Alzheimer’s disease R&D took major hits in the last few weeks as setbacks emerged for two of the field’s up-and-coming therapies.
Novo Nordisk’s highly anticipated readout for a GLP-1 pill after two years in late-stage Alzheimer’s studies disappointed shareholders with news that it had failed to beat a placebo. Just a few days earlier, Johnson & Johnson announced the discontinuation of a mid-stage tau-targeting program because the antibody candidate posdinemab didn’t slow clinical decline.
Are these just bumps in the road to a true Alzheimer’s game-changer, or do they reflect more significant challenges facing drugmakers?
While the results were disappointing, some experts see the setbacks as critical for better understanding the disease and potential treatments down the line.
“Alzheimer’s is a complex condition that will ultimately require precision medicine, with treatment and prevention approaches tailored to each patient’s unique biomarker profile,” said Dr. Howard Fillit, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, in a statement. “With more than 70% of the Alzheimer’s pipeline now focused on novel targets, we are poised to shape a new era of science.”
Novo’s big swing
GLP-1 drugs like Novo’s semaglutide, the main component in the blockbuster medications Ozempic and Wegovy, do more than help patients shed pounds, and researchers are working to discover other conditions they can treat.
Among potential new indications for semaglutide, Alzheimer’s became an attractive target after early research found that the drugs could curb inflammation, invigorate blood vessels and shelter neurons, according to the Alzheimer’s Association.
But even Novo’s leadership acknowledged the small odds for the two phase 3 trials with Martin Holst Lange, chief scientific officer and executive vice president of research and development, saying in a statement that “we felt we had a responsibility to explore semaglutide’s potential, despite a low likelihood of success.”
While semaglutide “resulted in improvement of Alzheimer’s disease-related biomarkers,” the effect “did not translate into a delay of disease progression,” according to the company.
The dissonance between biomarkers and clinical outcomes has long been a problem in Alzheimer’s — just ask Biogen and Eisai, whose anti-amyloid drug Aduhelm was ultimately pulled from the market last year in the wake of muddy trial results.
But this isn’t likely the end of the line for GLP-1s in Alzheimer’s research, said Fillit in his statement. The ADDF was an early investor in studies seeking a connection between the diabetes drugs and neurodegenerative diseases. The organization in 2011 put about $1 million into a study of the injectable GLP-1 liraglutide, sold by Novo as Victoza and Saxenda. Research into its neuroprotective effects has continued from there.
As for semaglutide, Fillit said there’s plenty to learn from the clinical stumble.
“While it is disappointing that the trials did not meet their primary endpoints, they show a fundamental shift in how we approach the development of Alzheimer’s treatments, expanding beyond amyloid to target the complete pathobiology of the disease,” Fillit said, noting that the drug could still play a role in combination therapy, potentially alongside anti-amyloid drugs like Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla.
Fillit said the late-stage effort, despite resulting in failure, “helps chart the path forward, demonstrating how rigorous studies targeting Alzheimer’s pathobiology can expand our understanding of the disease and guide the development of combination therapies to enable earlier and more effective interventions than ever before.”
J&J’s anti-tau trip-up
As anti-amyloid drugs struggle to make a sizable impact on Alzheimer’s outcomes, many pharma companies have turned to tau tangles as an alternative approach.
But with J&J’s anti-tau antibody posdinemab coming up short in a mid-stage study despite early promise and votes of confidence from fellow drugmakers, spirits are a little dampened. In a brief November release, the pharma giant said it would discontinue the trial.
Like Novo’s semaglutide burnout, though, J&J also implied there was much to learn about Alzheimer’s through failure, saying that the findings add to the understanding of the “deep complexity of the disease.”
As with many Alzheimer’s approaches, addressing the disease with the right drug at the right time is the key to success, which has made recruiting patients for clinical trials a difficult process. A deeper look at J&J’s data could provide insight for future R&D.
As Fiona Elwood, vice president and neurodegeneration disease area stronghold leader in neuroscience at J&J, told PharmaVoice at the beginning of the year: “We still have a lot of unknowns.”
Elwood at the time pointed to posdinemab as the company’s most promising candidate following other cuts to the Alzheimer’s pipeline. Now, with that lead program also cut, the drugmaker’s efforts will focus on the immunotherapy candidate JNJ-2056 as a potential early-disease option.
