New mid-stage data from Biogen’s Ionis-partnered therapy diranersen served to both validate the tau hypothesis in Alzheimer’s disease and raise questions that could soon be elucidated by anti-tau candidates from Denali Therapeutics, Eisai and Eli Lilly.
Biogen presented data at the Alzheimer’s Association International Conference Tuesday from a mid-stage trial of its antisense therapy showing a correlation between tau reduction and clinical benefit in patients with Alzheimer’s disease. While the data appear to validate the anti-tau hypothesis, Wall Street reacted mainly to the remaining questions as Biogen’s stock nosedived throughout the day.
Analysts, it appeared, were also largely nonplussed.
“CELIA, You’re Breaking My Heart,” declared RBC Capital Markets analysts, playing on the Phase 2 trial’s name. “Today’s data are mostly in line with our expectations, with some supportive signals, but also still maintain questions around how robust and replicable the data set is.”
The biggest disconnect, Mizuho wrote in its own investor note Tuesday, “is that tau reduction (the actual hypothesis for this program) didn’t always translate (in the higher dose arms) to obvious clinical benefit.” Indeed, while the lowest dose (60 mg) of diranersen elicited a 26% slowing of decline versus placebo on the Clinical Dementia Rating Sum of Boxes (CDR-SB) after 26 weeks, William Blair described an “inverse” dose response where increasing doses yielded less positive outcomes. Patients taking 115 mg of diranersen, for example, saw only a 14% slowing of their decline at 24 weeks.
Biogen acknowledged these puzzling data, which caused diranersen to miss its Phase 2 endpoint, in its Tuesday press release, but is charging ahead to Phase 3 regardless.
And while the dose discrepancies were much discussed across analyst firms, William Blair suggested Biogen’s stock tumble could likely be attributed to comparisons between diranersen—a tau-targeting antisense oligonucleotide (ASO)—and the two approved anti-amyloid therapies, Biogen and Eisai’s Leqembi and Eli Lilly’s Kisunla.
“Cross-trial comparison caveats apply, but [the 26% slowing of decline] is on the lower end of the range of 27%-29% slowing of cognitive decline on CDR-SB observed in the placebo-controlled anti-amyloid therapy studies for Leqembi . . . and Kisunla,” the analysts wrote. Biogen closed Tuesday trading down just over 8%, at $191.95 per share.
Still, most analysts and other experts agreed that Tuesday’s data were validating for Biogen and Ionis’ drug—particularly in comparison to past biopharma anti-tau attempts.
“On the positive, the CELIA study data does look clearly better than UCB’s bepranemab TOGETHER dataset, which we believe could support the hypothesis that intracellular tau knockdown is materially different to the monoclonal antibody approaches that have seen repeated clinical failures,” William Blair said.
Laura Nisenbaum, interim chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), also lauded the trial results as a win for the anti-tau approach.
“These are the first data from a randomized trial to show a tau-targeting drug producing both a robust biomarker effect and a signal of clinical benefit,” she said in a statement shared with BioSpace on Tuesday.
Finding the right anti-tau target
A successful tau-targeting treatment has been a long time coming.
In November 2024, UCB’s anti-tau Alzheimer’s candidate bepranemab failed to improve cognition and function in a Phase 2 trial—a month after Roche abandoned the collaboration. One year later, Johnson & Johnson’s anti-tau candidate posdinemab suffered a similar fate, failing to significantly slow clinical decline in its own Phase 2 study. This followed a Phase 2 flop for Eli Lilly’s anti-tau drug LY3372689, which occurred just after Kisunla’s FDA approval.
Bepranemab targets the mid-region of the tau protein, a strategy UCB Chief Scientific Officer Alistair Henry at the time called “an important strategy in altering the trajectory of the disease,” Fierce Biotech reported. Posdinemab likewise targets tau’s mid-domain.
Diranersen “is extremely unique,” Holly Kordasiewicz, head of development at Ionis, explained to BioSpace last week. It’s an ASO that targets the mRNA of the microtubule-associated protein tau (MAPT) gene, which encodes the tau protein, she continued, so the MAPT protein is never made. “If the protein isn’t made, then you don’t have the substrate for misfolding and toxicity that happens in Alzheimer’s disease and other tauopathies.”
Furthermore, while many investigational approaches have focused on targeting extracellular tau, diranersen is designed to reduce both the intracellular and extracellular forms of the protein, according to Biogen’s press release.
“The really remarkable thing that we’ve been able to demonstrate is that if you stop that upstream production of the normal protein, that you can actually have a reversal of the tau pathology,” Kordasiewicz said.
Another longtime Biogen partner, Eisai, is also developing a tau-targeted drug, etalanetug, in partnership with University College London. Phase 1b/2 data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference last December showed that etalanetug reduced all measurable forms of its target, microtubule binding region (MTBR)-tau243—a specific biomarker of tau tangle pathology in Alzheimer’s—in the cerebrospinal fluid and plasma of seven patients with mild-to-moderate disease.
The key to etalanetug’s success is binding at the seed location to stop this “spreading phenomenon” that is unique to Alzheimer’s disease, Eisai Chief Clinical Officer Lynn Kramer told BioSpace prior to CTAD. Etalanetug is being tested in a Phase 2/3 trial in combination with Leqembi in patients with dominantly inherited Alzheimer’s and in a Phase 2 trial for sporadic early disease, according to the company’s pipeline page.
Jefferies analysts, meanwhile, appear to be bullish on an earlier stage anti-tau candidate from Denali Therapeutics. Designed using Denali’s Oligonucleotide TransportVehicle platform, DNL628 also targets the MAPT gene to reduce tau protein. The candidate, currently in Phase 1b, was featured on Sunday in the company’s opening plenary address at AAIC.
Jefferies wrote that Biogen’s diranersen data could read across to DNL628, for which Denali is expecting safety and biomarker data in the first half of 2027. The analysts further suggested that DNL628 could surpass diranersen in terms of efficacy. Compared to diranersen, “DNL628 could be differentiated due to superior [blood-brain barrier] penetration (TfR brain shuttle), enabling improved homogeneous brain biodistribution (engaging in the deepest brain regions) and dosing convenience,” the firm said.
In a Wednesday note, Jefferies also highlighted Arrowhead Pharmaceuticals’ RNAi candidate, ARO-MAPT, which is designed to silence CNS expression of the MAPT gene. Biogen’s CELIA data de-risks this program as well, the analysts said, adding that the asset has shown uniform CNS-wide distribution with 70%–80% tau knockdown across deep brain structures, including the hippocampus, in nonhuman primates. Arrowhead kicked off a Phase 1/2a study of ARO-MAPT in December 2025.
Another major Alzheimer’s player, Eli Lilly—which also has several presentations at AAIC—has an intrathecally delivered siRNA molecule that knocks down tau in Phase 1 development. If this asset continues to advance, the company envisions “amyloid and tau therapies being used either sequentially or concurrently,” John Sims, Lilly’s associate VP and head of medical development for donanemab and global brand development, told BioSpace.
ADDF’s Nisenbaum in her Tuesday statement expressed cautious optimism about diranersen’s most recent data but said there are questions that still need to be answered.
“Tau is one of the two defining pathologies of Alzheimer’s disease and has long been difficult to target, which makes these results all the more notable,” she said. “But the dose-response discordance between the biomarker and clinical endpoints raises important questions about the optimal level of tau reduction and the right dose of diranersen to test in subsequent studies.”
