Johnson & Johnson’s attempt to develop a $5 billion-a-year Alzheimer’s disease drug has been rocked by a phase 2 flop. A scheduled data review found the anti-tau antibody posdinemab failed to significantly slow clinical decline, prompting J&J to stop the study.
Investigators randomized more than 500 people with early Alzheimer’s to receive one of two doses of the study drug or placebo. J&J selected change on iADRS, a scale that measures cognition and function, at Week 104 as the primary endpoint. The company looked at a range of clinical and imaging measures across its secondary endpoints.
J&J reported the failure of the Autonomy trial in a brief press release, revealing posdinemab didn’t achieve statistical significance in slowing clinical decline at a scheduled review. The failure led J&J to stop the trial. J&J said it will share a full evaluation of the data in due course.
The failure is another blow to the idea that monoclonal antibodies that bind tau can improve outcomes in Alzheimer’s. UCB’s anti-tau antibody bepranemab failed to improve cognition and function in people with early Alzheimer’s one year ago. While Roche cut ties to the candidate around the time of the flop, UCB focused on secondary endpoints to make the case that bepranemab has a future.
Bepranemab and posdinemab target tau’s mid-domain, setting them apart from antibodies that engage the N-terminus. UCB and J&J both identified targeting the mid-domain as the key to succeeding where other anti-tau antibodies failed.
John Reed, M.D., Ph.D., executive vice president for innovative medicine, R&D at J&J, sounded bullish on an earnings call last month, telling investors that “we have designed our antibody to attack a specific epitope in tau that's differentiated from what some others have exploited and feel confident in the ability to prevent the spread of tau based on the preclinical data.”
J&J was seeking to deliver a drug with that profile in the belief it could unlock a major sales opportunity. Bill Martin, Ph.D., global therapeutic area head for neuroscience at J&J, said at a company event two years ago that posdinemab “could potentially be available as early as 2028 with anticipated peak sales exceeding $5 billion.”
Posdinemab is part of a broader attempt by J&J to crack tau. Working with AC Immune, J&J has taken the tau active immunotherapy JNJ-2056 into phase 2. The drug candidate is designed to stimulate patients’ immune systems to produce antibodies against tau. At a Morgan Stanley event in September, Reed said J&J also has other tau programs “that are almost in the clinic.”
The J&J programs are part of an industrywide push to hit what Reed has called “the best target out there right now” for Alzheimer’s. Companies including Merck & Co. and Voyager Therapeutics are flying the flag for anti-tau antibodies.
Other programs are coming at the protein from different angles. Biogen has an antisense oligonucleotide that targets tau in phase 2. On an earnings call in late October, Priya Singhal, M.D., head of development at Biogen, said the struggles of anti-tau antibodies may reflect the targeting of extracellular forms of the protein. Biogen has identified intracellular tau engagement as a way to move the needle.