Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, Wessels AM, Shcherbinin S, Wang H, Monkul Nery ES, Collins EC, Solomon P, Salloway S, Apostolova LG, Hansson O, Ritchie C, Brooks DA, Mintun M, Skovronsky DM, TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. PubMed.

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Comments

  1. It is remarkable that we now have several anti-amyloid therapies that have been proven to slow down the disease progression of Alzheimer’s disease when initiated in amyloid-positive patients with amnestic MCI or mild dementia. While the donanemab Phase 2 and 3 trials required elevated signals in both amyloid- and tau-PET scans for enrolment, I think that a person with MCI who is amyloid-positive, but yet tau-PET-negative, should also have the opportunity to receive donanemab treatment if their cognitive symptoms are considered to be caused by AD. To me, there is no compelling reason to believe that donanemab should differ from lecanemab in this regard, especially since the results from the donanemab trials even suggested greater relative treatment benefits for patients in earlier disease stages. Therefore, a biomarker reflecting Aβ pathology, such as amyloid-PET, CSF Aβ42/p-tau, or plasma p-tau217/np-tau217, would, to my mind, suffice to confirm the presence of AD pathology in this clinical scenario, where the dementia expert deems AD to be the most likely cause of the patient's cognitive impairment.

    That said, accumulating evidence from both the donanemab and lecanemab trials indicates that AD patients with lower tau load, as determined by tau-PET imaging, respond even more favorably to anti-amyloid immunotherapies, without an increase in the risks of ARIA (amyloid-related imaging abnormalities). Consequently, the benefit/risk ratio for anti-amyloid immunotherapies is likely to be further enhanced in AD populations who do not yet exhibit a high tau load. As a result, knowledge of the individual patient's tau load could facilitate a more informed discussion between the treating physician and the patient before initiating treatment, similar to how information on the patient's APOE4 genotype informs discussions regarding the risk of ARIA. However, in most memory clinics, conducting tau-PET scans for all AD patients eligible for anti-amyloid immunotherapies is not currently feasible. Nevertheless, there is hope that we will soon have access to a blood test that can indicate whether a patient has a high tau load in the brain or not.

    View all comments by Oskar Hansson

  2. These data are a big step forward toward effective treatment and prevention in AD. Together with results from previous clinically effective and ineffective amyloid-modulating antibodies and low molecular-weight compounds, we should now be positioned to address critical questions toward the design of an optimal Aβ therapeutic in AD:

    • Is plaque dissolution an essential feature of Aβ efficacy? How would antibodies binding pGlu amyloid beta devoid of plaque dissolution score in clinical trials?
    • How critical is high selectivity versus nascent Aβ monomer?
    • What are the critical epitopes in common for early misfolded Aβ oligomeric species mediating pathology? Comparative and quantitative ex vivo binding profiles for aducanumab, lecanemab, donanemab, and a highly oligomer-selective comparator antibody for various soluble Aβ x-y species in AD brain, performed by unbiased methods of immuno-precipitation and quantifications, would help answer this question.
    • Are we prepared to rigorously analyze the biochemical reasons for clinical failures of pan-amyloid antibodies and secretase inhibitors? Based on clinical data of all amyloid-targeting drug candidates tested in Phase 3 so far, we could set up a refined, precise model for Aβ pathology in AD that would explain all clinical results (Hillen, 2019). This would comprise taking into account the physiology of nascent Aβ monomer (Zhou et al., 2022).

    Building on the Aβ dysfunction model: could we set up a refined pharmacokinetic model for target coverage of drug candidates focusing on early misfolded amyloid species at synaptic sites, considering limited brain availability of antibodies and small molecules?

    This strategy should help rationalize the design of the optimal amyloid beta based therapeutic, before we start tau-based combination treatments in clinical trials.

    References:

    Hillen H. The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer's Disease. Front Neurosci. 2019;13:1154. Epub 2019 Nov 7 PubMed.

    Zhou B, Lu JG, Siddu A, Wernig M, Südhof TC. Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Sci Transl Med. 2022 Oct 19;14(667):eabn9380. PubMed.

    View all comments by Heinz Hillen

  3. These results represent an important step forward to treat AD and offer an encouragement for increasing our efforts in designing new therapeutic strategies against Aβ. Approval by the FDA should be straightforward considering that the deceleration of AD progress occurred with an even higher rate than in the lecanemab trial.

    The fact remains that the efficacy of these mAb-based treatments depends on how early the disease is treated. We therefore need to invest in early diagnosis. I also wonder whether many of the previous potential therapeutics against AD that failed in clinical trials should be re-evaluated in clinically normal but biomarker-diagnosed AD cases.

    View all comments by Fabrizio Chiti

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