Roche’s ‘Brainshuttle’ Alzheimer’s Drug Heads for Phase 3 Trials
Experimental Alzheimer’s drug trontinemab appeared to clear plaques fast with few serious side effects in early trials. Roche says a Phase 3 will launch as soon as this year.
The blood-brain barrier is the gatekeeper that separates the brain from the rest of the body. It allows certain molecules and nutrients in while keeping toxins and harmful substances out. Its protection comes with a downside: It also makes it hard for Alzheimer’s drugs like Leqembi and Kisunla to get into the brain. These drugs require higher doses, which increases both cost and the risk of side effects.
Roche’s experimental anti-amyloid drug trontinemab is designed to overcome this challenge by tricking the blood-brain barrier, allowing low doses of the drug to clear amyloid plaques quickly. At the 2025 Alzheimer’s Association International Conference (AAIC) in Toronto, Roche shared new data and announced that they’ll be starting a Phase 3 trial of the drug later this year.
Tricking the blood-brain barrier to clear amyloid faster
Roche engineered trontinemab with a protein called a “Brainshuttle.” This Brainshuttle allows the drug to attach to a transferrin receptor — a protein on the blood-brain barrier that normally transports iron from the blood into the brain. When the receptor lets iron in, trontinemab crosses with it.
This design boosts the amount of drug that reaches the brain. Early trials show faster beta-amyloid clearance at lower doses and far fewer side effects.
At AAIC 2025, Roche shared safety data from its 149-person Phase 1/2b trial testing low and high doses of the drug. The trial wasn’t very diverse: About 90 percent of participants were white.
Amyloid clearance was fast: After 24 weeks, 91 percent of participants were no longer amyloid positive. Rates of ARIA — brain swelling and microbleeds, common side effects with anti-amyloid drugs — were much lower than seen with Leqembi or Kisunla.
Only four participants developed brain swelling, all mild, which resolved within four to eight weeks. Seven participants developed brain bleeds.
One participant died of a microhemorrhage during the trial. They had pre-existing bleeding in the brain, and afterward the company changed the protocol to exclude people with similar high-risk conditions.
Trontinemab does come with one drawback: Nearly half of participants experienced infusion-related reactions — mild symptoms like chills, headache, fever, or nausea — mostly during the first dose. Pre-treating with anti-inflammatory steroids reduced this risk.
About 14 percent of participants developed mild anemia (low iron levels in the blood). It’s not clear whether this was caused by the drug, which uses the iron receptor to enter the brain, but all cases resolved.
Several panelists at AAIC were optimistic. Dr. Reisa Sperling, a Harvard neurologist running a major Alzheimer’s prevention trial, called the combination of rapid amyloid clearance and low ARIA rates “incredible.”
Will trontinemab slow cognitive decline?
Clearing out amyloid plaques alone isn’t always enough to slow symptoms. Phase 1 and 2 trials are designed to test safety and feasibility, not whether a drug works.
Trontinemab was developed by fusing the Brainshuttle to gantenerumab, Roche’s previous anti-amyloid drug that failed to slow cognitive decline. Ganterenumab targets a slightly different form of beta-amyloid than Leqembi and Kisunla, and was slower at clearing plaques.
At AAIC 2025, Dr. Catherine Mummery, a neurology professor at University College London, argued that anti-amyloid drugs are more effective if they clear plaques fast. That was gantenerumab’s weakness — it worked too slowly.
Dr. David Weisman, a neurologist at Abington Neurological Associates, sees potential. “I think and hope that based on Roche’s deep knowledge about gantenerumab they will have a positive trial,” he told Being Patient.
Roche will launch two identical Phase 3 trials later this year — TRONTIER 1 and TRONTIER 2. Each 18-month trial will enroll 800 people with mild cognitive impairment and early Alzheimer’s across 18 countries. Participants will receive drug or placebo infusions every four weeks during a 24-week ramp-up period, then every 12 weeks for the next 48 weeks. Roche also plans a prevention trial in the near future.
Prescreening is already underway through the TRAVELLER study at sites in the U.S. and Canada. Participants receive a blood test and a simple cognitive test; a positive result may qualify them for screening in TRONTIER 1, TRONTIER 2, or future studies. People can re-enter prescreening later to see if they qualify in the future.
“What we all want to see is whether this very dramatic biomarker response and favorable safety profile will translate into perhaps even more robust clinical benefit than currently approved drugs,” Dr. Gil Rabinovici, a professor at the University of California in San Francisco, said during the panel.
