After a new study found that lecanemab, an experimental Alzheimer's drug developed by Eisai and Biogen, slowed cognitive and functional decline by 27% compared to a placebo, Alzheimer's patients have a renewed hope for an effective treatment—but experts still have unanswered questions about the drug.
On Tuesday, researchers published the "highly statistically significant" results from the CLARITY-AD study, which included 1,795 patients with mild cognitive impairment caused by Alzheimer's disease, or early-stage Alzheimer's.
During the 18 months of the study, patients who received lecanemab performed 0.45 points better on the Clinical Dementia Rating sum of boxes (CDR-SB) test—which measures six domains of cognitive decline with a score ranging from zero to 18, with a higher score meaning more severe cognitive decline—than those receiving a placebo, results that the drugmakers said hit the threshold of statistical significance.
According to Ivan Cheung, chair of Eisai's U.S. operations and global head of its Alzheimer's unit, lecanemab's positive effects emerged six months into the trial and were largest at the 18-month point.
The companies also said in a press release that lecanemab met its secondary goals of reducing toxic plaques within the brain and slowing decline on three other measures of memory and function.
Around 21% of the participants in the study experienced brain swelling or brain bleeding that was visible on PET scans after taking lecanemab, and less than 3% of those patients had symptomatic cases. According to the companies, those side effects were within expectations.
The companies said FDA has agreed the results of the CLARITY-AD trial can serve to verify the clinical benefit of lecanemab, and officials from Eisai said they intend to seek full FDA approval for the drug after they receive an expedited approval.
While the CLARITY-AD study had promising results, many experts still have unanswered questions about lecanemab.
According to Eisai, the drug produced a "clinically meaningful" benefit, which would help improve patients' memory and ability to complete basic tasks. However, many experts have been less optimistic, citing data that suggest lecanemab's observed benefit—at best—falls on the margins of what is considered meaningful, STAT+ reports.
In a 2019 study, published in Alzheimer's and Dementia, researchers analyzed data from roughly 35,000 patients with dementia to find a "minimal clinically important difference," or a baseline to help determine how much CDR-SB scores have to change before a doctor can determine a patient's condition is worsening.
Among all patients, the threshold for meaningful change was a change of around 1.2 on the CDR-SB. For those with early-stage and mild Alzheimer's, it fell between 0.98 and 1.63. The absolute minimum change that qualified as "meaningful decline" in the study was a 0.5 increase.
Mia Yang, a geriatrician at Wake Forest, noted that a half-point change would not provide much of a benefit to a patient with more advanced Alzheimer's.
"I'm cautiously optimistic that it could be potentially meaningful for those folks who are in the mild stage," Yang said about lecanemab.
Still, many experts have highlighted the challenges the drug's side effects posed during the study. Roughly 20% of patients who got lecanemab reported ARIA—a temporary swelling of the brain that commonly occurs during amyloid-targeting treatments.
Once patients test positive for ARIA, the study conductors typically know that the patients are receiving the drug instead of the placebo, potentially exposing the study to bias. An efficacy analysis of patients who received lecanemab and did not experience ARIA could help researchers more accurately assess its benefits.
In addition, many experts have voiced concerns over the potential cost of the drug. After Aduhelm was approved, it was initially priced with an annual cost of $56,000 and approved for all Alzheimer's patients, which had a significant impact on the U.S. health system.
According to Eisai, lecanemab's "annual value-based price" could fall between $9,249 and $35,605. Still, even with significantly lower prices and more stringent eligibility requirements, a new Alzheimer's drug would likely cost the U.S. health system billions every year, Axios reports.
If FDA approves lecanemab, CMS will have to determine if and how the drug will be covered. "If the data is what the companies say it is, we believe it will be hard for CMS to refuse coverage," said Chris Meekins, a Raymond James analyst who estimated that the earliest Medicare could begin reimbursing for lecanemab is toward the end of the third quarter of 2023.
"FDA approval seems likely, but CMS determination [is] another bridge to cross," said Wedbush's Laura Chico. "It's a positive to see the study reach statistical significance, with FDA previously signaling this would be a prerequisite for approval. However, what CMS will see as a clinically meaningful outcome remains to be determined." (Feuerstein et al., STAT+ [subscription required], 9/29; Joseph, STAT, 9/28; Owens/Bettelheim, Axios, 9/29; Walrath, Boston Business Journal, 9/29)
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