Among the 17 treated participants, amyloid plaque fell from 109 to 26 centiloids during the trial, approximately the threshold for amyloid-negativity. During the gap, it reaccumulated at a rate of about 4 centiloids per year; this is similar to the rate of plaque buildup in an early AD population. The clinical benefit, as measured by iADRS and CDR-SB, was sustained during the gap, with lines continuing to slightly diverge compared to the 43 people who received placebo.

Meanwhile, the rate of tangle buildup had slowed during donanemab treatment by as much as 60 percent in frontal cortex, and somewhat less in neocortex. Eighteen months after the end of the trial, tangles continued to accumulate at this slower rate in people who had received donanemab. The findings hint at sustained benefit, though there was no tau PET data from the previous placebo group as a comparator.

Curiously, plasma p-tau217 showed a different profile from tangles. It fell about 20 percent during treatment and stabilized at that level for the next 18 months. This may be because p-tau217 reflects plaques more than tangles (Mar 2020 news; Aug 2022 conference news; Dec 2022 conference news).

Evans noted that the ongoing donanemab Phase 3 extension study will offer a deeper look at long-term effects, as participants will be rolled into that long-term extension with no gap, no unblinding of treatment groups, and more tau PET data. Top-line results from that study are expected to read out in June, hence LTE data are still several years away.

Time to Heal? A model of amyloid immunotherapy suggests that plaque clearance phase is followed by recovery and improving brain health (blue), resulting in a flattening of the trajectory of clinical decline (green). [Courtesy of Roger Nitsch.]

Complementing these data, Roger Nitsch of Neurimmune, Switzerland, presented four-year findings from the Phase 1b Prime extension study of aducanumab. He noted this is the first four-year immunotherapy data to be discussed. Biogen showed three-year data from this trial five years ago, and the few remaining Prime participants have since been folded into Biogen’s ongoing Embark extension trial, with some of them now approaching a decade of treatment (May 2018 news; Nov 2021 conference news). In the Prime extension study, the placebo group was shifted to a low dose of 3 mg/kg aducanumab, as was the initial 1 mg/kg treatment group. The other treatment groups, of 3, 6, and 10 mg/kg remained on those doses throughout the extension. The numbers of participants remaining in the study at four years was about a dozen per treatment group.

Small as they are, the data separated cleanly by dose, with those on the lower doses continuing to steeply decline on the CDR-SB. By contrast, the 18 people taking 10 mg/kg cleared more amyloid than the other groups, and their CDR-SB scores leveled out into a shallower trajectory, seeming to stabilize at year four. At the end of the study, the highest-dose group scored 4.5 points better on the CDR-SB than did the lowest-dose groups. Clinical outcomes improve with higher dosing and treatment duration, Nitsch concluded.

To Nitsch’s mind, the data evoke a model of amyloid immunotherapy that might progress in three stages: 12 to 18 months of amyloid clearance, followed by a phase of lessening neurotoxicity where biomarkers worsen more slowly compared to untreated patients and, finally, a stabilization phase where cognitive decline might level out. In this model, interrupting the amyloid cascade would allow gliosis to subside, resilience mechanisms to kick in, and the brain to—dare we say—heal.

Future data will help determine whether the aging brain has such capacity. Nitsch noted that more than 6,000 people have taken part in trials of aducanumab, donanemab, and lecanemab to date. Many of them are now in long-term extension studies. In addition, secondary prevention studies such as AHEAD 3-45, DIAN Tau NexGen, and Trailblazer-Alz3 enroll thousands more (Jul 2021 news; Nov 2021 conference news). The field should soon have more concrete answers to the question of long-term benefits.—Madolyn Bowman Rogers