Fully Loaded: Secondary Prevention Studies of Lecanemab, Donanemab

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2024 - 17th:

Anti-amyloid antibodies lecanemab and donanemab are in clinical use now, but that does not mean research on them has stopped. At the Clinical Trials on Alzheimer’s Disease conference, held October 29-November 1 in Madrid, speakers updated the audience on new or ongoing studies. For lecanemab, they focused on the secondary prevention trial AHEAD 3-45, now fully enrolled. They showed how plasma prescreening panned out, along with preliminary baseline data for this population. Likewise, donanemab’s secondary prevention trial Trailblazer-Alz3 finished enrolling; its baseline data showed that it captured a slightly different population than did AHEAD, with less genetic risk.

  • Secondary prevention trial AHEAD 3-45 is full.
  • Ditto for donanemab’s Trailblazer-Alz3.
  • New antibody remternetug is enrolling Phase 3.

On new studies, Lilly scientists presented efforts to gather real-world data on donanemab’s effectiveness, and debuted the Phase 3 trial design for donanemab’s successor, remternetug, which patients can inject under the skin.

During CTAD, news broke that Eisai had completed its Food and Drug Administration submission for subcutaneous lecanemab. This formulation would be given as a weekly maintenance dose of 360 mg, after people have finished their intravenous course. Previously, Eisai had requested approval for IV maintenance dosing, as well (May 2024 news). And days after CTAD, news broke that European regulators reversed their July 2024 rejection of lecanemab, and are now recommending approval (EMA release).

Preclinical Populations. On the plaque accumulation curve (red), the A3 cohort (orange circle) is at an earlier stage than the A45 cohort (red circle). [Courtesy of Paul Aisen.]

Lecanemab Secondary Prevention Study Now Fully Enrolled
Lecanemab was approved for people with mild cognitive impairment or mild dementia due to Alzheimer’s, but trial data show it works better if given earlier. The AHEAD 3-45 study, a pair of sister trials, homes in on this point, testing lecanemab’s ability to delay the onset of symptoms. Both trials enroll cognitively healthy people with plaque in their brains; in A3, they have between 20-40 centiloids, in A45, they have more than 40 (Nov 2020 conference news).

Because finding people with preclinical AD requires testing huge numbers of healthy ones, trial leaders prescreened with a blood test, using the ratio of p-tau217 to non-phosphorylated tau217 to predict amyloid positivity. Previously, they had reported that this screened out two-thirds of potential participants (Aug 2021 conference news; Nov 2021 conference news).

In Madrid, Reisa Sperling of Brigham and Women’s Hospital, Boston, shared a final look at the screening process for AHEAD, which finished enrolling in October. The plasma p-tau217 ratio, when combined with the plasma Aβ42/40 ratio, age, and APOE genotype, identified people with amyloid plaque with an AUC of 0.95. Among the one-third of screened participants who were positive on this marker and went on to get an amyloid PET scan, around 60 percent qualified for the trial—a big improvement over the 25 percent success rate of PET scans before plasma prescreening, Sperling said.

Between the amyloid loads of 5 to 100 centiloids, the plasma p-tau217 ratio (p-tau217r) rose in tandem with plaque, enabling Sperling’s team to adjust the p-tau217r cutoff to select for different amounts of amyloid burden. When trialists used a higher cutoff to identify people specifically for the A45 study, 75 percent of those who passed plasma screening also qualified by PET. Most had plaque loads between 40 and 100 centiloids, but a few of these cognitively healthy adults had more, going as high as 160 centiloids, Sperling said.

At the other end of the scale, people who were amyloid-positive below 20 centiloids are being followed in the APEX observational study. Altogether, study personnel screened 20,721 people and performed 4,443 PET scans to find 1,621 participants; 448 are enrolled in A3, 1,173 in A45. By comparison, in the A4 study, 4,600 scans were needed to find 1,169 participants, a 25 percent success rate (Mar 2023 news).

Other scientists in Madrid likewise reported success with plasma p-tau217 prescreening—for example, in a trial of the anti-tau antibody posdinemab, this step halved the number of PET scans needed (Nov 2024 conference news).

Paul Aisen, University of Southern California, San Diego, presented baseline characteristics of the A3 and A45 trial populations. In A3, the average age is 68; in A45, 70. In both studies, almost two-thirds of participants are women; most are college-educated. Eighty percent have a family history of dementia, 73 percent carry at least one APOE4 allele. All have a baseline global CDR of 0. That said, around 10 percent of both cohorts have slight decline on the CDR-SB, with a score of 0.5 or 1 on this more sensitive measure, indicating the total AHEAD population is not completely asymptomatic.

