The new Alzheimer’s drug known as Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi in the phase 3 trial.
In an anticipated breakthrough, the Food and Drug Administration (FDA) is on the verge of approving a third new Alzheimer’s drug, marking a significant advancement in the battle against this debilitating disease.
However, these medications seem to be most effective during the early onset of Alzheimer’s, implying that alternative treatments will be crucial for patients at a more advanced stage of the disease, as stated by Dr. Gil Rabinovici, the director of the Alzheimer’s Disease Research Center at the University of California, San Francisco (UCSF).
In a recently published JAMA editorial, Dr. Rabinovici proposes that we are now on the threshold of a new epoch of molecular therapies for Alzheimer’s and similar neurodegenerative conditions. This view was presented alongside the promising results from the latest trial of the Alzheimer’s drug, donanemab. It should be noted that Dr. Rabinovici did not participate in the trial.
Like its predecessors, aducanumab (Aduhelm) and lecanemab (Leqembi), donanemab is a monoclonal antibody. These drugs primarily target amyloid plaques in the brain, aggregates of protein that interfere with cellular function and facilitate the rapid proliferation of another protein, tau. Both amyloid and tau are key players in the progression of Alzheimer’s disease.
Clinical trials demonstrated that donanemab reduced cognitive decline by 35% compared to placebo in patients with mild-to-moderate tau concentrations in the brain. This aligns with the results observed with Leqembi, which was given FDA approval earlier this month. The trial also revealed that patients treated with donanemab had a 40% reduced risk of progression from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.
The efficacy of donanemab in eradicating amyloid plaques surpassed that of Aduhelm and Leqembi. It also led to decreased tau levels in the blood, although it was not successful in reducing tau levels in a crucial area of the brain.
Despite these optimistic results, Dr. Rabinovici asserts that a comprehensive analysis is required to grasp the full impact of these findings on patient outcomes.
Patients at a more severe stage of the disease derived negligible benefit in comparison to placebo recipients. Coupled with the potential for serious side effects, this raises the need for improved, safer treatments, Dr. Rabinovici said. He suggests the use of donanemab should be confined to patients with mild disease stages, as indicated by low-to-moderate tau levels.
All three Alzheimer’s drugs, including donanemab, were linked with ARIA – Amyloid-Related Imaging Abnormalities, which may cause brain swelling and microbleeds. Severe ARIA was reported in 3.7% of patients, which included three fatalities. Risk levels were elevated in patients with the APOE4 gene, which is associated with an increased risk of Alzheimer’s. Consequently, Dr. Rabinovici recommends genetic testing prior to treatment with monoclonal antibodies.
While ARIA has been handled safely in clinical trials, caution should be exercised as these drugs enter general medical practice. Dr. Rabinovici suggests regular MRI monitoring, with treatment cessation or suspension in the event of ARIA.
The clinical trial was criticized for its lack of racial and ethnic diversity, with only 8.6% of the 1,251 participants being non-white. Dr. Rabinovici emphasized the ethical implications of this issue, given the higher rates of dementia reported in Black and Latino populations.
In light of the projected high costs of donanemab and the high demand among patients, Dr. Rabinovici suggested limiting treatment duration to the time necessary to clear the brain of amyloid plaques, the approach adopted in the trial. Such a strategy could dramatically enhance the viability of treatment for patients, healthcare professionals, insurance companies, and healthcare systems alike.
Source: 10.1001/jama.2023.13239
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