The amyloid theory continues to grasp at life as Eli Lilly has unveiled new phase 2 data from donanemab that show it can help Alzheimer’s disease patients by clearing these plaques out of the brain.
Lilly’s donanemab (once known as LY3002813), works an active immunotherapy designed to stimulate the patient’s immune system to attack and destroy beta amyloid plaques that are believed to form in the brain and spur the memory-wasting disease.
The amyloid hypothesis has been tried, tested and failed time and again, though Lilly says its drug and target are both a little different. Its antibody goes after a modified form of beta amyloid called N3pG, and targeting this showed in its midstage results a “significant slowing of decline in a composite measure of cognition and daily function in patients with early symptomatic Alzheimer's disease compared to placebo.”
Going down into the data (which are sparse as it’s currently only a top-line look), it hit its primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer's Disease Rating Scale (iADRS), slowing decline by 32% relative to placebo, which Lilly said was statistically significant. It was however done in a trial with fewer than 300 patients.
The iADRS is a clinical composite tool combining the cognitive measure ADAS-Cog13 and functional measure ADCS-iADL, what Lilly says are "two commonly used measures" in Alzheimer's disease.
But it was not all good news: Donanemab “did not reach nominal statistical significance on every secondary endpoint,” but full data have not yet been released. Lilly has promised a full breakdown in the future.
This will be a generally positive for Alzheimer’s research, which has suffered setback after setback for 15 years. It’s also another boost for those who believe in the power of the “amyloid hypothesis,” whereby production of beta amyloid in the brain initiates a cascade of events leading to the clinical syndrome of Alzheimer’s. But there are still many questions to be answered here.
The drug that has come closest to backing up this amyloid idea is Biogen’s aducanumab, which binds to aggregated beta amyloid and causes it to be cleared from the body.
It had, in fact, had been on the edge of being scrapped, but Biogen drilled down into the data and thought it saw a glimmer of hope, so it's gone to the FDA for approval. Its PDUFA is in March, but an expert outside panel said it shouldn't be approved late last year.
This is also a rare glimmer for Lilly in Alzheimer’s. In February last year, Roche and Lilly reported results from the DIAN-TU trial of two drugs—gantenerumab and solanezumab—that failed to deliver any improvement after at least four years of therapy in people with an early-onset, inherited form of the disease.
Lilly’s solanezumab is a humanized antibody that targets the central region of beta amyloid, while Roche’s gantenerumab is a fully human antibody that binds to beta amyloid at the center and at one end of the molecule. Researchers are now digging into subgroups of patients to see whether the combo yielded any benefits in one or more of them.
Solanezumab also failed in mild Alzheimer’s patients a few years back, but it’s still working through a study, A4, in people with amyloid buildup but no signs of cognitive impairment.
Lilly is also looking at a higher dose of solanezumab than it used in earlier studies, with results also expected in late 2022, although a new readout from the trial has already linked high amyloid levels with early-stage disease.
Lilly’s shares jumped 16% on the news in early trading Monday ahead of the annual J.P. Morgan healthcare conference 2021 start.