Racial and ethnic minorities comprised more than a quarter of the screening population; alas, they were more likely to have negative amyloid scans, hence 90 percent of the final participants were once again white.

What about tau PET? Many participants had positive scans, Sperling reported. In the A3 group, tangle accumulation in the medial temporal lobe was common, less so in the neocortex. The A45 group had a higher tangle load in both the MTL and neocortex. Higher tangle loads correlated with subtle cognitive deficits on the PACC5 cognitive test, though the relationship was weak, at r=0.13 for MTL tau and 0.16 for neocortical tau, Sperling said.

The trials will run for four years. Aisen noted that in both, participants will be randomized evenly to placebo or lecanemab, and will titrate up, receiving 5 mg/kg for two months, 10 mg/kg thereafter. The main difference between the studies is that A3 participants, who have less plaque, will get a single monthly dose throughout the trial, while A45 participants will get doses every two weeks for the first two years, monthly thereafter. After four years, participants will transition to a 12-week, open-label extension, in which everyone will receive biweekly doses again, so that former placebo patients get effective plaque clearance, Aisen told Alzforum.

Because lecanemab is an approved therapy for early symptomatic AD, participants who develop cognitive problems during the trial may enter the OLE early. To qualify for that, participants must score higher than 0 on the CDR at two successive visits, and be judged to have MCI or mild dementia by a site clinician.

For A3, which is a Phase 2 trial, the primary outcome will be amyloid PET, with tau PET secondary and the PACC5 and other cognitive tests exploratory. For A45, a Phase 3 trial, PACC5 is the primary outcome, with amyloid and tau PET secondary. This trial also measures plasma and cerebrospinal fluid markers, additional cognitive tests, and participant self-reports.

Reaching Farther. The decentralized design of Trailblazer-Alz3 allowed researchers to recruit people from more U.S. states (right) than did the A4 trial (left). [Courtesy of Eli Lilly.]

Donanemab Secondary Prevention Study Tries Decentralized Design
Donanemab has its own prevention study, Trailblazer-Alz3, run by Eli Lilly. It finished enrolling in August 2024. Previously, the company had reported that participants will receive nine monthly infusions of donanemab or placebo, with the primary outcome being time to clinical worsening on the CDR. The trial will follow participants until 350 of them have progressed in this way (Aug 2024 conference news).

In Madrid, Lilly’s Karen Holdridge fleshed out details. To find enough participants, including people in remote areas, the trial used a decentralized design whereby initial cognitive screening happened via the modified telephone interview for cognitive status (TICS-m), and amyloid positivity was determined by a p-tau217 blood test. Holdridge noted that Lilly went out into community settings to find people, manning mobile research units and drawing blood at health fairs. Participants received tablets on which to take cognitive tests at home every six months. This design allowed Lilly to enroll people from 40 U.S. states. Compared with previous trials, that is better geographic representation, particularly in the American south and west (image above). “We cast a broad net,” Holdridge noted.

Screen failures were higher than in AHEAD 3-45, with about 80 percent of prospective participants disqualified by the plasma p-tau217 screen. In total, study personnel screened 63,124 people in the U.S. and Japan to find 2,196 participants. Curiously, 499 of them dropped out before beginning infusions, leaving 1,697 people in the trial.

Participants are 70 years old on average; two-thirds are women, and most have completed college. As in AHEAD 3-45, racial and ethnic minorities were more likely to be amyloid-negative, generating a final cohort of 90 percent non-Hispanic whites. Half the participants have an AD family history, lower than the 80 percent in AHEAD 3-45. All were genotyped for APOE; nearly half are APOE4 heterozygote, 8 percent homozygote, again lower than AHEAD’s numbers. Participants can choose whether to find out their genotype from a genetic counselor.

Earlier Population. In the Trailblazer-Alz3 cohort (left), participants with a CDR of 0.5 have less plaque (top) and fewer tangles (bottom) compared with CDR 0.5 participants in the Phase 3 Trailblazer-Alz2 trial (right). [Courtesy of Eli Lilly.]

Unlike in AHEAD 3-45, not all Trailblazer-Alz3 participants are cognitively normal at CDR 0. Because the TICS-m was used for screening, about one-third of the cohort is CDR 0.5, which is considered mild cognitive impairment. Even so, Holdridge said the methodology captured an earlier AD population than did donanemab’s Phase 3 trial, Trailblazer-Alz2.

