New clinical trial data released by Eli Lilly on Wednesday has provided the most promising results of any potential Alzheimer’s disease treatment yet. In a randomized, double-blinded, controlled phase III trial, the experimental drug donanemab significantly slowed cognitive decline in patients compared to placebo, with nearly half of those on the drug experiencing no decline at all a year later. The findings will likely pave the way for approval by the Food and Drug Administration, though the drug appears to carry a risk of rare but potentially life-threatening side effects.
Donanemab is the latest drug meant to target a suspected key aspect of Alzheimer’s disease, the most common form of dementia. It’s an antibody that attacks amyloid beta, a naturally occurring protein that can misfold and eventually form into hardy clumps called plaques. These plaques are thought to drive the gradual destruction of the brain, in combination with the accumulation of another misfolded protein called tau (the final stage of these tau clumps are called tangles). Some scientists have theorized that you can stop or slow down the progression of early Alzheimer’s by using drugs like donanemab to break down plaques and/or prevent amyloid clumps from reaching that stage.
Eli Lilly’s TRAILBLAZER-ALZ 2 trial involved more than 1,100 people diagnosed with early Alzheimer’s. The participants were randomized to receive regular infusions of donanemab or a placebo and were then tracked for 18 months.
According to the company, the drug met all of the primary and secondary goals of the trial. Compared to placebo, donanemab overall slowed the rate of cognitive decline in patients by 35%; these patients also had a 40% less decline in their reported ability to perform daily activities. Around 47% of patients on the drug experienced no significant cognitive decline a year into the study, compared to 29% on placebo. And 71% of patients appeared to achieve clearance of their plaques by the 18-month mark.
“These are the strongest phase 3 data for an Alzheimer’s treatment to date. This further underscores the inflection point we are at for the Alzheimer’s field,” said Maria Carrillo, chief science officer of the Alzheimer’s Association, in a statement following the release of the results.
For comparison, Biogen and Eisai’s lecanemab, the most recent FDA-approved drug of this class, was found to slow down cognitive decline by 27% in its largest trial. Their earlier approved drug, called Aduhelm, had even weaker trial results, to the point that many outside experts protested the FDA’s decision to grant Aduhelm an accelerated approval.
The fallout surrounding Aduhelm’s approval eventually led to Medicare enforcing a stricter policy on the coverage of these antibody-based drugs, one still in place today. This policy mandates that people on Medicare can only receive coverage for Aduhelm and similar drugs given an accelerated approval in a context of a clinical trial or other type of approved study. It does provide broader coverage for drugs granted a typical approval, however. Eli Lilly had petitioned for an accelerated approval of donanemab in January but was denied by the FDA. The company now plans to file for traditional approval by the end of this quarter.
While the presented results are the best for this drug class so far, they haven’t been vetted yet by outside scientists, an important part of the scientific process. The real-world impact of donanemab also remains to be seen. Many experts have expected lecanemab to only provide a modest delay of Alzheimer’s progression, perhaps only amounting to a few extra months.
Another concern is the drug’s side effects. Like others of its kind, donanemab was found to increase the risk of brain bleeding in patients. Most reported cases of this adverse effect in the trial were mild or moderate, but at least two patients are believed to have died as a result, with a third death inconclusively linked to the side effect. These side effects may still be outweighed by the clinical benefits provided by donanemab, especially given that Alzheimer’s disease is currently 100% fatal.
Perhaps the most important aspect here is the continued, if incremental, improvements we’re now seeing with experimental Alzheimer’s drugs. On their own, the current and upcoming generation of anti-plaque drugs will likely not cure Alzheimer’s. But a combination of these drugs with other treatments in the future might eventually substantially improve and prolong the lives of those afflicted with the memory-robbing ailment.
“The progress we’ve seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease,” said Carrillo.