Donanemab Mops Up Plaque Faster Than Aduhelm

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2022:

Of the four anti-amyloid antibodies that wipe out plaque, Lilly’s donanemab is the only one still in a pivotal Phase 3 trial. The field will have to wait until mid-2023 for those results, but in the meantime, researchers at the 15th Clinical Trials on Alzheimer’s Disease conference, held November 29 to December 2 in San Francisco and online, got a glimpse at fresh biomarker data. Stephen Salloway of Butler Hospital in Providence, Rhode Island, presented preliminary results from TRAILBLAZER-ALZ 4, a head-to-head comparison of donanemab and aducanumab’s plaque-clearing ability.

  • In six months of treatment, donanemab cleared four times as much plaque as did aducanumab
  • Donanemab also cut p-tau217 by a quarter, while aducanumab had no effect
  • The trial did not measure cognition, leaving unanswered whether speedier removal is better.

As expected based on earlier studies with both drugs, donanemab banished plaque more rapidly, mopping up four times as much as aducanumab did in the first six months of treatment. More than a third of people taking donanemab fell below the threshold for global amyloid positivity in this time frame.

Dawn Brooks, who leads global development of donanemab at Lilly, said the data support the idea that treatment with donanemab could be quite rapid. Once a person becomes amyloid-negative, Lilly stops dosing. Brooks believes this short course of administration will be attractive to patients, limiting the cost and burden of treatment.

Fast Start. In six months of treatment, donanemab reached full dosing faster than aducanumab and cleared far more plaque (left). As a result, plasma p-tau217 dropped on donanemab as well (right). [Courtesy of Eli Lilly.]

In the earlier Phase 2 TRAILBLAZER study, plaque plummeted on donanemab, with 40 percent of people becoming amyloid-negative by six months, and 68 percent by 18 months. Downstream biomarkers such as p-tau217 and GFAP also fell (Mar 2021 conference news; Aug 2021conference news; Oct 2022 news). These data led Lilly to test donanemab directly against aducanumab, the only anti-amyloid antibody so far approved for clinical use by the U.S. Food and Drug Administration (Jun 2021 news).

TRAILBLAZER-ALZ 4 is an open-label Phase 3 trial that enrolled 140 people with early symptomatic AD at 31 U.S. sites. Participants had an average age of 73 and MMSE of 24. Half of them received aducanumab, which was titrated according to the FDA label: 1 mg/kg for the first two months, then 3 mg/kg for two, and 6 mg/kg for two. Per this scheme, the full dose of 10 mg/kg was reached by seven months. Donanemab was titrated more quickly: 700 mg/month for the first three months, the full dose of 1,400 mg/month thereafter. The study’s primary outcome was amount of plaque removal at six months, before aducanumab had reached full dosing.

Lilly purchased aducanumab for this study. It did not include lecanemab in this comparison, partly because lecanemab is not approved, i.e., not as easily available, and partly—maybe, just maybe—because the difference in plaque removal speed might not have been as dramatic as with aducanumab.

When compared in this way, the difference in plaque removal between donanemab and aducanumab was stark. Participants on donanemab lost an average of 62 centiloids, those on aducanumab, 16. As a result, 38 percent of participants on donanemab dropped below the threshold for amyloid positivity, compared to 2 percent on aducanumab. Plasma p-tau217 tracked with plaque removal, falling 25 percent on donanemab at six months but staying flat on aducanumab.

The amount of ARIA-E was similar on each drug, around 22 percent, with the majority of those cases being asymptomatic. Salloway noted these data suggest that the speed of amyloid removal does not drive ARIA.

TRAILBLAZER-ALZ 4 collects no clinical data. This leaves unanswered the question of whether faster plaque removal is clinically better than slower removal. TRAILBLAZER 4 will continue to 18 months, allowing more analysis of how plaque removal changes over time as aducanumab dosing catches up.

Participants on donanemab will discontinue the drug once they become amyloid-negative, which Lilly defines as 11 centiloids. Some researchers have speculated that this short duration treatment may be necessary because donanemab triggers the generation of anti-drug antibodies that might dampen its efficacy over time. However, Brooks said Lilly has found no decrease in the amount of donanemab in the bloodstream over the course of 18 months of treatment, and has not needed to adjust antibody dosing within this time frame.

In donanemab's Phase 2, plaque burden took six months to creep back up over the 11 centiloids threshold after clearance. Brooks told Alzforum that p-tau217 stayed down for at least a year after dosing stopped. “We demonstrated that the change in a key downstream tau pathology biomarker was not dependent on continuing donanemab treatment, but rather was tied to the reduction in amyloid plaques,” she wrote to Alzforum.

Other scientists think a maintenance dose with an anti-amyloid antibody may be necessary. Lilly did not respond to a question regarding whether, or when, additional treatment with donanemab or another amyloid-removing drug might be needed as plaque reaccumulates.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Donanemab
  2. Aduhelm

News Citations

  1. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
  2. On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
  3. In TRAILBLAZER, Plasma GFAP Falls, but NfL Continues to Rise
  4. Aducanumab Approved to Treat Alzheimer’s Disease

Other Citations

  1. lecanemab

Further Reading

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