percent of participants in Part 1 and 8 percent in Part 2 developed mild, transient anemia. Roche has reduced blood draws in Part 2, expecting fewer cases as a result.
ARIA rates remain low despite robust amyloid reduction. In Part 2 of the study, two participants in the 1.8 mg dose group experienced mild, asymptomatic ARIA-E.
The Future of Brain Shuttle Technology
Catherine Mummery of University College London called the trontinemab data "fantastically exciting," viewing such strategies as a promising way to improve monoclonal antibodies. She stated that active transport mechanisms to cross the blood-brain barrier will dramatically accelerate amyloid removal and reduce ARIA rates.
Other companies are also developing BBB-crossing anti-Aβ immunotherapies. Denali Therapeutics is developing an antibody transport vehicle (ATV) with reduced effector function. BioArctic is developing the BrainTransporter (BT), which retains full effector function and has shown improved brain penetration in preclinical studies. Aliada Therapeutics is testing ALIA-1758, which targets both TfR and CD98 for brain entry. Abbvie recently acquired Aliada to advance ALIA-1758.
Costantino Iadecola of Weill Cornell Medical College cautioned that trontinemab is not immune from causing ARIA and that studies are too small to draw definitive conclusions about ARIA rates. He suggested that future screening could include a comprehensive neurovascular assessment to calculate a neurovascular health score.
