Lilly’s Alzheimer’s drug set to join Leqembi after FDA vote

An FDA advisory committee has delivered a strong endorsement to Eli Lilly’s Alzheimer’s disease therapy donanemab, voting unanimously that the safety and efficacy of the amyloid-busting drug support its approval.

The independent advisors on the Peripheral and Central Nervous System Drugs Advisory Committee voted by 11 to zero that donanemab’s benefits outweigh its risks, and by the same margin that the data submitted by Lilly to support its efficacy was convincing.

The outcome – which came after the FDA delayed its review of the drug twice – puts donanemab on course to join Eisai and Biogen’s Leqembi (lecanemab) on the US market as a treatment for people in the early stages of Alzheimer’s disease.

There are still some outstanding questions raised by the panel about Lilly’s data, which overall showed that the drug achieved a 35% reduction compared to placebo on the iADRS measure of cognitive function after 18 months.

Panellists said there were holes in the data for the drug – for example, how it performs in relation to the levels of tau protein in patients, as well as the role of the APOE4 gene, which raises the risk of getting Alzheimer’s dementia.

The FDA said the drug seems to be more effective in those with lower levels of tau, raising the possibility at least that it could select wording on the label to target donanemab to that group, although Lilly insists its data suggests the drug is effective in all subgroups.

Its clinical studies excluded patients with very low or zero tau, however, and among discussions was whether it would be better to wait to start treatment until levels increase. However, that could run counter to the long-held view that earlier treatment with amyloid-targeting therapies is the key to their success in Alzheimer’s.

Requiring testing for tau could be a major break on the drug’s uptake if approved, but the mood of the meeting seemed to suggest there was little support for putting additional barriers in front of patients.

There was also a reduced benefit with donanemab in patients who carry APOE4, as well as an increased risk of serious side effects, although patient advocates at the meeting argued that Alzheimer’s is so damaging that even patients at elevated risk should be able to access treatment.

There was discussion about how long treatment with the drug should continue if it does get approval. In its trials, Lilly stopped dosing with donanemab after amyloid plaques were cleared from the brains of treated subjects, whereas Leqembi is intended to be used continuously, on the assumption that it can stop plaques returning and also blocks amyloid protofibrils that are also thought to damage neurons.

As with Leqembi, there are concerns with donanemab’s potential to cause side effects, and particularly a life-threatening reaction known as ARIA, which can result in brain swelling and bleeding.

The FDA’s position was that these risks are inherent with amyloid drugs and likely could be managed with appropriate warnings on donanemab’s label. Panellists, meanwhile, seemed to like the potential to stop treatment with donanemab after plaque removal, which could reduce the risk of serious side effects developing.

Donanemab also only needs to be infused once a month, compared to every two weeks with Eisai and Biogen’s drug, although, they recently filed for approval of monthly doses in the maintenance phase of treatment.

A once-weekly subcutaneous formulation of Leqembi has also started a rolling biologics license application in the US, which would do away with the need for regular visits to an infusion clinic.

Leqembi’s commercial uptake has been very slow, reaching $19 million in the first quarter of the calendar year, although Eisai recently updated its financial guidance for the drug, saying it expects prescribing to ramp up in its current fiscal year to reach more than $360 million.

The positive vote was welcomed by Dr Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), who noted, however, that it is important to look at it in the wider treatment landscape for Alzheimer’s, which is moving towards a combination therapy and precision medicine approach.

“If approved, donanemab will expand the first class of disease-modifying drugs, serving as the building blocks for future generations of drugs,” he said. “Anti-amyloids are not a silver bullet, but they offer opportunities for patients to modify the course of the disease while the field works towards developing more novel therapies that target the underlying biology.”