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AMSTERDAM -- Investigational donanemab significantly slowed clinical progression at 76 weeks in people with early symptomatic Alzheimer's disease who had amyloid and tau pathology, the phase III trial showed.

The drug, which targets a modified form of beta amyloid known as N3pG, showed significant slowing versus placebo on measures of cognition and daily function, reported John Sims, MD, of drugmaker Eli Lilly in Indianapolis, at the 2023 Alzheimer's Association International Conference (AAIC). Results were published simultaneously in .

Donanemab met the primary endpoint of change from baseline to 76 weeks in the Integrated Alzheimer's Disease Rating Scale (), slowing decline relative to placebo. At 76 weeks, mean change on the iADRS was -10.19 in the donanemab group versus -13.11 in the placebo group for all participants in the study (P<0.001).

Among those who had only low or medium tau pathology -- 68.1% of the study population -- mean change was -6.02 in the donanemab group versus -9.27 in the placebo group (P<0.001). Scores on the iADRS range from 0-144, with lower scores indicating greater impairment.

On a key secondary endpoint, the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, mean change at 76 weeks was 1.72 with donanemab and 2.42 with placebo (P<0.001) in the total study population. For those with low or medium tau, CDR-SB change was 1.20 with donanemab and 1.88 with placebo (P<0.001). CDR-SB scores range from 0-18 with higher scores indicating greater impairment.

For the subset of participants who had low or medium tau, the findings translated to a 4.36-month delay in progression in iADRS scores and a 7.53-month delay on CDR-SB scores, Sims noted. Findings were similar in APOE4 non-carriers and in heterozygous carriers, but not in homozygous carriers.

Amyloid-related imaging abnormalities (ARIA) of edema or effusion (ARIA-E) occurred in 24.0% of the donanemab group and 2.1% of the placebo group. ARIA of microhemorrhages and hemosiderin deposits (ARIA-H) emerged in 19.7% of the donanemab group and 7.4% of placebo. Infusion reactions occurred in 8.7% of the donanemab group and in 0.5% with placebo.

Three participants in the donanemab group with serious ARIA subsequently died, said co-investigator Stephen Salloway, MD, of Brown University in Providence, Rhode Island, who spoke during the AAIC presentation.

None were prescribed anti-coagulants or anti-platelet medications, Salloway noted. Two developed severe ARIA-E, one following re-treatment after ARIA-E resolved and severe ARIA-H stabilized. Another had superficial siderosis at baseline and later developed a large intracerebral hemorrhage. Two of the patients who died were heterozygous APOE carriers and one was a non-carrier.

The results highlight the complexity of Alzheimer's disease itself, noted Eric Widera, MD, of the University of California San Francisco, and co-authors, in one of several editorials .

Earlier this month, when the FDA granted full approval to lecanemab (Leqembi), another anti-amyloid monoclonal antibody for Alzheimer's disease, it required a about the risks associated with ARIA.

From a practical standpoint, "the modest benefits would likely not be questioned by patients, clinicians, or payers if amyloid antibodies were low risk, inexpensive, and simple to administer," Widera and colleagues wrote.

"However, they are none of these," they continued. "The harms include infusion reactions and ARIA. Although ARIA may often be asymptomatic to mild in nature, they can lead to life-threatening events including what was likely three treatment-related deaths in each of the donanemab and lecanemab studies."

TRAILBLAZER-ALZ 2 randomized 1,736 amyloid-positive patients with mild cognitive impairment or mild dementia (mean age was 73 and 57% were women) to 72 weeks of placebo or donanemab 1,400 mg infused once every 4 weeks. The cohort was divided into those with low or medium tau levels (1,182 people) or all tau levels combined, which included 552 people with high tau.

At 76 weeks, brain amyloid plaque level decreased in the overall study population by 87.0 centiloids with donanemab, and decreased by 0.67 centiloids with placebo. In the subset with low or medium tau, amyloid decreased by 88.0 centiloids with donanemab treatment and increased by 0.2 centiloids in the placebo group.

Overall, the findings were well-received by many AAIC attendees, though, some researchers, like Jennifer Manly, PhD, of Columbia University in New York City, and Kacie Deters, PhD, of the University of California in Los Angeles, challenged their meaning.

"Donanemab was very effective at eliminating its target, cerebral amyloid, but the clinical effect was comparatively weak," they observed in an . "Overall, cognition and daily function continued to decline in all participants."

In addition, Black and other minority Alzheimer's patients were under-enrolled in the study, giving investigators no real insight into how the antibody might affect disease course in those populations, Manly and Deters noted.

"Given the wide availability of these drugs following U.S. Food and Drug Administration approval and the disproportionate burden of cognitive impairment and dementia due to Alzheimer's disease in many of these groups, it is critical that clinicians, patients, and families understand the limits of what is known," they wrote.