The name of the experimental drug was heard so frequently in hotel hallways at the conference that it sounded like an incantation: aducanumab, aducanumab, aducanumab.
Regardless of the eventual FDA verdict on Biogen’s once-bagged, now-revived anti-amyloid antibody, data from clinical trials of the treatment have inarguably altered the course of drug discovery and development for Alzheimer’s disease.
That was the message delivered by San Diego’s Paul Aisen, an industry veteran and head of the University of Southern California’s Alzheimer’s Therapeutic Research Institute, speaking Friday at the Clinical Trials on Alzheimer’s Disease congress.
The Biogen (NASDAQ: [[ticker:BIIB]]) announcement in October that it planned to ask the FDA to review the drug, in addition to turning the latest conventional wisdom on the use of amyloid-targeting drugs on its head, changed the trajectory of Aisen’s talk: His Friday keynote, initially titled “Failure after failure: Where do we go from here?” was in recent weeks recast as “And now what? Where are we headed in AD drug development?”
The day prior he spoke in favor of the investigational treatment, which targets amyloid beta lesions in the brain, following a presentation of data from the Phase 3 trials of the drug that are slated for submission to regulators in early 2020. On Friday, Aisen used the turnaround in the drug’s fate—studies of aducanumab were ended, and the drug nominally shelved, in March—to argue for a number of changes in how the industry conducts research into possible treatments for the increasingly common memory-robbing disease.
Here are three takeaways from his talk:
—Be wary of interim analyses. Biogen learned this the hard way. Its vice president of clinical development, Samantha Budd Haeberlein, called the early cessation “highly unfortunate” in a presentation Thursday on the larger dataset the company subsequently analyzed. The timing was especially so, with the data cutoff for the initial analysis taking place shortly after the trial design was changed to give some patients higher doses of the drug. Data from endpoints measuring cognition can be “variable and noisy,” Aisen emphasized, so researchers need to be “very careful about interim decision-making in trials.”
—Don’t let side effects deter development. “We have had an intolerance in general to safety challenges,” Aisen said, noting that concern over side effects had a role in determining the doses given in trials of bapineuzumab, an anti-amyloid antibody that was discarded in 2012 after failing late-stage testing. Edema, or swelling caused by leaky blood vessels in the brain, and small brain microhemorrhages—side effects commonly associated with amyloid-modifying antibodies—may be manageable in the context of treatment that slows disease progression, he said. That’s important in light of indications that higher doses of antibodies appear to be more effective.
—The amyloid hypothesis deserves industry attention. Aisen views aducanumab’s revival as evidence that the protein has proved itself worthy of the hype, and is a “big turnaround” point for the hypothesis. “I think we have tended in this field to make some errors, and one is to overgeneralize trial failures,” he said. “Each failure is very specific to the trial conditions, the population, the dose, [and] the measures.” Those failures shouldn’t take away from the role amyloid accumulation plays in the disease process, he said, calling it “by far the strongest rationale.”
Data that will bolster or cast doubt on anti-amyloid drugs are slated to come in 2020 and beyond. Results from tests of the Eli Lilly (NYSE: [[ticker:LLY]]) drug solanezumab and Roche’s gantenerumab in patients with a genetic predisposition to develop the disease are anticipated in December 2020. Biogen is also advancing another antibody, BAN2401, in patients with early Alzheimer’s disease; data from a Phase 3 trial of that drug are expected in 2022.
