First Success Stories From Alzheimer’s Secondary Prevention Trial

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

Often in medicine, case studies, their lack of statistical power notwithstanding, tell a more dramatic tale than summary data. In the first secondary prevention trial run by the Dominantly Inherited Alzheimer Network Trials Unit, overall findings were hopeful, but not a home run. As discussed at the Alzheimer’s Association International Conference, held July 28 to August 1 in Philadelphia, nearly two dozen mutation carriers who took gantenerumab for eight years had half the risk of developing symptoms as did untreated controls (see previous story in this series). Breaking open these group averages, however, the study showcases that at least in a few pioneering people, AD prevention is currently happening.

  • In some dominantly inherited AD mutation carriers, amyloid immunotherapy prevented tangles.
  • In others with mild symptoms, lowering plaque restored memory to normal.
  • New trials in this population will test the effects of complete plaque clearance.

In Philadelphia, Tammie Benzinger of Washington University in St. Louis highlighted the stark effects immunotherapy can have on amyloid and tau PET scans. Benzinger contrasted two participants. One started the double-blind study while being amyloid- and tau-negative, but received placebo. By the beginning of the OLE, this person had become positive on both scans and, even on high-dose gantenerumab, plaques and tangles continued to worsen. The other person started the double-blind study with a low amyloid load and no tangles, and received gantenerumab. By the beginning of the OLE, this person had fallen below the amyloid positivity threshold. During the OLE, sub-threshold plaques vanished, and tau PET remained negative.

Some people’s memories improved on treatment. Alireza Atri of the Banner Sun Health Research Institute in Sun City, Arizona, discussed one person who started the trial on gantenerumab. During the gap year, they reached their family’s estimated year of onset (EYO), and began to have memory problems, with CDR going from zero to 0.5. After resuming treatment with gantenerumab, the CDR fell back to zero. At the end of the OLE, the person was six years past EYO with normal cognition, even though their final amyloid load was slightly higher than at the start of the trial 10 years earlier.

Consider this case: Another person started the OLE almost 10 years past EYO with a CDR of 0.5. For this participant, too, CDR dropped back to zero during the OLE and has remained there, now at almost 12 years past EYO. Though the person’s amyloid load has fallen, it remains above the positivity threshold. Atri did not show tau PET scans for these cases. Other studies have closely correlated tangles with cognitive decline.

At the Dominantly Inherited Alzheimer Disease Family Conference held before AAIC, personal stories added poignancy to these data. They reveal how, for the trailblazers to plunge into these trials, small twists of fate can lead to heartbreakingly different outcomes. One woman said her husband remained cognitively healthy throughout the placebo-controlled portion of the trial, though he was six years past EYO by its end. Then during the gap year, he declined rapidly, and had to enter a care facility. He no longer qualifies for antibody treatment. His wife believes he was on gantenerumab in the trial and that it granted him an extra six years of quality life. She mourns that he lost ground so fast when the study ended.

Other participants continue to do well. One woman, now two years past EYO and still cognitively healthy, said she hadn’t realized how much dread was weighing on her until she passed that milestone. With no idea how much time she may have left, she is preparing for future memory problems. “I’m in stoppage time,” she quipped, using a soccer term. Another woman has paid for private amyloid PET scans to track her progress because DIAN does not disclose research results. Now past her EYO, she is amyloid-negative and remains healthy. She and others now live to see how much time treatment has bought them.

Some DIAN participants remain skeptical of how much trials will help, but are stepping up anyway. Many do not yet know their mutation status. In DIAN trials, the placebo-controlled portion does not require genetic testing, and noncarriers are put on placebo. Alas, subjecting noncarriers to the side effect risk of amyloid antibodies is unethical, hence open-label treatment is only for carriers. Some agonize over whether they are ready to learn their status. “I’m torturing myself about getting tested,” one man said, explaining, “I know how the movie ends.”

Helping to navigate these issues is one of the goals of Youngtimers, a nonprofit founded to support families with autosomal-dominant AD. The organization provides practical resources, such as information about genetic testing, long-term care insurance, the use of IVF to avoid passing on the mutation, and grief counseling. It offers emotional support as well, creating a space for people to connect with others going through the same things. Currently, Youngtimers is raising funds to expand mental health support for participants at the network’s sites, as ADAD is known to wreak havoc in families struggling to cope. In addition, the organization advocates for patients, so their concerns can improve clinical trial design. “Youngtimers gives a platform for families to have a voice,” said co-founder Lindsay Hohsfield, a research professor at the University of California, Irvine.

