More Major Milestones In Alzheimer’s Treatment Within Reach

After decades of research, the past 12 months have seen major breakthroughs in the search for an effective therapeutic targeting the progression of Alzheimer’s disease. The biggest news of 2023 was full approval by the US Food and Drug Administration of Leqembi, marketed by Eisai and Biogen. It’s the first anti-amyloid antibody to gain this regulatory status, something we anticipated would occur following the release of promising clinical trial data. The FDA approval enabled immediate Medicare coverage for the drug in the US. Clinical success has continued for both Leqembi and Eli Lilly’s competitor product donanemab, as shown by data presented at the Clinical Trials on Alzheimer’s Disease conference. In December, Eisai and Biogen announced the positive approval and price listing of Leqembi in Japan, the second largest market for the two companies.

As we outlined last June, several practical hurdles remain before new Alzheimer’s drugs are truly accessible to all eligible patients. Commercial operations have ramped up for Leqembi in the US, but as of late January, only 2,000 patients had received treatment; Eisai set a goal of 10,000 patients getting the treatment by the end of March. We did not see commercial uptake of donanemab in 2023 because the FDA’s assessment is taking longer than expected, delaying an approval decision until at least Q1 of this year.

We believe the biggest milestones in Alzheimer’s are yet to come. To make a real impact, we will need practical solutions — a set of effective therapeutics which are tolerable, easy to administer and accessible via a simple diagnostic pathway instead of being reliant on complex, expensive procedures. So, what progress can we expect to make over the next 12 months? Here’s what to watch out for in 2024.

Simplifying diagnosis with an emphasis on blood testing

Anti-amyloid therapies are only indicated for patients with confirmed amyloid pathology. The established method for this is PET imaging, so it was excellent news when the Centers for Medicare and Medicaid Services in October expanded PET imaging coverage for Alzheimer's disease. However, amyloid PET remains a time-consuming and specialized procedure, presenting a barrier to widespread use. Therefore, the race is on to prove the validity of minimally invasive blood testing as an alternative diagnostic method.

Pharmaceutical companies and public institutions are investing in blood testing solutions. A £5 million project will pilot the implementation of Alzheimer’s blood tests in the UK National Health Service. Meanwhile, the development of commercial tests is accelerating. Roche is collaborating with Eli Lilly on a blood plasma test that was granted FDA Breakthrough Device Designation. Eisai is predicting the use of triage blood testing during 2024. This means that blood tests could be used as initial screening, reducing the number of patients needing confirmatory PET imaging and freeing up capacity at PET centers. This advancement alone could make a huge difference to the number of patients with access to treatment by the end of this year.

Rapid progress towards a less burdensome subcutaneous treatment delivery

Spending an hour regularly at an infusion center to receive therapies intravenously is a strong disincentive to pursue treatment. However, Eisai is already tackling this, including a subcutaneous substudy with the open label expansion phase of the Clarity AD trial for Leqembi. Patients received subcutaneous Leqembi administration weekly, enabling direct comparison with biweekly intravenous administration. Preliminary results at six months of treatment showed that subcutaneous administration was associated with 14% greater amyloid plaque removal versus intravenous administration, according to results shared at last fall’s Clinical Trials on Alzheimer’s Disease conference. The safety profile was similar, although requires further analysis to determine any significant differences. Eisai is aiming for regulatory submission for the subcutaneous form by the end of Q1 2024.

Eli Lilly has no current plans for a subcutaneous version of donanemab. However, the company is testing its next generation product remternetug with both subcutaneous and intravenous administration. It will be interesting to see whether Lilly makes moves to accelerate these efforts following the positive data for subcutaneous Leqembi.

Continued momentum in scientific understanding of the disease

While the efficacy of anti-amyloid drugs was a major scientific breakthrough, there are key remaining areas of uncertainty. The most crucial is the safety profile, since both Leqembi and donanemab are associated with a risk of brain swelling and microhemorrhages known as ARIA-E and ARIA-H, respectively.

Progress to date has focused on identifying risk factors for ARIA. Beyond the already known association between APOE ε4 carrier status and ARIA, Eli Lilly has identified five further factors associated with ARIA-E, including arterial blood pressure, counteracted by the use of antihypertensives. Eisai also found that maximum steady state drug concentration was the strongest predictor of ARIA-E. As the main dose-limiting factor holding back improved efficacy, finding new tactics to reduce safety risk is an avenue we expect to be explored this year.

The next scientific uncertainty is the role of tau. Alzheimer's disease is characterized by both amyloid plaques and tau tangles in the brain, yet treatment so far targets amyloid alone. Leqembi is approved for use in patients regardless of tau pathology and has recently shown good efficacy in patients with low tau. However, donanemab’s pivotal trial stratified patients by tau level, enrolling no patients with very low tau levels. It will be interesting to see the population for which donanemab gets approved. Any treatment eligibility requirement for specific tau levels would mean an even more complex route to diagnosis involving tau PET imaging.

It is believed that low tau represents an earlier stage of disease, but the role tau plays is unclear. Further therapeutic approaches targeting tau could answer this, including Eisai’s anti-tau antibody, now being tested in a Phase II/III trial in combination with Leqembi.

While it may take several years for widespread use of Alzheimer’s drugs, we are excited for the progress around the corner. By the end of 2024, diagnosis could begin to be unlocked with the introduction of blood test screening, a subcutaneous treatment option could offer new promise, and options for managing safety, while maintaining efficacy, could emerge. With Alzheimer’s disease being the fastest growing cause of death worldwide, it is crucial these steps happen in parallel to accelerate progress. We will see advances in the US first, but we hope that worldwide access will follow, with lower cost diagnosis and treatment options to tackle the global crisis and reduce the growing burden on society.