Legacy of A4 Secondary Prevention Study Goes Beyond Negative Result

The decade-long Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study wrapped up this month. According to top-line results announced March 8 by Eli Lilly, more than four years of treatment with the anti-amyloid antibody solanezumab did not slow cognitive decline or progression in amyloid-positive people who were cognitively healthy at baseline. Solanezumab, which targets Aβ monomers, did not dent plaque deposition either. The results were expected, given the antibody’s earlier failure to help people with more advanced disease and with dominantly inherited Alzheimer's disease.

  • Solanezumab did not slow Alzheimer’s in cognitively healthy people in the A4 study.
  • Plaque continued to accumulate, and correlated with progression.
  • The study compiled a massive dataset on preclinical AD that will be made publicly available.

Despite the negative findings, researchers called A4 itself a success, because it helps pave the way for subsequent trials of hopefully effective investigational drugs. This secondary prevention study was the first of its kind in non-genetic populations, allowing researchers to test methods for recruiting people with preclinical AD and measuring subtle cognitive decline. Not only did A4 prove such trials are feasible, but it also generated an enormous dataset that scientists think will be a treasure trove for future Alzheimer’s research. “The A4 dataset is the largest, deepest look yet into preclinical AD,” Paul Aisen at the University of Southern California, San Diego, told Alzforum. Aisen co-led the study along with Reisa Sperling at Brigham and Women’s Hospital, Boston, and researchers from Lilly.

Aisen credited the beginnings of the A4 concept to an Alzforum webinar that discussed the feasibility of running trials in preclinical populations, with the trial launching three years later, in 2013 (May 2010 webinar; Jan 2013 news). After solanezumab proved to have but a tiny effect on cognition in Lilly's Phase 3 Expedition trials in symptomatic populations, A4 researchers upped the dose in their trial fourfold. They also lengthened the duration of treatment by more than a year, hoping to eke out a therapeutic effect (Nov 2016 news; Dec 2016 conference news; Jun 2017 news).

Thanks to these adjustments, the final data are definitive, if not what researchers and trial participants were hoping for. Not only did solanezumab not help, but people on drug tended to become worse, losing an average of 1.7 points on the Preclinical Alzheimer Cognitive Composite, compared with 1.4 points for those on placebo. The difference was not statistically significant. Even so, A4 researchers are analyzing the data to determine whether depletion of Aβ monomers by solanezumab might have somehow been harmful. To start, they will look for a correlation between the fourfold dose increase and worse cognition in individuals, Aisen said.

For context, the DIAN-TU secondary prevention trial in people carrying an autosomal-dominant APP or presenilin mutation started in 2012, and in 2017 also upped the solanezumab dose fourfold after the Expedition results. In 2020, solanezumab showed no treatment benefit, even a slight worsening on some cognitive measures and the NfL biomarker in the treatment group (Apr 2010 conference news; Bateman Q&A; Scheltens comment).

The PACC was developed for the A4 study, and the final data demonstrate that it was successful in picking up decline in this very early population (Jun 2014 news). Researchers compared data from the 1,169 A4 participants with that from 529 amyloid-negative participants in the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. LEARN participants initially screened for A4, but PET scans revealed they were below the amyloid cutoff. Rather than turn these participants away, researchers enrolled them in an observational study as a comparator group. They improved on the PACC over time due to practice effects, while A4 participants declined. Likewise, A4 participants gradually worsened on the Cognitive Function Index, a test developed to detect clinically meaningful signals in people with subjective memory concerns, while LEARN participants stayed stable (Mar 2015 news). “The data confirm our ideas about what preclinical AD looks like,” Aisen said.

The findings also highlight the role of amyloid. In A4, the more plaque a person had at baseline by amyloid PET, the more likely that person was to develop AD symptoms during the trial. The relationship was statistically significant. Overall, about one-third of participants progressed to symptomatic AD. Plaque continued to accumulate similarly in people on solanezumab or placebo, going from an average of 66 centiloids to 78 in the solanezumab group and 84 in the placebo group. The difference was not statistically significant. “The data strengthen the hypothesis that amyloid is driving this very early stage of AD,” Aisen noted.

Other biomarker data from A4 are still being analyzed. They include MRI scans, tau PET, cerebrospinal fluid and plasma analysis. A4 researchers plan to present the key findings at this summer’s Alzheimer’s Association International Conference, held July 16-20 in Amsterdam. In addition, all the data, scans, and samples from A4 and LEARN will be made publicly available to other researchers, in accordance with Collaboration for Alzheimer’s Prevention guidelines (Jul 2016 news). CAP calls for trial data to be accessible within 18 months, but Aisen noted A4 investigators are aiming to have everything online within a year. Baseline and screening data from A4 (select A4 on the link) are already available, and have been downloaded some 1,500 times.

