Getting approval will only be the first challenge facing lecanemab

Biogen and Eisai are riding high on the wave of optimism set in motion by the top-line data drop for Alzheimer's therapy lecanemab – but a number of breakwaters could lie ahead.

First and most obviously is the detailed data from the Clarity AD study reported this week, which will be revealed at the Clinical Trials on Alzheimer's Congress (CTAD) in November.

The results have been billed as a clear win, with a reduction in cognitive decline accompanying the clearance of amyloid plaques that characterise the disease – which could be a first for an amyloid-targeting drug – and across-the-board improvements in primary and secondary endpoints.

It's impossible to make a judgment before the data are presented and published in a peer-review journal, but seem to already be well ahead of the data for Aduhelm (aducanumab), which was effectively approved using amyloid clearance as a biomarker.

Eisai and Biogen have reported a 27% reduction in clinical decline compared to placebo at 18 months on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale, equivalent to a 0.45 point advantage.

According to Prof Peter Passmore, an ageing and geriatric medicine specialist at Queen's University Belfast, the benefits "seem to be small and the debate will be around how clinically relevant the changes are in CDR SB."

Dr Catherine Mummery, a consultant neurologist at University College London Hospitals NHS Foundation Trust (UCLH), said the results are "exciting", but agreed that the size of the effect is small.

"What we cannot know yet is whether that effect increases over time in an individual. That would be predicted, but is untested – time will tell," she suggested.

Another key factor to consider is the safety profile of the drug, particularly with regard to amyloid-related imaging abnormalities (ARIA) that are always a risk with amyloid-targeting drugs, causing oedema (ARIA-E) and haemorrhages (ARIA-H).

In Clarity AD, the rate of ARIA-E was 12.5% overall, but was symptomatic in just 2.8% of patients, while for ARIAH-H the rates were 17% and 0.7%, respectively.

GlobalData notes that the side effect could be a barrier for lecanemab use as it will require patient monitoring, but points out that the rates are a "significant improvement" on Aduhelm, which had an ARIA-E rate of 35% of patients taking the approved dose in clinical trials.

Assuming the FDA decides that the efficacy and safety data for lecanemab is strong, it could opt to approve the drug via the accelerated approval mechanism – with a decision on that due by 6 January – or wait to review the full marketing application, including the Clarity AD results that will be submitted in the first quarter of next year.

If approved, cost and reimbursement will be the next big challenges. Biogen's initial decision to price Aduhelm at $56,000 per year prompted an outcry that quickly resulted in the company slashing it in half to $28,000, although that was still not enough to rescue the product.

Reimbursement was the main stumbling block, with the Centres for Medicare and Medicaid Services (CMS) restricting the drug to use in clinical trials in its National Coverage Determination (NCD), concluding that "questions still need to be answered" about the role of aducanumab and other amyloid-targeting drugs in Alzheimer's treatment. It also set a benchmark for efficacy as a 0.5 to 1.0-point improvement on the CDR-SB.

In effect, the CMS has limited reimbursement of future anti-amyloid drugs approved like Aduhelm via the accelerated pathway. So, unless it changes its position, lecanemab and other late-stage amyloid drugs, like Eli Lilly's donanemab and Roche's gantenerumab, could see their use restricted until full approval.

"A 0.45 point advantage on an 18-point scale, where the accepted minimum worthwhile difference ranges from 0.5 to 1.0 points, will mean that there are going to be some very difficult conversations and decisions in the next weeks and months," commented Prof Rob Howard, a specialist in old age psychiatry at UCL.

Of course, if the Clarity AD results do turn out to be convincing, the CMS could soon come under intense pressure to relax its restrictions, given the lack of effective Alzheimer's therapies, and could be more amenable to doing so if Biogen and Eisai resist the temptation to price lecanemab high.

There will still be much debate about the exact license granted to the drug and cost-effectiveness deliberations, according to Prof Passmore.

He pointed out that services to administer the injections frequently, and the required radiology and clinical monitoring for patients, "will all need to be factored in on top of the simple cost of the drug."

Moreover, there is the possibility of strong demand for an amyloid drug that is free of the baggage that weighed down Aduhelm, and a growing need to identify patients in the early-stages of Alzheimer's who stand to benefit from treatment.

"Up to now, many people have not come forward when they first worry about their memory, as there were no treatments for dementia," said Dr Liz Coulthard, associate professor in dementia neurology at the University of Bristol.

"It is very likely more people will come to see their doctor now – and we, as doctors, need to be ready. Most people with mild memory symptoms will not have Alzheimer's disease. We need to develop an effective and quick triage system so we can reassure people without Alzheimer's and offer treatment to those with Alzheimer's."

GlobalData is betting on approval of lecanemab and the lifting of reimbursement restrictions, with a prediction of $2.76 billion in sales of the drug in the top eight pharma markets (US, France, Germany, Italy, Spain, UK, Japan, and China) by 2030.

Analysts at JP Morgan are even more confident if the drug is fully approved, forecasting peak sales between $6 billion and $10 billion.