Lilly’s Alzheimer’s Struggles Continue as Preclinical Disease Asset Fails Phase III

Photo shows Eli Lilly building and parking lot/Courtesy of Cristina Arias/Getty Images

Eli Lilly isn’t having a good year in Alzheimer’s disease. Data released Wednesday from the Phase III A4 study showed solanezumab fell short of its primary endpoint, failing to slow cognitive decline in patients with preclinical Alzheimer’s disease. 

As a result, Lilly is ending clinical development of the asset, John Sims, head of medical, global brand development – solanezumab, Lilly, said in a prepared statement.

A4 was a “first-of-its-kind secondary prevention trial,” enrolling more than 1,100 participants who had evidence of amyloid plaque build-up in the brain but no clinical impairment otherwise. The study’s primary outcome was cognitive decline as measured by the Preclinical Alzheimer Cognitive Composite (PACC), a validated tool that evaluates episodic memory, timed executive function and global cognition.

On average, patients treated with solanezumab saw a 1.69-point drop in PACC scores, while placebo counterparts had a mean PACC reduction of 1.4 points. The difference was not statistically significant.

Lilly’s candidate also failed to demonstrate significant benefit in secondary efficacy measures such as disease progression from preclinical to symptomatic Alzheimer’s disease.

Solanezumab is a monoclonal antibody designed to target the amyloid protein to address early Alzheimer’s disease. Unlike Lilly’s other Alzheimer’s candidates – donanemab and remternetug – solanezumab can only bind to soluble monomeric forms of amyloid β and cannot remove plaques that have already deposited in the brain.

In A4, amyloid plaques continued to accumulate in both the solanezumab and placebo arms, with deposits increasing by 12.1 and 17.5 centiloids over the course of the study, respectively.

These results suggest amyloid remains a key driver of cognitive decline even in preclinical Alzheimer’s and that “we may need to be more aggressive with amyloid removal even at this very early stage of disease,” Reisa Sperling, M.D., neurologist at the Brigham and Women's Hospital and A4 project director, said in a prepared statement.

A Rough Three Months 

Solanezumab’s Phase III failure is Lilly’s latest stumble in its quest to bring an Alzheimer’s disease treatment to the market.

In January, the FDA rejected the company’s bid for accelerated approval of donanemab, its most mature Alzheimer’s asset. In its complete response letter, the regulator requested more data establishing the antibody’s safety and efficacy.

Lilly supported donanemab’s accelerated regulatory application with data from the Phase II TRAILBLAZER-ALZ study, which had more than 100 participants. However, the study allowed patients to stop treatment once brain amyloid plaques had been cleared past a certain level. As a result, fewer than 100 patients had been treated with donanemab for 12 continuous months.

Topline data from the TRAILBLAZER-ALZ 2 trial are expected in the coming months, which Lilly will use as part of an application for traditional approval of donanemab.

While Lilly’s stocks took a slight hit, some experts believe the FDA made the right call, noting that while donanemab has demonstrated it can clear amyloid plaques, its effects on overall function have not yet been established.

Lilly is also pushing remternetug through the clinic. The molecule, which binds to amyloid deposits in the brain, is in Phase III for the disease’s early stages.