Background

Donanemab is a monoclonal antibody that targets and breaks up amyloid beta plaques, which build up in the brain as Alzheimer's worsens over time. Although the medication is not a cure for the disease, it can slow its progression.

In a Phase 3 clinical trial, Eli Lilly enrolled 1,736 patients with early symptoms of Alzheimer's, as well as signs of both amyloid and tau. The patients were stratified by their tau levels: low-to-medium, intermediate, and high.

Those assigned to receive donanemab were allowed to stop the treatment once they reached a pre-defined level of amyloid clearance. Around half of the patients who received donanemab reached the benchmark at 12 months and seven out of every 10 patients reached the benchmark at 18 months.

Overall, researchers found that donanemab slowed cognitive decline by 35% in patients with intermediate levels of tau. For patients with low-to-medium levels of tau, the treatment slowed cognitive decline by almost 39%, or roughly the same as a delay of 4.4 to 7.5 months.

However, patients who had high levels of tau, which represented more advanced Alzheimer's, did not see the same benefit from the drug. According to a post-hoc analysis of this group, there was no difference between those who received the treatment and those who received a placebo.

"Compared with significant differences in the low/medium tau population, this supports the hypothesis that a greater benefit from amyloid-lowering therapies may occur when initiated at an earlier disease stage," the researchers wrote.

Among patients who received the treatment in earlier stages of the disease, 47% had no signs of Alzheimer's progression after one year compared to 29% among the placebo group. In the combined groups, 36% of the treatment group had no signs of progression compared to 23% of the placebo group.

Advisory panel unanimously recommends donanemab

Members of the panel ultimately determined that donanemab's ability to slow cognitive decline outweighed its safety risks. FDA usually follows the advice of the independent advisory committee but is not required to. The agency will make a final decision on the drug's approval later this year.

"The benefits outweigh the risks, as long as the risks are being monitored," said Kathleen Poston, a neurologist at Stanford University and a member of the panel.

However, advisors on the panel did express some concerns about the risks posed to a small group of patients with two copies of the APOE4 gene variant, since those patients are more likely to experience side effects of brain swelling with amyloid-clearing treatments. The advisors also expressed concerns about the low representation of African American and Latin American people in the trials.

Eli Lilly also elected to stop treating patients as soon as their brain scan indicated their amyloid proteins had cleared, which members of the committee said made the drug more appealing, as patients could avoid monthly infusions, some of the risks of the treatment, and could see lower costs.

The possibility of stopping treatment "could actually be a motivational factor for patients to stay compliant," said Sarah Dolan, a member of the panel representing consumers. However, she noted that "there will always be a concern in the back of their head: Is it coming back? Am I getting worse?"

"It's a huge cost savings for the society, we're talking about expensive treatment, expensive surveillance," said Tanya Simuni of Northwestern University.

Constantino Iadecola, from Weill Cornell Medicine, said it's unclear how to monitor patients after they stop taking the drug. "Monitoring is going to be necessary," he said, adding, "how soon will you have to intervene if you have a signal of amyloid going up?"

Researchers at Eli Lilly estimated it would take roughly four years for amyloid levels to increase over the threshold again.

In addition, given that trial participants with intermediate levels of tau declined more slowly than those on donanemab whose tau levels were high, FDA questioned whether patients should be required to have tau brain scans before taking the drug.

Members of the committee determined there shouldn't be a requirement for assessing tau, due to the practical challenges of having to scan patients for the protein.

"Imposing a requirement for tau imaging is not necessary and would raise serious practical and access concerns to the treatment," said Thomas Montine, from Stanford University, who chaired the panel.

Some committee members were concerned that there was fewer trial data on patients with no or low levels of tau, as patients with no or low levels of tau were excluded from the Phase 3 trial. However, many said they felt reassured by the biomarkers data in Eli Lilly's addendum study which did include those patients.

"Inclusion in these types of trials are easier for patients of certain social, ethno-racial groups, and geographical location. Inclusion of requirement for PET [scans for] tau will further limit the number of patients who can have access to these types of medications," said Nilüfer Ertekin-Taner, chair of the department of neuroscience at Mayo Clinic and a member of the panel.

"It's a nuanced situation where, on the one hand, we do need to have the additional data on the no and very low tau population, and, on the other hand, we should not require having tau PET for access to these medications," she added. (Chen/Feuerstein, STAT+ [subscription required], 6/10; Kolata/Belluck, New York Times, 6/10; Perrone, Associated Press, 6/10)

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