Roche expands phase 3 plans for Alzheimer's drug

Roche has added another phase 3 trial in its programme for Alzheimer's disease candidate trontinemab and will now test the drug in preclinical-stage patients at elevated risk of cognitive decline.

The new study will run alongside two earlier-announced trials in early symptomatic Alzheimer's – TRONTIER 1 and 2 – which are due to start later this year. The design of the new preclinical study hasn't been revealed yet, but it will have the goal of potentially delaying or preventing the progression of the disease to symptomatic stages.

At the ongoing Alzheimer's Association International Conference (AAIC) in Toronto, Canada, Roche presented new data from a phase 1b/2a trial of trontinemab, which showed that it reduced amyloid levels below the 24 centiloid threshold – a commonly used cut-off point used to predict whether a patient is likely to go on to develop Alzheimer's dementia – in 92% of participants after 28 weeks at a dose of 3.6mg/kg.

Moreover, 72% achieved deep clearance below 11 centiloids, often used to identify individuals who may be in the early stages of amyloid accumulation, according to Roche, which also said treatment was associated with a low (less than 5%) rate of a brain swelling side effect of amyloid-targeting drugs known as ARIA-E.

New data shows that the reductions in amyloid were also accompanied by falls in other Alzheimer's biomarkers, including total tau, phosphorylated Tau (pTau)181, pTau217, and neurogranin measured in CSF and plasma.

Trontinemab has emerged from Roche'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 central nervous system.

The company is hoping that it will offer an improved clinical profile compared to the two approved anti-amyloid drugs for Alzheimer's, Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab), which have started rolling out into the market.

It is estimated 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 with its Brainshuttle antibody.

The company has also started a pre-screening study called TRAVELLER that will endeavour to select patients for its trials based on a brief clinical assessment and a positive result using its Elecsys pTau217 blood test, rather than a PET scan.

The company said that could "enable broader community outreach and extend access to these trials to more diverse populations representative of Alzheimer's disease."