Whether certain groups of early Alzheimer's patients are more likely than others to benefit from investigational donanemab is a key question FDA advisors will try to untangle when they .
In released ahead of next Monday's meeting of the agency's advisory committee, FDA staffers questioned whether tau levels should play a role in determining who might qualify for donanemab treatment, if the drug is eventually approved.
The Peripheral and Central Nervous System Drugs committee will discuss whether the benefits of donanemab outweigh its risks for people with early Alzheimer's disease. If approved, donanemab will be the third amyloid-targeted drug to come to market: the first being the controversial aducanumab (Aduhelm), which received accelerated approval but was subsequently abandoned, and the second being lecanemab (Leqembi), which received full FDA approval last year.
Donanemab, which targets a modified form of beta amyloid known as N3pG, was tested in the phase III TRAILBLAZER-ALZ 2 trial (referred to as Study AACI in the FDA's briefing documents) of 1,736 early Alzheimer's patients.
The drug met the primary endpoint of change from baseline in the (iADRS), 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 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 to 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 to 18 with higher scores indicating greater impairment.
People with no or very low tau were excluded from the study, leading FDA reviewers to question whether donanemab should be restricted to Alzheimer's patients with a specific tau burden. In before the meeting, however, the company argued that they expected donanemab to show benefits regardless of tau levels and that tau can be an important marker of disease progression but does not predict drug response.
FDA staffers pointed out that Lilly changed the primary endpoint from CDR-SB to iADRS during the pivotal trial, and the FDA did not agree with the change.
Like other anti-amyloid drugs, donanemab's safety issues center around amyloid-related imaging abnormalities with edema or effusion (ARIA-E), ARIA with microhemorrhages and hemosiderin deposits (ARIA-H), cerebral hemorrhage, and infusion-related reactions. Lecanemab carries a , which occurs more frequently in APOE4 homozygotes.
In TRAILBLAZER-ALZ 2, 24% of donanemab-treated participants had ARIA-E and 31.4% had ARIA-H. Two ARIA-related deaths were attributed to donanemab. Intracerebral hemorrhages greater than 1 cm in diameter were reported in 0.5% of donanemab-treated patients, and infusion reactions occurred in 8.7% of the donanemab group.
Data from a third-party vendor that included mortality outcomes for participants who discontinued the trial suggested that 19 deaths occurred among people on donanemab (2.3%) compared with 16 deaths among people on placebo (1.9%) during the study period, the FDA noted. But other than ARIA-related deaths, "the deaths did not appear to be causally related to donanemab and there was no unusual grouping of deaths that would suggest a causal relationship," the agency wrote.
In TRAILBLAZER-ALZ 2, donanemab was dosed until amyloid was cleared, not continuously like other anti-amyloid agents. The FDA has asked its advisory committee to discuss this idea Monday.
The committee will vote on two questions: whether available data show that donanemab effectively treats the Alzheimer's population that was enrolled in the drug's clinical trials and whether the drug's benefits outweigh its risks. The FDA isn't required to follow its advisory committees' recommendations, but it often does.