Roche preps phase 3 for 'Brainshuttle' Alzheimer's drug
Graphical representation of Brainshuttle antibody at the blood-brain barrier.
Buoyed by new results from a phase 1b/2a trial, Roche has said it plans to start a phase 3 programme for an Alzheimer's disease candidate from its Brainshuttle programme, a technology designed to help large molecules enter the central nervous system.
The drug, called trontinemab, showed in the study that it could achieve rapid and deep reductions in amyloid beta plaques in the brain, one of the characteristics of Alzheimer's. Roche said its profile suggests it could offer an advance on the current generation of amyloid-targeting drugs.
It also validates the company's Brainshuttle antibody engineering platform, which adds a "side chain" to antibodies that binds to receptors on the blood-brain barrier (BBB) – designed to protect the brain from toxins and pathogens – and allows them to make it into the CNS.
It has been found that less than 1% of some anti-amyloid antibodies end up in the CNS where they can exert their activity, but Roche has estimated that it can improve that by 50 times or more.
Preliminary results from the 111-subject study revealed that a 3.6mg/kg dose of trontinemab reduced amyloid levels below the 24 centiloid threshold – a commonly used cutoff point used to predict whether a patient is likely to go on to develop Alzheimer's dementia – in 81% of participants after 28 weeks.
"Based on data in the field, both the speed of amyloid lowering, and the ability to lower below the amyloid positivity threshold early on, are important to achieve clinically meaningful benefit in early Alzheimer's disease," said Roche in a statement on the results, which were presented at the International Conference on Alzheimer's and Parkinson's Diseases in Vienna, Austria.
The reduction in amyloid was accompanied by reductions in cerebrospinal fluid (CSF) and plasma of other biomarkers of Alzheimer's, including total tau, phosphorylated Tau (pTau181 and pTau217), and neurogranin.
Moreover, trontinemab was also associated with a lower rate of an amyloid-related imaging abnormality (ARIA) side effect, brain swelling, than the two approved anti-amyloid drugs – Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab). ARIA was seen in less than 5% of patients treated with trontinemab, with all cases mild and all but one asymptomatic.
Roche has been attempting to develop an Alzheimer's drug for some time, and its first attempts with two other anti-amyloid antibodies – crenezumab and gantenerumab – ended in failure.
Since then, the launch of Leqembi and Kisunla has renewed interest in the anti-amyloid approach, although early take-up of the new drugs has been slow due to their modest efficacy and potential to cause serious side effects.
