Crenezumab

Roche’s biggest bet in the Alzheimer’s disease space may be its phase 3-stage amyloid asset, but the Swiss pharma is keeping its options open when it comes to targeting tau. Tau is one of two proteins that become deformed and clumped in Alzheimer’s, with the other, amyloid beta, already successfully targeted by Biogen’s Leqembi and Eli Lilly’s Kisunla. At the Alzheimer’s Association International Conference in London this week, Biogen shared phase 2 data from diranersen, an antisense oligonucleotide that blocks the production of tau by binding to its precursor mRNA. Speaking to Fierce on the sidelines of the conference, Roche’s Head of Early Development in Neuroscience and Rare Diseases, Luka Kulic, M.D., Ph.D., namechecked Biogen’s data as “interesting,” while also raising “ some questions .” Roche once had an anti-tau antibody in the works, courtesy of a $120 million upfront pact with UCB for bepranemab, but the Swiss pharma walked away in 2024 , just days before the therapy failed a phase 2 test. While Roche doesn’t have a tau candidate in the clinic at the moment, the company “of course remains very interested” in tackling tau, Kulic said. “That's a key major player in Alzheimer's disease.” Roche didn’t arrive at AAIC empty-handed. The drugmaker presented interim data from an open-label extension (OLE) of its phase 1b/2a Brainshuttle AD study of its anti-amyloid-beta antibody trontinemab. The readout included patients for whom a PET scan had shown they still had beta-amyloid plaques in the brain. These patients received monthly doses of trontinemab until the PET scan no longer showed any plaques, at which point they switched to maintenance therapy. Meanwhile, patients who began with a negative scan were put on a maintenance regimen straight away. “What we observed was … sustained—and even the further continued—reduction in amyloid,” Kulic said. “Even in the group that was amyloid PET negative at OLE baseline, there is some movement of the amyloid PET signal.” “So we are able, from a very low signal to [go] even lower,” he added. The “most exciting part” was noting a concurrent reduction in certain plasma biomarkers, such as the inflammation marker glial fibrillary acidic protein, he added. “It continues to further decrease, so to further trend towards normalization, which was an exciting finding for us,” said Kulic, who acknowledged that the small size of the study means there remain caveats at this stage. It was also good news on the safety front, with just two cases of amyloid-related imaging abnormality-edema (ARIA-E)—a swelling of the brain associated with anti-amyloid beta antibodies—among the 126 patients. But with two amyloid drugs for Alzheimer’s already on the market in the form of Leqembi and Kisunla, does Roche think trontinemab has what it takes to stand out? “The profile that we have seen in the Brainshuttle AD study, with the really very low incidence of ARIA-E and the very rapid and profound amyloid lowering, gives us confidence that we might have a differentiated profile,” Kulic said. The positive signs from the data so far are a welcome validation for Roche’s decision to stick with the amyloid hypothesis, despite a couple of high-profile setbacks. Back in 2022, the company saw gantenerumab and crenezumab fail to prove they could reduce the rate of cognitive decline in various phase 3 studies, leading Roche to abandon both programs . “What we have learned is that … we need to really get rid of a substantial amount of amyloid to see clinical efficacy,” Kulic said. The real proof of whether trontinemab has resolved this issue will be a pair of phase 3 studies, which began recruiting patients in September 2025 and are expected to read out in 2028. Those trials, called Trontier 1 and 2, are enrolling patients with early symptomatic Alzheimer's disease. Still, Roche is set to launch a separate late-stage study in the next couple of months focusing on patients who aren’t yet cognitively impaired despite showing evidence of amyloid pathology. Further back in the pipeline is a gamma secretase modulator that’s designed as a potential oral treatment for the neurodegenerative condition, with phase 2 data set to read out next year. There’s also a phase 1-stage drug aimed at down-regulating the production of apolipoprotein E, which Kulic described as a “major genetic player in Alzheimer's disease.” One thing that sets trontinemab apart is that it’s the most advanced anti-beta antibody to use brain shuttle technology. Specifically, the therapy harnesses transferrin receptor (TFR) to drive the drug into the brain. The TFR pathway is also being explored in Alzheimer’s prospects from the likes of Novartis , and Kulic acknowledged that transfferin “obviously works very well for amyloid-lowering antibodies.” However, Roche is also on the lookout for other routes to shuttle drugs to the brain, a strategy that culminated in a $2 billion biobucks pact with Manifold Bio last year. “One of the ideas behind the Manifold deal is to identify novel receptors,” he said. “For different targets, different indications, different modalities, there might be other receptors that might be more suitable.” “So we remain open to exploring different ways to overcome the blood-brain barrier,” Kulic added.