J&J abandons Alzheimer's antibody in setback for tau

Hopes that anti-tau drugs could join those targeting amyloid as treatments for Alzheimer's disease have been dented by the failure of a phase 2b trial of Johnson & Johnson's posdinemab.

The AuTonomy study of posdinemab had been designed as a proof-of-concept for the anti-tau antibody in early-stage Alzheimer's patients, but the drug failed to show a statistically significant reduction in cognitive decline, and the study has been discontinued on the advice of the data monitoring committee.

AuTonomy was comparing posdinemab (JNJ-63733657) given by intravenous infusion to placebo in more than 500 subjects, with the primary outcome measure being their performance on the Integrated Alzheimer's Disease Rating Scale (iADRS). It had been due to generate its first results next year and continue to follow patients into the 2030s.

One of the hallmarks of Alzheimer's is the accumulation of hyperphosphorylated, insoluble tau aggregates in the central nervous system, which clump together to form neurofibrillary 'tangles'.

For many years, the hope has been that interrupting that process and preventing the formation of tau tangles could slow down cognitive decline in Alzheimer's in a manner analogous to the benefits – albeit modest – seen with drugs that address the formation of amyloid plaques, namely Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab).

Tau tangles are also a feature of other neurodegenerative diseases, including Parkinson's and amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND).

In a statement, J&J said the disappointing results "underscore the deep complexity of the disease" and will help to "shape ongoing and future research as the understanding of Alzheimer's biology evolves."

The posdinemab failure is the latest in a string of setbacks for the tau class, coming just over a year after Eli Lilly's LY3372689 – an O-GlcNAcase (OGA) inhibitor – failed a phase 2 study in early symptomatic Alzheimer's. Lilly also abandoned antibody-based tau inhibitor zagotenemab in 2021, while last year Roche handed back rights to its AC Immune-partnered candidate semorinemab – both decisions coming on the back of disappointing phase 2 data.

J&J is also running mid-stage trials of a tau active immunotherapy codenamed JNJ-2056 for Alzheimer's, while other active tau programmes include Eisai's antibody-based etalanetug (E-2814) in phase 2 and small-molecule drugs from Annovis Bio (buntanetap and TauRx Therapeutics (HMTM).

The latter drug was filed for approval in the UK last year, and remains under review after multiple requests from the UK medicines regulator, the MHRA, for additional data. Buntanetap, meanwhile, is a phase 3 trial in early Alzheimer's.

Image by Vicki Becker from Pixabay