Five takeaways from the new donanemab data

Headlines about the results of TRAILBLAZER-ALZ2 trial of Eli Lilly’s Alzheimer’s drug candidate donanemab are spreading around the world, with some going as far as to suggest this could herald the ‘beginning of the end of the disease’.

The full date from the trial won’t be presented for a while, so for now, much of the commentary is focused firmly on the details revealed in Lilly’s press release and comparisons with the results previously made available with Eisai and Biogen’s already-approved Leqembi (lecanemab), which works in a similar way.

Here are five important things to consider about donanemab, the study, and the implications for understanding and treating Alzheimer’s.

1 – Consistent efficacy data

The headline result from TRAILBLAZER-ALZ2 is that it slowed the pace of Alzheimer’s by about a third compared to placebo among patients in the early stages of the disease. Experts are encouraged that the effects are similar to those seen with recent trials of amyloid-lowering therapies, including Leqembi and Eisai and Biogen’s predecessor drug Aduhelm (aducanumab), and also consistent within Lilly’s study itself – hitting both the iARDS and CDR-SB rating sales.

Neurologists have been quick to stress that the results, even if confirmed, will not ultimately prevent disease progression, so there is still a lot of work to be done trying to develop new drugs and strategies that may modify the underlying disease process. Nonetheless, there’s no doubt that holding up the decline is important, and having one disease-modifying approach serves as a foundation that may, in future, be built on by the use of other therapies in combination.

One key observation is that the trial was designed so that donanemab was given as a monthly infusion until amyloid was cleared from the brain, and for now, it isn’t clear whether its effects will tail off after treatment is stopped.

Also not to be underestimated is that along with the data on cognitive decline, the trial also showed a 40% slowing in the decline of activities of daily living – such as driving, using a telephone, carrying out hobbies and chores or managing finances – that can be so important to patients’ quality of life and wellbeing.

2 – Safety concern

While the efficacy data is looking encouraging, there is one red flag among the safety data from TRAILBLAZER-ALZ2, namely 24% of patients showing a brain swelling or bleeding side effect known as ARIA, which was deemed serious in 1.6% of cases. Two deaths – and possibly a third – resulted from the side effect.

Patient deaths linked to ARIA have also been reported with Leqembi, although Eisai and Biogen’s drug seemed less likely to cause the side effect overall – with the usual caveat of trying to compare data from different studies. There has been some work suggesting ARIA may be more likely to occur in people with a genetic mutation that predisposes people to develop Alzheimer’s, which if confirmed, could provide a way to screen at-risk patients.

Some neurologists also argue that ARIA is rare, generally manageable, and often resolves after stopping the drug, so should not be an impediment to the use of these drugs. That said, the safety issue impinges directly on the third takeaway, as follows:

3 – Diagnosis and monitoring

Assuming regulators decide that the risk-benefit ratio of donanemab is acceptable and approve the drug, healthcare systems will have to be able to identify suitable subjects for treatment, and monitor them carefully for side effects. That involves a PET scan for diagnosis, as well as routine MRI scans to check for ARIA and infusion centres to deliver the drug – access to which may not be widely available even in countries with well-developed healthcare systems.

To give the UK as an example, only a tiny percentage of patients have PET scans or sampling of the cerebrospinal fluid using a lumbar puncture to give a diagnosis of Alzheimer’s, so there would have to be a sea-change in the clinical pathway to diagnosis if donanemab or Leqembi were to be available as routine therapy.

That also raises the thorny issue of cost. Leqembi has a list price in the US of $26,500 per year, and even if donanemab is approved and competition reduces costs, it may be hard for health systems to afford treatment.

For now, that is academic as in the US, reimbursement of the drugs is restricted to clinical trials, although the Centers for Medicare and Medicaid Services (CMS) said recently that Medicare will cover Leqembi if it gets full approval.

4 – Dosing advantage?

One factor that might be in donanemab’s favour is that it is administered by infusion once a month, while Leqembi has to be given every two weeks, meaning Lilly’s drug may place less of a burden on infusion services if it reaches the market.

Also worth considering is that Leqembi is dosed every two weeks on an ongoing basis, while – as noted – donanemab was given only until amyloid was cleared from the brain in this clinical trial. It’s likely too soon to reflect on that too closely, but it may be that Lilly’s drug will be suitable for intermittent use, with patients monitored for safety and cognition in between courses. Lilly has said it will discuss dosing in more detail when it presents the results of TRAILBLAZER-ALZ2 later this year.

5 – Role of tau protein

Lilly has received praise for designing its trial in such a way that as well as gauging the effect of the drug on amyloid, it also takes into account tau, another protein biomarker for Alzheimer’s. According to Lilly, donanemab worked well in patients with an intermediate level of tau protein, but was less effective in patients with higher levels suggesting they had more advanced disease.

That suggests tau is exerting its pathogenic effects in a different way to amyloid, raising the prospect that targeting both together might lead to even greater efficacy.

Overall, it is undeniable that the donanemab results have been interpreted fairly widely as another step towards validation of the amyloid hypothesis of Alzheimer’s, helping to answer the perennial question – does amyloid cause Alzheimer’s, or does Alzheimer’s cause amyloid?

After getting a look at the donanemab data in more detail, attention will undoubtedly shift to ongoing studies of donanemab and other amyloid therapies in patients with earlier-stage disease and no symptoms.