Questions, Questions for Donanemab, Lecanemab

Series - Alzheimer's Association International Conference (AAIC) 2024:

As amyloid immunotherapy is being rolled out, mostly in specialty care thus far, both treating physicians and researchers have many questions about it. Scientists at the Alzheimer’s Association International Conference, held last month in Philadelphia, offered a glimpse at some answers. For the FDA-approved donanemab, it appears that baseline amyloid load best predicts when to stop dosing, and that it may tell the doctor what the right time point might be to confirm with a second PET scan that the amyloid is gone. 

  • Donanemab is being trialed in the Colombian kindred, Down’s syndrome.
  • Baseline plaque load best predicts amyloid clearance on donanemab.
  • The fluid biomarker MTBR-243 tau tracks tangle response to lecanemab.
  • The relationship between plaque clearance and cognition is fuzzy.

Lilly also presented a few trial updates, including a new one in Down’s, details about its Trailblazer-Alz3 study, and that donanemab is going to be evaluated in the Alzheimer Prevention Initiative’s Colombian cohort.

For lecanemab, scientists at AAIC highlighted the promise of the fluid tau marker MTBR-243 to track tangle load, and they modeled how plaque clearance relates to cognitive benefit in an attempt to address a nagging question about this relationship.

See, You’re Negative. In donanemab trials, participants were amyloid-positive (gold) at baseline (top), and amyloid-negative by the end of the trial (middle). These latter scans were indistinguishable from those of people who never had amyloid (bottom), showing that visual reads could be used to determine a patient’s amyloid is gone. [Courtesy of Eli Lilly.]

New Donanemab Trials
First, the news. Robert Alexander of Banner Alzheimer’s Institute in Sun City, Arizona, reported that API has picked donanemab as the next drug to test in the large Colombian kindred who carry the Paisa presenilin 1 mutation that causes AD in mid-life. The first drug tested in this cohort, the oligomer-specific antibody crenezumab, nudged cognitive, imaging, and fluid biomarkers in the right direction but missed statistical significance (Jun 2022 news; Aug 2022 conference news). Ever since dosing in this study ended, a year and a half ago, participants have been waiting for the next opportunity (Dec 2022 conference news).

That will be donanemab. Donanemab targets plaque and mops it up fast. This may be an advantage in dominantly inherited AD, where fibrils also accumulate fast. Alexander said the study will enroll both mutation carriers and noncarriers, so that participants need not find out their mutation status. Noncarriers will be on placebo throughout the trial, taking both a pill and an infusion. For carriers, the trial will have two stages. In part one, all carriers will receive donanemab, plus a placebo pill. Amyloid PET scans will be done at baseline, nine, and 18 months. Once a person’s plaque load has fallen below 11 centiloids, they will transition into the second part of the study. All carriers will move to part two by 18 months. “Essentially, we’re trying to get everyone to the same baseline,” Alexander said. Below 11 centiloids baseline, that is.

In part two, scientists will swap the placebo pill for an active small molecule in carriers. They will use a factorial design with four treatment groups. One group will be randomized to the active molecule alone, one to donanemab alone, one to both, and one to placebo only. Placebo controls will be used for both drugs, so participants will not know their group. The idea is to learn which treatment best staves off plaque resumption, biomarker change, and cognitive decline in the years after donanemab has removed participants’ baseline amyloid. This trial may also help answer the niggling question of whether continued donanemab treatment after plaque clearance would be beneficial.

Alexander did not discuss what type of small molecule might be used. Roche is evaluating a γ-secretase modulator, RG6289, in Phase 2a (Aug 2024 conference news). Despite efforts to reactivate BACE inhibitors for low-dose treatment to keep amyloid formation at bay, none have re-entered clinical trials as yet.

In his talk, Alexander also offered small updates on Trailblazer-Alz3. This secondary prevention trial has been in the works for three years (Jul 2021 news). It is now fully enrolled, with 2,600 participants across the U.S. and Japan. All were cognitively healthy at baseline, posting a CDR of zero. Their amyloid positivity was confirmed via plasma p-tau217 rather than amyloid PET, simplifying enrollment and lowering cost.

All participants will receive nine monthly infusions of donanemab or placebo. The primary outcome is the time until they develop mild cognitive impairment as per a CDR 0.5 on two consecutive tests. The trial needs to record 350 such events to reach statistical significance. According to Alexander, the trial will genotype APOE, with disclosure optional, and include amyloid and tau PET substudies, using florbetapir and flortaucipir. The trial is expected to run until 2027.