Subsequent studies, such as the AHEAD 3-45 trial of lecanemab in preclinical AD, have benefited from the lessons of A4. For example, in A4, participants were recruited based on age alone, because previous data had found that about one in three people over the age of 65 had amyloid plaque. While this worked, A4 required about 4,600 amyloid PET scans to reach its enrollment goal. In AHEAD 3-45, people are prescreened with plasma Aβ tests, cutting down the time and expense of recruitment (Nov 2021 conference news).

What will happen to the A4 participants? They have invested as many as eight years of their lives in a therapy that turned out not to work. Aisen noted that AHEAD researchers are adjusting the protocol of that study to encourage former A4 participants to join. They are also helping A4 participants find other opportunities, such as entering Lilly’s Trailblazer-Alz3 preclinical study of donanemab (Jul 2021 news).

Stephen Salloway at Butler Hospital in Providence, Rhode Island, a site investigator for A4, praised the perseverance of participants. “There is a great deal to learn from the A4 and LEARN data, and we want to again thank the wonderful dedication of the study teams and participants for making these advances possible,” he wrote (full comment below).—Madolyn Bowman Rogers

Comments

  1. I want to thank the amazing contributions and dedication of the study participants, some for more than eight years, to the A4 study. We had a great sense of excitement when we provided the first infusion to launch the A4 study at Butler Hospital in June of 2014. We felt we were opening a new era in Alzheimer’s prevention and the event was covered by news outlets from around the world.

    Though the results are disappointing, the A4 study demonstrated that it was possible to screen large numbers of cognitively unimpaired older individuals for AD risk. Many were found to be at lower risk. Today we have sensitive blood tests to make this screening process much more efficient and cost-effective.

    We need better prognostic markers to identify those most likely to progress and benefit from treatment during the study. We also need better measures of target engagement and treatment response to ensure we are on track to meet outcomes.

    And we need treatments, alone and in combination, with larger effects. There is a great deal to learn from the A4 and LEARN data, and we want to again thank the wonderful dedication of the study teams and participants for making these advances possible.

    View all comments by Stephen Salloway

  2. Since the A4 study was first started in 2013, it represents a ground-breaking public-private partnership that first tested the hypothesis that individuals with evidence of amyloid plaques, but without cognitive impairment, might benefit from disease-modifying drugs for AD. Drs. Reisa Sperling and Paul Aisen, and many others, are to be commended for their efforts (as a disclosure, while an employee of Eli Lilly and Company, I was substantially involved with the A4 study).

    Following a negative result in the solanezumab EXPEDITION3 (Honig et al., 2018) study in late 2016, using a dose of 400 mg every four weeks in patients with mild dementia due to AD, the dose of solanezumab was increased from 400 mg to 1,600 mg every four weeks in the A4 study. The A4 study was completed this year, and earlier this month top-line results were provided via press releases. Unfortunately, the study did not show any benefit from solanezumab in this preclinical AD population.

    The data from A4 will be made publicly available through ATRI, which will allow the field to learn as much as possible from this rigorously conducted trial, and more complete results will undoubtedly be presented at major medical meetings and in peer-reviewed publications. Based on the information in the press release alone, some additional questions are raised, and additional analyses come to mind.

    Solanezumab very specifically targets Aβ monomers, and for that reason would not be expected to have dramatic effects on amyloid plaques. Although plaque load did increase in participants taking solanezumab as well as placebo, the increase in plaque load was somewhat less in the solanezumab group (12.1 centiloids) compared to those given placebo (17.5 centiloids). Despite this possible effect on plaque load, directionally the clinical results for the primary outcome and several secondary outcomes favored placebo.

    While this could just represent statistical variation, interestingly for the EXPEDITION studies, for patients with mild dementia given 400 mg solanezumab every four weeks, the trends, some achieving nominal statistical significance, consistently favored solanezumab. This was true for a planned secondary analysis of patients with mild dementia in the pooled EXPEDITION and EXPEDITION2 studies (Siemers et al., 2016) as well as the EXPEDITION3 study (Honig et al., 2018). Comparisons of clinical outcomes in the EXPEDITION studies compared to the A4 study could yield important insights for the field regarding the role of Aβ monomers in AD pathology and cognitive function.

    While the results of the A4 study are disappointing, those who completed the study, most importantly the participants and their study partners, are to be congratulated. The field fortunately has seen some recent successes, and we as a field will continue to learn and build on those successes in part through analyses of the A4 study results.

    References:

    Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. PubMed.

    Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2015 Aug 1; PubMed.

    View all comments by Eric Siemers

  3. As the first participant to receive an infusion in the A4 Study, I am honored to offer a few comments on my experience. I completed the entire study, over 8½ years of periodic medical tests, including MRI and PET scans, blood draws, and electrocardiograms. Every four weeks, I drove 36 miles round trip from my home to Butler Hospital Memory and Aging Program in Providence, Rhode Island, for my infusions. I had cognitive tests every three visits.