Ultimately, many DIAN participants are looking beyond their own welfare. As one man still shy of his EYO said, “I hope to be part of the solution for ending Alzheimer’s.”

Testing Prevention Paradigms
How much more time could treatment buy people who inherit an AD mutation? Randall Bateman of WashU presented two possible models in Philadelphia. If Alzheimer’s worsens at a steady rate, then a 50 percent slowing in decline at presymptomatic stages would grant people five more years prior to dementia. However, if instead there is a threshold at which degeneration takes off beyond the reach of anti-amyloid therapy, a 50 percent delay in reaching this tipping point could result in 15 more years of cognitive health. Recent data support the latter hypothesis, tying an inflection point to the spread of tangles into the neocortex. This has been dubbed the “cataustrophe” by Keith Johnson at Massachusetts General Hospital, Boston (Apr 2022 news; Apr 2023 conference news).

Future trials will show which, if any, of these models is correct. They will also answer questions such as what happens with continued treatment after plaques are gone, and what switching from one anti-amyloid therapy to another will do. Three trials are now underway in the DIAN cohort.

For former DIAN-TU-001 participants, the researchers offer the Amyloid Removal Trial. ART is a five-year, open-label study of lecanemab. It will test whether plaques can be fully removed in mutation carriers, and how that affects downstream biomarkers and longer-term disease progression. ART will also examine long-term safety and rates of ARIA (see upcoming conference story). The first ART participant was dosed in June, and the trial will be fully enrolled by early 2025.

The Tau NexGen trial evaluates combination amyloid and tau treatments in DIAN participants who are within 10 years of their EYO in either direction (Nov 2021 conference news). The trial is ongoing. Its first arm, testing Eisai’s anti-tau antibody E2814 along with lecanemab, is challenging for its participants, as both antibodies require infusions. Even so, it is fully enrolled, with 197 participants. At the family meeting, several people spoke of their dedication to making this their “full-time job” in order to save their children. Two additional tau drugs for the other arms have yet to be selected. Enrollment for these portions of the trial remains open.

For mutation carriers more than 10 years younger than EYO, the DIAN-TU is starting up its much-delayed primary prevention trial. DIAN personnel previously announced they had chosen remternetug as the drug (May 2024 news). A successor to donanemab, remternetug has fewer side effects and clears plaque faster, an advantage in dominantly inherited AD where amyloid production is in overdrive (Apr 2023 conference news). 

In Philadelphia, Eric McDade of WashU offered new details on the study design. The trial will enroll 240 mutation carriers and noncarriers, who can be as young as 18. These younger ages create tough choices for some, because whether remternetug affects pregnancy has not been studied. Women will have to defer starting a family while in the trial. Youngtimers raised this issue, and McDade listened. As a result, the placebo-controlled portion of the trial will last only two years, enabling more young women to participate and still have time to start their families.

This trial is easier on the participants than Tau NexGen. They will inject remternetug under their skin once every three months. The primary outcome will be amyloid PET, with fluid biomarkers as secondaries. After the placebo-controlled portion ends, participants will have the option to enter a four-year open-label extension, which will require learning their mutation status. In this portion, cognition will be added as a secondary outcome. The trial will begin dosing next year in the U.S., Canada, U.K., and Europe, and in 2026 in Australia and Latin America.

Outside of McDade’s talk, AAIC this year featured no news on remternetug, whose separate LOAD Phase 3 trial is enrolling.

Janice Smith at Roche, the maker of gantenerumab, noted that the DIAN data has been “hugely informative” for the company, helping it to select biomarkers for other trials. The company has been heartened by the signs that dementia can be delayed or perhaps prevented. “These data encourage us to go early,” Smith said in Philadelphia. For its part, Roche is betting on gantenerumab’s successor trontinemab, a Phase 1/2 antibody that looks to quickly remove plaques without causing ARIA. It also has a Phase 2 γ-secretase modulator that may one day become interesting for dominantly inherited Alzheimer’s, too (see upcoming story).—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Gantenerumab
  2. E2814
  3. Remternetug
  4. Donanemab
  5. Trontinemab
  6. RG6289

News Citations

  1. Living Among Us: People Whose Alzheimer’s Is Already Being Prevented
  2. From Near and Far, Aβ Beckons Tau to Tangle in the Cortex
  3. What Happens After Amyloid Plaque Removal? Who Benefits Most?
  4. Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists
  5. Gaining a Foothold: Amyloid Immunotherapy in Clinical Practice
  6. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle

External Citations

  1. Youngtimers

Further Reading

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