Finally, Eli Lilly is now evaluating donanemab in Down’s. People with this syndrome inherit three copies of the amyloid precursor protein, and have a 95 percent lifetime risk of developing AD dementia. Because of this,  the new clinical staging criteria for AD consider DS “stage 0,” along with familial ADAD mutations (Aug 2023 conference news). DS advocates have been demanding that immunotherapy be studied and made available to their loved ones. Michael Rafii of the University of Southern California will lead this Phase 4 trial to test safety and efficacy of escalating doses of donanemab versus placebo.

For these patients, safety is a particular worry in the design of an immunotherapy trial. A recent paper from scientists led by Lei Liu at Brigham and Women’s Hospital, Boston, examined binding of lecanemab to postmortem tissue sections from 15 DS brains. Donors were between 43 and 68 years old when they died. In each case, lecanemab detected parenchymal plaques, but also bound strongly to blood vessels, suggesting the presence of extensive cerebral amyloid angiopathy, the main risk factor for ARIA (Liu et al., 2024; Aug 2023 conference news).

In Philadelphia, Donna Wilcock of Indiana University, Indianapolis, a co-author on the paper, added that people with DS have an exacerbated inflammatory response and white-matter changes at baseline (Aug 2023 conference news). “They have a much greater risk of ARIA. I’m very concerned,” Wilcock said. One solution could be to start immunotherapy earlier in these patients, before CAA has formed, she suggested.

How Does the Doctor Determine When to Stop Donanemab?
Aside from describing new trials, talks in Philadelphia shed light on questions researchers want answered. Lilly’s Emily Collins addressed how to know when patients on donanemab should get a second amyloid PET scan to determine if their plaque is gone. Analyzing Phase 3 trial data, she found the best predictor for that was baseline plaque load. People who had completely cleared plaque by six months had started with an average of 85 centiloids; people who cleared it by one year, 104 centiloids; and by 18 months, 116. Thus, a patient’s baseline load could provide a rough guideline for clinicians on when to check for amyloid negativity. Collins noted that amyloid-negative scans from the Trailblazer trials resemble those from ADNI participants who never had amyloid, suggesting that visual reads would suffice to determine clearance (image above).

Will determining amyloid clearance always require expensive PET scans? Research has advanced plasma p-tau217 as an alternative indicator of brain amyloid. This blood-based biomarker predicts presence of plaques with high accuracy, and in trials it dropped as plaques were cleared (Dec 2023 conference news; Aug 2024 conference story). Alas, it may not be that straightforward. In donanemab trials, plasma p-tau217 did not predict amyloid negativity, Collins reported, its AUC of 0.55 being little better than chance. This could be because plasma p-tau217 also reflects tangle load, which plaque clearance barely budged, Collins said.

Tangle Trend? In the Clarity AD trial, MTBR-243 rose more slowly in the CSF of patients on lecanemab (green) than in those on placebo (black). [Courtesy of Kristin Wildsmith, Eisai Inc.]

Can a Fluid Biomarker Track Tangles?
Right as immunotherapies are entering clinical care, the toolbox of fluid-based tau markers is expanding, and scientists are intensely interested in using them to track what immunotherapy does to tangle load, which correlates more strongly with cognition. In her talk, Kristin Wildsmith of Eisai presented evidence that lecanemab slows accumulation of neurofibrillary tangles. Wildsmith and colleagues, including Kanta Horie at Washington University, St. Louis, used cerebrospinal fluid MTBR-243 as a proxy for tangle formation. Previously, Horie had found that levels of this tau fragment, which spans the microtubule binding region, correlate closely and linearly with tau PET, unlike other AD markers, such as p-tau217 (Dec 2020 news; Aug 2023 conference news). Wildsmith believes the fragment sheds from tangles as they form, leaking into the CSF.

In the Clarity AD Phase 3 clinical trial, tau PET signals trended higher in people on placebo, hinting that lecanemab slows tangle accumulation. Could CSF MTBR-243 detect this? Wildsmith showed data from a subset of 167 people in the 18-month trial who had CSF samples at baseline and follow-ups. At the trial’s start, CSF MTBR-243 correlated tightly with the tau PET signal across all six Braak stage regions. By 18 months, CSF MTBR-243 had inched up 23 percent in the 83 people on placebo and 14 percent in the 84 people on lecanemab (image above). The difference was not statistically significant, which Wildsmith attributed to the small sample size.

She noted that the trajectories resembled what was observed using tau PET. The data strengthen evidence that MTBR-243 might eventually become a fluid biomarker for tangles (see also Aug 2024 conference news).