    The announcement that the treatments with “Solanezumab did not slow cognitive decline in Alzheimer’s Disease or reduce risk of progression…” was unanticipated. After all, I seemed as cognitive at the end as I was in the beginning. I was disappointed.

    However, I soon realized in spite of these results, I effectively accomplished my goals. Goals I set after my brother’s death at age 76 with Alzheimer’s disease and at the beginning of the A4 Study were: hope, trust, commitment.

    Hope that I would be given a preventable treatment for AD. But instead, I successfully added to the vast reservoir of data that will be mined by research scientists to conquer the cause and find the solution to this disease.

    Trust that I would be treated professionally and with the utmost safety and care. The staff in the Memory and Aging Program exceeded my expectations with kindness, support, and interest in my progress through the trial. This gave me the incentive to advocate and encourage participation in future trials.

    Commitment to complete the trial for future generations. The information learned from the A4 study will lead to better treatments that will help my children and grandchildren prevent AD. My study partner and the rest of my family gave me encouragement and support throughout the trial. They are proud and accepting of the time and effort they invested to complete the study, regardless of the results.

    This trial opened new opportunities to continue my education by learning and understanding the complexity of AD and its sequential prevention and cure. I became more mindful to improve my nutrition, exercise, and mental stimulation. Even with my amyloid plaques, I will continue to assist Alzheimer’s disease research for future generations. I will continue my goals by finding another trial that fits my abilities and again add to the reservoir of data so a prevention or cure will be reached.

    View all comments by Peter Bristol

  4. Earlier this month, the A4 study reported their results. Some of the participants were part of this study for eight years. That commitment and dedication is what will move the needle in our field. We are deeply indebted to these individuals—and all research participants—for their commitment to helping to move science forward.

    I was particularly moved by Peter Bristol’s comment to this story. All the work we do at the Alzheimer’s Association is motivated by people living with Alzheimer’s and other dementia, research participants, their caregivers and family members. What Peter shared inspires and confirms our obligation to share data with study participants and the field. I am especially grateful for his (and his fellow participants’) patience, persistence, engagement and advocacy.

    I “tip my hat” to the A4 and LEARN study leadership team. Though this was a negative study, innovative and valuable systems were developed, along with a deep well of data to be analyzed and reported. This deeper understanding will inform our next and future trials and move us even faster forward. The team has expressed a passionate commitment to share their data with the dementia research community, and with the study participants.

    LEARN was a first in many ways for the Alzheimer’s Association in our role as a research funder. Awarding the funding to create and provide ongoing support for LEARN, with GHR Foundation and other philanthropic partners, was a groundbreaking “strategic grant” for the Association. This funding leveraged the incredible infrastructure of the A4 study to enroll participants in LEARN, and allowed us to add the newly developed (at that time) initial tau imaging scans to both A4 baseline and LEARN. This also enabled the study to expand the public private partnership with the Association and the study team, the NIH funding and the study sponsors to look at something from a different angle; to ask, and begin to answer, additional important questions.

    View all comments by Maria Carrillo

  5. We hope that the field will find alternative ways to target amyloid and the other pertinent pathologies. However, at this stage, the study results reinforce our understanding that to have a positive impact on clinical decline, it is important for drugs to significantly reduce amyloid plaque, as has been shown for early symptomatic disease.

    We don’t yet have tau PET data, CSF data and blood biomarkers data in-house, or analyses complete, but look forward to sharing any insights regarding associations on predicting progressors at a medical conference later this year.

    View all comments by John Sims

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References

Therapeutics Citations

  1. Solanezumab
  2. Leqembi

Webinar Citations

  1. Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD

News Citations

  1. Solanezumab Selected for Alzheimer’s A4 Prevention Trial
  2. Lilliputian Effect Size Fells Phase 3 Trial of Solanezumab, Leaving Its Future Uncertain
  3. CTAD: Solanezumab Seen to Nudge AD Ever so Slightly
  4. A4 Researchers Raise Solanezumab Dosage, Lengthen the Trial
  5. In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
  6. Test Battery Picks Up Cognitive Decline in Normal Populations
  7. Test Tracks Preclinical Functional Decline
  8. CAP Articulates Plan for Sharing Data from Trials of Preclinical Alzheimer’s Disease
  9. Plasma Aβ—First Sign of AD, But Tough to Measure Prospectively?
  10. Can Donanemab Prevent AD? Phase 3 TRAILBLAZER-ALZ3 Aims to Find Out

External Citations

  1. announced
  2. A4
  3. Longitudinal Evaluation of Amyloid Risk and Neurodegeneration
  4. Baseline and screening data from A4
  5. AHEAD 3-45

Further Reading

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