This was borne out by baseline amyloid and tau PET scans done in substudies of 432 people opting for amyloid PET, 331 for tau PET. On amyloid scans, people who were CDR 0.5 had an average of 71 centiloids, similar to the 63 centiloids in the CDR 0 group. This compares with 103 centiloids for the CDR 0.5 group in Trailblazer-Alz2. On tau scans, those at CDR 0.5 averaged 1.1 SUVR—a little higher than the 1.04 in the CDR 0 group but lower than the 1.31 in the CDR 0.5 group in Trailblazer-Alz2 (image above). Scientists in Madrid agreed with Holdridge that this is a different population than other antibody studies have enrolled, with fewer genetic risk factors.

In addition to this prevention study, Lilly is running two trials to collect real-world evidence on donanemab’s safety and effectiveness. In Madrid, Lilly’s Ann Hartry described them. One, dubbed Platform for Early Alzheimer’s in Real Life (PEARL), invites clinicians in the U.S. to refer patients on immunotherapy to the study; screening and data collection are done remotely. Much of the data collection is passive, leveraging Medicare claims to gather demographics, diagnoses, test results, and treatments. The study will gather five years of retrospective data and five years of prospective data for each participant. Hartry categorized this as “low-touch” yet able to collect regulatory-grade data.

The other one, Trailblazer-Real US, will compare how patients on donanemab or standard Alzheimer’s care fare after five years. The primary outcome will be time to the first loss of independence. The study will also measure neuropsychiatric status and caregiver burden.

Donanemab was approved for clinical use in the U.S. in July, and is ramping up slowly, with an estimated 700 patients now on it. Joy Snider at Washington University in St. Louis noted that, as with lecanemab, institutions have to build infrastructure to start administering. These include hospital formulary approval, pharmacy and infusion center training, and electronic medical record order sets. At WashU, this will be finalized as of November 20, after which infusions can begin. Snider believes that, once available, some patients will opt for donanemab over lecanemab. “Many patients are looking for less frequent infusions, so the monthly [dosing] versus biweekly for lecanemab will be attractive, as is the idea that you can stop infusions after 18 months,” she wrote to Alzforum.

Remternetug Enters Phase 3
Donanemab may soon face competition from within Lilly itself. The company’s successor molecule, remternetug, targets the same amyloid species as donanemab but removes plaque faster while triggering fewer anti-drug antibodies or infusion reactions. Unlike donanemab, remternetug has been designed to be injected under the skin (Apr 2023 conference news).

In Madrid, Kevin Biglan at Lilly described a new, global Phase 3 trial, Trailrunner-Alz3. Enrollment began in October, with a goal of recruiting 1,200 people between 55 and 80 who have preclinical AD or mild cognitive impairment. To capture an early population, researchers have set cutoffs of 27 or higher on the MMSE, and below 6 on the FAQ. Screening for amyloid positivity will be by way of Lilly’s plasma p-tau217 test.

Like the donanemab prevention study, Trailrunner-Alz3 will be decentralized, where participants self-administer doses at home and will have options for where to get MRI scans. Cognitive tests will be sent to a single center to be rated, reducing variability.

Participants will take remternetug or placebo for 18 months, followed by an observation period during which participants will stay blinded and get cognitive assessments every six months. The primary outcome will be time to clinical worsening on the CDR, with other cognitive tests as secondary outcomes. The trial will include an amyloid and tau PET substudy with 400 participants. Once enough people have worsened, Lilly will lock the data and invite participants into an OLE, where the placebo group will get access to remternetug.

One detail of this study caused some consternation in Madrid. Biglan noted that the trial will not exclude people who have had previous amyloid immunotherapy, so long as that therapy concluded more than five antibody half-lives before screening. One audience member pointed out that because the trial does not measure baseline amyloid load, it might be hard to quantify remternetug’s effect in a mixed population where some participants have little plaque. Biglan said Lilly plans to “front-load” its PET substudy to get a better idea of baseline loads.

Remternetug is being tested in the Dominantly Inherited Alzheimer Disease Trials Unit’s primary prevention trial (May 2024 news; Aug 2024 conference news).—Madolyn Bowman Rogers.

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Remternetug
  4. Posdinemab

News Citations

  1. Gaining a Foothold: Amyloid Immunotherapy in Clinical Practice
  2. BAN2401 Forges AHEAD into Phase 3, Preclinical AD
  3. Lecanemab Post Hoc: Is Continual Treatment Required for Cognitive Benefit?
  4. Plasma Aβ—First Sign of AD, But Tough to Measure Prospectively?
  5. Legacy of A4 Secondary Prevention Study Goes Beyond Negative Result
  6. Finally, Therapeutic Antibodies Start to Reduce Tangles
  7. Questions, Questions for Donanemab, Lecanemab
  8. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
  9. First Success Stories From Alzheimer’s Secondary Prevention Trial

External Citations

  1. submission
  2. EMA release

Further Reading

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