It’s Not Just Amyloid. Modeling from Eisai shows that amyloid and non-amyloid pathways both affect cognition. Amyloid pathways act early and gradually, non-amyloid late and fast. [Courtesy of Eisai.]

How Does Plaque Removal Relate to Cognition?
Another burning question is how amyloid clearance correlates to cognitive benefit at the level of individual participants. Many scientists have asked to see spaghetti plots of the data. In Philadelphia, Eisai did not show such data. Brian Willis of Eisai told the audience that such plots are not very informative because the relationship between plaque clearance and cognition is complicated. As disease worsens, factors other than amyloid, such as tangles and synapse loss, exert an ever-greater effect on memory (image above). The more plaque a person starts with, the further along in disease they already are and the faster their cognition declines from there because more non-amyloid processes contribute. At the same time, the more plaque a person starts with, the more amyloid immunotherapy removes, confounding clearance and cognition data. As a result, the overall relationship is murky, with individual-level outcomes appearing as “data clouds” instead of linear relationships, noted Eisai’s Michael Irizarry.

Exposure-Response. Integrating pharmacokinetics of amyloid accumulation and clearance, with the effect of both amyloid- and non-amyloid-driven processes on cognition, Eisai’s model predicts amyloid-driven progression to be linear only between 0 and 105 centiloids. [Courtesy of Eisai.]

Eisai scientists created an exposure-response model that takes confounding factors into account. Willis said the model uses data from Phase 2 and 3 lecanemab studies and their open-label extensions, comprising 4,575 amyloid PET scans and 8,456 CDR-SB scores. It also incorporates what is known about the pharmacokinetics of plaque buildup and degradation, and includes a function for non-amyloid-driven cognitive decline. This type of decline kicks in at plaque loads above 105 centiloids, the scientists calculated. Between 0 and 105 centiloids, plaque accumulation correlates roughly linearly with amyloid-driven disease progression, allowing scientists to model the exposure-response relationship within this range (image above).

When tested against Phase 3 trial data, the model predicted a slowing of cognitive decline of 0.43 points on the CDR-SB at 18 months, close to the actual value of 0.45. Extrapolating forward, the model predicted that three years of treatment would slow decline by 1.45 points; four years, by 2.15. Because there are no placebo-controlled data past 18 months, these predictions cannot be verified.

Willis said the model could be used to predict a given person’s immunotherapy result. For someone who started with 40 centiloids of plaque, 18 months of lecanemab would affect their CDR-SB by less than a quarter of a point—a tiny effect. However, because the person is at an early disease stage with slow decline, this would represent a 40 percent slowing of progression. For someone who started with 80 centiloids, 18 months of treatment would slow decline by half a point on the CDR-SB, which would represent only 31 percent slowing of progression. As with modeling from other antibody programs, the data emphasize the importance of treating early.—Madolyn Bowman Rogers and Tom Fagan

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References

Therapeutics Citations

  1. Donanemab
  2. Leqembi
  3. Crenezumab
  4. RG6289

News Citations

  1. API Colombian Trial of Crenezumab Missed Primary Endpoints
  2. Crenezumab Secondaries Negative; Gantenerumab OLE Hints at Efficacy
  3. Gantenerumab Mystery: How Did It Lose Potency in Phase 3?
  4. How Presenilin Mutations Hobble γ-Secretase Predicts Onset, Progression
  5. Can Donanemab Prevent AD? Phase 3 TRAILBLAZER-ALZ3 Aims to Find Out
  6. Revised Again: Alzheimer's Diagnostic Criteria Get Another Makeover
  7. Is ARIA an Inflammatory Reaction to Vascular Amyloid?
  8. At the Heart of Alzheimer’s in Down’s: Cerebrovascular Disease
  9. Two New p-Tau217 Blood Tests Join a Crowded Field
  10. In Head-to-Head Testing, P-Tau217/Tau217 Comes Out on Top. By a Hair.
  11. MTBR-243 Tau: A Fluid Biomarker for Tangles Themselves?
  12. CSF MTBR-tau-243 Tracks Tangles, Plummets in Response to Antibody
  13. A Plasma Test for Tangles?

Paper Citations

  1. Liu L, Saba A, Pascual JR, Miller MB, Hennessey EL, Lott IT, Brickman AM, Wilcock DM, Harp JP, Schmitt FA, Selkoe DJ, Chhatwal JP, Head E. Lecanemab and Vascular-Amyloid Deposition in Brains of People With Down Syndrome. JAMA Neurol. 2024 Oct 1;81(10):1066-1072. PubMed.

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