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Silver Spring/Maryland – The US Food and Drug Administration (FDA) has approved aducanumab (Aduhelm, 2021), which is no longer available on the market, and lecanemab (Leqembi, 2023), a third monoclonal antibody for the treatment of early stages of Alzheimer’s disease, donanemab (Kisunla), which is intended to eliminate beta-amyloids from the brain.

In contrast to lecanemab, donanemab offers patients the possibility of taking breaks from treatment. The FDA’s product information contains warnings about the complications ARIA-H and ARIA-E visible in magnetic resonance imaging, which are the result of the rapid degradation of beta-amyloid in the brain.

Monoclonal antibodies can bind to the beta-amyloids in the brain that are deposited outside the cells during Alzheimer’s disease. The beta-amyloids are then eliminated via an immune reaction.

The reduction in the amyloid load, which can be observed in positron emission tomography (PET), is intended to prevent (further) neurons from being damaged and cognitive performance from declining further. A recovery from dementia is not to be expected.

After several antibodies failed to stop the progression of dementia in clinical trials in the past, Biogen’s Aduhelm was approved in the USA (not in Europe) in June 2021.

Approval came after the second attempt, and the results of the clinical trials did not convince most neurologists. The manufacturer stopped selling the drug after a few months due to a lack of demand.

The results for the antibodies lecanemab and donanemab were much more favorable. These two antibodies reduce the amyloid load in the brain significantly more than aducanumab. In the approval-relevant studies Clarity AD on lecanemab and TRAILBLAZER-ALZ 2 on donanemab, dementia progressed more slowly than in the placebo group. However, a complete halt to the disease could not be achieved.

Lecanemab was approved in the USA in January 2023, but this is still pending in Europe. The FDA has now also approved donanemab, which the manufacturer Lilly plans to offer as Kisunla. The use of both drugs is limited to patients in the early stages of the disease when there are only mild cognitive impairments. The prerequisite is the detection of amyloid deposits in the brain, ideally by PET (with lecanemab, a cerebrospinal fluid test is also sufficient).

As far as the results from the studies can be compared, donanemab achieved a greater reduction in amyloid load: in the TRAILBLAZER ALZ 2 study by 87 centiloids after 76 weeks compared to 59.1 centiloids under lecanemab in the Clarity AD study.

This more effective removal of amyloids means that patients can interrupt treatment with Kisunla after a certain period of time. In the TRAILBLAZER ALZ 2 study, according to the product information, this was possible for 17% of patients after 24 weeks of treatment, 47% at week 52 and 69% at week 76. Treatment breaks are not planned for Leqembi.

After stopping donanemab, amyloid levels may rise again because donanemab does not stop the disease process. It is not yet clear how long the treatment breaks may last and when treatment must be restarted.

The radical removal of beta-amyloids is not without consequences. Changes can occur in the brain that are visible in magnetic resonance imaging as “amyloid-related imaging abnormalities” (ARIA). There are two forms: ARIA-H (hemosiderin) are probably the result of slight bleeding, which usually has no consequences. ARIA-E indicate edema. In most cases, this has no consequences. However, focal neurological deficits can occur, similar to an ischemic stroke.

The Kisunla product information states that the frequency of ARIA-H is 25% (versus 11% in the placebo group). ARIA-E was found in 24% versus 2%. The product information contains a boxed warning for this. Patients who are homozygous for the gene variant ApoE epsilon 4, a known risk factor for Alzheimer’s disease, are particularly affected. The product information for Lecanemab (Leqembi) also points out the risk of ARIA.

Another possible complication is allergic reactions that occur during the infusion or within 30 minutes afterward. The FDA also points out the possibility of headaches, which, according to the product information, were reported by 13% of patients versus 10% in the placebo group.

One advantage of Kisunla could be the longer intervals between doses. The infusions only need to be repeated every four weeks. With Leqembi, this is necessary every two weeks.

Neither drug can stop dementia. However, further cognitive decline is slowed. The primary endpoint of the TRAILBLAZER-ALZ 2 study was the Integrated Alzheimer’s Disease Rating Scale (iADRS). It assesses the patient’s condition on a scale of 0 to 144 points, with lower scores indicating greater cognitive and functional impairment.

In the donanemab group, there was a loss of 10.2 points over the course of 76 weeks of treatment compared to a loss of 13.1 points in the placebo group. The difference of 2.92 points was, according to the publication in the American Medical Journal (JAMA 2023; DOI: 10.1001/jama.2023.13239) with a 95% confidence interval of 1.51 to 4.33 points.

Significant benefits were also found in almost all secondary endpoints, including the ADAS-Cog13 (Alzheimer’s Disease Assessment Scale-Cognitive Subscale), the ADCS-iADL (Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living) scale, and the CDR-SB (Clinical Dementia Rating Scale-Sum of Boxes) scale.

Despite the less frequent infusions, the treatment costs for Kisunla in the US are higher at $32,000 per year than for Leqembi at $26,000 per year. A representative of the manufacturer explained this to the press with the prospect of breaks in therapy, so that the total costs for both drugs could be the same. © rme/aerzteblatt.de