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Today, the US Food and Drug Administration granted full clinical approval to Eli Lilly to market donanemab, brand name KISUNLA, for the treatment of early Alzheimer’s disease, including Mild Cognitive Impairment (MCI) or mild dementia. Donanemab is a monoclonal antibody against the beta-amyloid protein that accumulates in the brain of people with Alzheimer’s disease. This represents the second ever full approval for a drug that directly targets the biology of Alzheimer’s disease.

Image by Andrew Harnik/AP

Donanemab was shown in a Phase 2 and then in a Phase 3 trial to have a significant impact on brain amyloid burden. In the phase 3 trial, more than three-quarters of participants receiving donanemab had their amyloid lowered to “not elevated” levels by the end of the 18-month study. In fact, in the trials of donanemab, Eli Lilly took the novel approach of stopping treatment once participants achieved this biomarker response to therapy. Accordingly, the FDA-approved label for the medication indicates that physicians may consider stopping treatment once amyloid has been reduced to “minimal levels on amyloid PET imaging.”

Full approval was achieved not because of the treatment’s effect on biomarkers, but instead because treatment with donanemab slowed clinical disease progression, compared to placebo, on the study primary outcome as well as all of the key secondary clinical outcomes—affirming its efficacy. Efficacy was greatest in patients who were deemed earliest in disease, defined in the trial using tau PET scans to determine whether participants had low/medium tau burden or might fall into a higher tau burden group. That participants were required to have at least low/medium tau to be enrolled in the trials had produced some conjecture about whether an approved label would require a similar requirement in clinical practice. But at a recent FDA Advisory Panel, advisors were largely aligned on concerns that such a requirement would represent an unnecessary barrier to access and, worse, could lead to a widening of current healthcare disparities in the treatment of Alzheimer’s disease because of poor access to tau PET imaging in some communities. The approved label only indicates that patients should have the presence of amyloid confirmed prior to beginning therapy; there are no specific requirements on tau PET.

Donanemab joins lecanemab as the only approved disease-targeting therapies for Alzheimer’s disease. Beside the label indication of potentially stopping treatment after amyloid levels have been reduced, donanemab from lecanemab differs in a few other ways. Donanemab is administered through monthly infusions, while lecanemab requires twice-a-month infusions. Both treatments have the same important safety risks, namely Amyloid-Related Imaging Abnormalities (ARIA), which consists of bleeding or swelling in the brain. Because of this safety profile, and because treatment risks are higher in carrier of the e4 allele of the apolipoprotein E (APOE) genotype, the approval for both medications also indicates that APOE testing should be performed before prescribing. Comparisons of the two treatments’ safety and efficacy results are not appropriate, because differences in the patient populations in the trials are difficult if not impossible to account for. Donanemab has been announced a price of $32,000 for 1-year, compared to $26,500 for lecanemab.

Overall, this represents another incredible milestone in the research progress being made in Alzheimer’s disease. Important reminders are warranted, however. These drugs may slow, but do not seem to stop let alone reverse progression of clinical decline. If donanemab treatment is stopped after amyloid has been cleared from the brain, whether or when disease progression resumes is not yet known.  The treatments are appropriate for some but not all people suffering from MCI or dementia. Ongoing studies assess whether starting these treatments even before memory problems begin can maximize their benefit. Better, safer, and more convenient therapies to prevent or treat Alzheimer’s disease symptoms continue to be needed, as are therapies for other causes of MCI and dementia. Nevertheless, this progress is a very positive sign that research is on the right track and more progress is on the way.