At the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/OD), during the ‘Abeta Targeting Therapies in AD’ symposium on 3 April, Roche presented interim trial data for its novel anti-amyloid monoclonal antibody (mAb), trontinemab, to clinically validate its proprietary Brainshuttle technology for the treatment of prodromal or mild to moderate AD. The presentation showcased promising results from early clinical experience, with trontinemab highlighting the technology’s ability to enhance brain penetration beyond what has been achieved with the currently marketed mAbs, Eisai/Biogen’s Leqembi and Eli Lilly’s Kisunla.
The data from the Phase Ib/IIa Brainshuttle AD study revealed that trontinemab achieved rapid and robust amyloid plaque reduction at low systemic doses. The study evaluated multiple doses, including 1.8mg/kg (n=76) and 3.6mg/kg (n=38) doses administered intravenously every four weeks, where rapid and significant amyloid lowering was observed. The data showed adjusted mean reductions from baseline in amyloid positron emission tomography (PET) of 78 centiloids at 28 weeks at the 1.8mg/kg dose and 96 centiloids at 28 weeks at the 3.6mg/kg dose. The 3.6mg/kg dose showed approximately 60% amyloid reduction after just eight weeks (Day 50) following two doses of treatment. By the end of the 28-week treatment period, 81% of participants in the 3.6mg/kg cohort were below the amyloid positivity threshold of 24 centiloids. The presentation also highlighted that there were no nonresponders to treatment at the 28-week follow-up.
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Beyond the primary amyloid PET endpoint, a second presentation focusing on the interim biomarker results of trontinemab highlighted improvements in multiple fluid biomarkers in cerebrospinal fluid (CSF) and plasma. A CSF analysis at 25 weeks with the 3.6mg/kg dose showed an 84% increase in Aβ42/40 ratio, a 29% reduction in CSF phosphorylated tau 181 (p-tau181), a 21% reduction in neurogranin, and a 22% reduction in total tau. Plasma biomarkers showed similar trends, with a particularly notable 36% reduction in p-tau181 and a 51% reduction in p-tau217 at the 3.6mg/kg dose after six months of treatment. Beyond the efficacy outcomes denoted by biomarkers, the favourable safety profile with low incidence of amyloid-related imaging abnormalities (ARIA) was notable. Only three cases of ARIA-E (oedema/effusion) were reported in the 1.8mg/kg cohort (3.9%), with no cases observed in the higher 3.6mg/kg dose group as of the November 2024 data cutoff. All three ARIA-E cases were mild to moderate in radiologic severity and resolved within four to eight weeks. No concurrent ARIA-E and ARIA-H (microhaemorrhages/superficial siderosis) events were observed. The current disease-modifying therapies approved for the treatment of early AD, Leqembi and Kisunla, are associated with a higher risk of ARIA, leading to their slow uptake to date.
The encouraging interim results supported Roche’s decision to move trontinemab into a pivotal Phase III programme, which Roche plans to initiate later in 2025. If the Phase III trials confirm these early results, trontinemab may represent a significant advancement in anti-amyloid therapy, potentially offering more rapid and complete amyloid clearance at lower systemic doses than the currently approved treatments, and with a potentially improved safety profile. The Brainshuttle technology was received with enthusiasm from the audience present at the AD/PD session as the platform could also have broader implications beyond AD, potentially enabling the more efficient delivery of various antibody therapies to the central nervous system for other neurological conditions where the blood-brain barrier has been a significant therapeutic challenge.
