Early data suggest Roche’s antibody may safely and quickly remove amyloid plaque for patients with Alzheimer’s disease, though the midstage study has been tied to one death.
The interim data come from a phase 1b/2a clinical trial assessing Roche’s trontinemab in participants with mild-to-moderate Alzheimer’s disease and were shared Oct. 30 at the Clinical Trials on Alzheimer’s Disease annual conference in Madrid.
The patient death occurred in a dose expansion part of the study, the second of three segments. The 78-year-old woman experienced a brain bleed in her right front lobe, dying on day 44 of the study.
Roche said a screening MRI demonstrated signs of cerebral amyloid angiopathy (CAA), a condition in which amyloid—a protein associated with Alzheimer’s progression—builds up on artery walls in the brain, potentially prompting bleeding. Further imaging suggests that the woman may have had a genetic predisposition that increased her risk of CAA, according to a presentation from the company.
The woman’s death prompted an “in-depth evaluation of the case,” according to the Roche presentation. The assessment triggered a protocol change so participants with superficial siderosis—chronic bleeding that can be caused by CAA and impacts the brain or spinal cord—are excluded from the trial.
The new measures align with recently published proper use recommendations for Leqembi, Eisai’s and Biogen’s FDA-approved anti-amyloid beta therapy. Both Leqembi and Eli Lilly’s Kisunla labels include warnings about possible strokes induced by brain bleeds.
As for Roche, the trial remains active, with researchers deeming trontinemab to have “an overall favorable safety profile,” citing the “very limited” number of amyloid-related imaging abnormalities-edema/effusion (ARIA-E) cases observed. ARIA suggests a risk of brain bleeds or swelling and is a primary concern for the class of amyloid medicines.
Only three ARIA-E cases were reported in the first two portions of the trial as of Sept. 2, according to Roche. This is a relatively low occurrence of the adverse event, but the pharma will need to replicate the findings in future, larger studies.
The first part of Roche’s study enrolled 60 patients across four cohorts of increasing dose levels or placebo. Part two, which has not yet wrapped, includes 100 people in two groups: patients receiving 1.8 mg/kg of trontinemab or placebo, or patients receiving 3.6 mg/kg or placebo. The woman who died was part of the 1.8 mg/kg arm.
Results from the completed first part of the trial demonstrate “rapid and robust amyloid plaque depletion” in the two higher dose groups—1.8 mg/kg and 3.6 mg/kg—after 12 to 28 weeks of treatment, according to Roche. For the 3.6 mg/kg arm, amyloid plaque depleted by 91 centiloid units (CL) after 12 weeks and dropped 107 CL after 28 weeks.
The early data also tied trontinemab to significant changes in Alzheimer’s biomarkers, such as total tau, according to Roche.
Trontinemab is an amyloid-beta antibody Roche developed using its in-house Brainshuttle tech. The science is designed to boost penetration across the blood-brain barrier (BBB).
The Big Pharma is one of several touting BBB tech across the neuroscience landscape, with AbbVie paying $1.4 billion to buy Aliada Therapeutics just a few days ago. Aliada touts an Alzheimer’s disease drug candidate designed to improve on the first generation of anti-amyloid-beta antibodies.
Elsewhere, Eli Lilly has secured access to Qinotto’s platform, while Eisai struck up a deal to develop a candidate that uses BioArctic's BrainTransporter tech.
While Alzheimer’s is a notoriously difficult-to-treat condition, Roche has had a particularly tough go at it. At the end of 2022, two phase 3 trials run by Roche subsidiary Genentech failed to prove the worth of an anti-amyloid beta antibody known as gantenerumab. As hopes of crossing the FDA finish line diminished, the pharma later discontinued development of the asset.