Latest Brainshuttle AD Study Interim Data Support Continued Trontinemab Development for Alzheimer Disease

Luka Kulic, MD

New blinded data from part 1 and 2 of the phase 1b/2a Brainshuttle AD study (NCT04639050) revealed that treatment with investigational trontinemab (Roche) resulted in rapid and robust amyloid plaque clearances and changes in relevant downstream biomarkers among patients with prodromal or mild to moderate Alzheimer disease (AD). Trontinemab is a new version of the anti-amyloid monoclonal antibody gantenerumab, engineered to more easily cross the blood-brain barrier using Roche’s "brain shuttle" technology.¹

Part 1 of the Brainshuttle™ AD study employs a staggered, parallel-group design with participants recruited into four initial dose cohorts: 0.2 mg/kg, 0.6 mg/kg, 1.8 mg/kg, and 3.6 mg/kg. Based on emerging data, Part 2 may expand the dose levels tested to gather a more comprehensive safety and PK/PD profile in a larger sample, with over 60 participants per expanded cohort.

The interim analysis, presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, included 160 participants, aged 50 to 85 years, enrolled in part 1 and part 2 of the study, with September 2, 2024, as the data cutoff. In total, 60 participants comprised part 1 and 100 made up part 2. Participants were asked to be on treatment for 28 weeks, followed by a 28-week safety follow-up period.

Presented by Luka Kulic, MD, Therapeutic Area Leader Dementias at Roche, treatment with trontinemab at doses of 3.6 mg/kg resulted in rapid and robust amyloid plaque depletion of –107 cL after 28 weeks. In addition, most of this group were amyloid negative at this time point, upgrading from a mean baseline amyloid value of 119 cL to 13 cL at the 28-week mark. Cerebrospinal fluid (CSF) samples, measured by the Roche NeuroToolKit, further showcased trontinemab’s impact on key downstream biomarkers. All told, treated patients demonstrated a 30% decrease in CSF total tau, 34% decrease in CSF phosphorylated tau 181, and a 29% decrease in CSF neurogranin, each collected at week 25.

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Trontinemab was considered safe; however, there was one fatal case of an intracerebral macrohemorrhage in part 2 of the study. The patient, a 78-year-old woman in cohort 3, had large occipital area of superficial siderosis, consistent with diagnosis of probable cerebral amyloid angiopathy (CAA), at MRI screening. Superficial siderosis in patients with CAA is considered a key MRI prognostic factor for future macrohemorrhages. Investigators conducted an in-depth evaluation of the case, which led to a study protocol amendment and exclusion of participants with superficial siderosis from the study. Of note, the patient’s genetic predisposition (APOE e2/e3 genotype), may have contributed to an increased CAA risk.

As of the September 2nd cutoff, a total of 3 amyloid-related imaging abnormalities (ARIA)-edema cases were identified across part 1 and 2, which included 155 patients with available data. Notably, all 3 were on doses of 1.8 mg/kg trontinemab. There were 7 total ARIA cases of microhemorrhages and hemosiderin deposition, most of which were in cohort 3 (1.8 mg/kg) in part 2 (n = 4) of the trial. There was no documented cases of concurrent ARIA-E and ARIA-H at the same time.

In part 2 of the study, investigators observed a reduced incidence of infusion-related reactions (IRRs), which was mitigated through an implemented premedication protocol. Overall, between cohort 3 (1.8 mg/kg) and cohort 4 (3.6 mg/kg) of part 2, 23 (38.3%) and 13 (32.5%) individuals, respectively, had IRRs. In comparison, 12 (75.0%) and 7 (43.8%) patients in cohorts 3 and 4, respectively, in part 1, had IRRs. In addition, there was a lower incidence of anemia in part 2 of the study, which investigators stated may be explained by lower blood volume drawn in part 2 vs part 1.

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REFERENCES
1. Kulic L, Alcaraz F, Klein G, et al. Latest interim results from the Brainshuttle AD study, a phase 1b/2a study of trontinemab in people with Alzheimer’s disease. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1, 2024; Madrid, Spain. LB01