Major progress has been achieved in AD drug development, with several anti-amyloid agents recently reporting promising clinical and biomarker effects in late-stage trials. The three antibodies aducanumab, gantenerumab, and BAN2401, and the small molecule ALZ-801, have also shown acceptable long-term safety. Therefore, confirmation of their efficacy may lead to the approval and marketing of this first wave of disease-modifying treatments over the next 3 to 5 years.
Engagement of amyloid oligomers drives clinical and biomarker efficacy
A substantial body of evidence supports the role of Aβ oligomers as early triggers of AD pathology [
1‐
3]. Brain levels of neurotoxic soluble Aβ oligomers, rather than plaques or fibrils, correlate closely with onset and progression of AD symptoms [
6,
8,
37]. Aβ oligomers damage synapses, induce tau hyperphosphorylation and neuroinflammation, and impair memory formation in preclinical models, as well as brains of AD patients [
8,
37‐
39]. The most synaptotoxic species are the small oligomers, ranging from dimers to dodecamers, and pyroglutamate forms of Aβ oligomers [
40]. Recent clinical trial results with aducanumab, BAN2401, and gantenerumab confirmed that agents that engage amyloid oligomers also reduce downstream tau pathology [
13,
19,
20,
22,
23,
27] and cognitive decline [
19,
23].
The four late-stage anti-amyloid agents with clinical efficacy and biomarker effects include three injectable antibodies and the oral small molecule, ALZ-801. The common characteristic shared by these agents is their ability to target neurotoxic soluble Aβ oligomers [
2,
3]. Aducanumab and gantenerumab preferentially target insoluble amyloid plaques and fibrils and engage oligomers only partially [
11,
12], while BAN2401 preferentially targets oligomers over plaques [
10], and ALZ-801 selectively blocks the formation of Aβ oligomers without binding amyloid plaque [
15‐
17].
The degree of Aβ oligomer selectivity appears to be a key factor that together with PK properties determines the clinical profile of each anti-amyloid agent. Both aducanumab phase 3 data and BAN2401 phase 2 data showed significant effects on cognition and function [
19,
23], and the degree of benefit parallels their respective selectivity for soluble oligomers versus insoluble amyloid plaques (Table
1), with BAN2401 delivering larger clinical benefits likely due to better selectivity for oligomers. Gantenerumab did not show clinical efficacy in the SCarlet RoAD or Marguerite RoAD phase 3 trials [
13,
20,
22] and is currently being evaluated in two additional GRADUATE phase 3 trials in early AD to assess the high dose of 1020 mg SC injection administered monthly. Gantenerumab also recently failed on clinical endpoints in the DIAN-TU study in familial AD, potentially due to the small sample size, the mix of presymptomatic and symptomatic subjects, and the late introduction of the higher gantenerumab dose, where only 37% of the subjects received the high dose of 1200 mg monthly SC injections [
21]. ALZ-801 which selectively blocks the formation of Aβ oligomers showed significant, clinically meaningful effects on cognition and function in APOE4/4 homozygotes [
31], which were similar in magnitude to BAN2401 benefits in APOE4 carriers [
23]. One explanation for the higher efficacy of these agents in APOE4 carriers versus noncarriers is their several-fold higher burden of soluble Aβ oligomers [
41].
In remarkable contrast to the association between the level of engagement of soluble Aβ oligomers and clinical efficacy, no such association has been reported for the clearance of insoluble amyloid plaques and clinical efficacy. Aducanumab and BAN2401 showed compelling dose-dependent lowering of amyloid plaques in phase 3 and 2 trials [
11,
19,
23], with several doses robustly clearing plaque on amyloid PET imaging, yet only long exposures to the highest doses of aducanumab and BAN2401 resulted in significant efficacy, suggesting that prolonged engagement of Aβ oligomers at the highest doses is necessary for clinical benefit. Therefore, plaque clearance alone does not explain clinical efficacy, and amyloid plaque formation may be a protective mechanism by which soluble oligomers are sequestered to limit their neurotoxicity [
42]. In line with this hypothesis, the anti-amyloid antibody bapineuzumab and other agents that target primarily amyloid plaques and fibrils failed to show efficacy [
43]. Agents that target amyloid monomers, such as the anti-amyloid antibody solanezumab, failed in multiple phase 3 trials [
29], or even caused cognitive worsening as observed in phase 3 trials of several beta secretase inhibitors that inhibit the formation of monomers.
All three anti-amyloid antibodies reduced CSF p-tau, the biomarker which best correlates with tau pathology and cognitive decline. While the effective levels of antibodies achieved in the brain and their specificity for amyloid oligomers were predictive of cognitive benefit, this was not the case for CSF p-tau. Although gantenerumab in the DIAN-TU study showed larger p-tau effects than aducanumab and BAN2401 (31% versus 13–15%), it failed to show efficacy on clinical endpoints in the DIAN-TU study or other trials. In addition to CSF p-tau, aducanumab also showed effects on tau PET imaging in the EMERGE trial [
19]. Both BAN2401 and gantenerumab phase 2 data showed significant effects on CSF NfL [
13,
23,
27], and gantenerumab also showed consistent effects on t-tau. Both NfL and t-tau are considered downstream biomarkers of neuronal injury [
44,
45]. The consistency of amyloid antibody effects on CSF p-tau, t-tau, and NfL supports the important role of these biomarkers in future AD trials.
Hippocampal atrophy assessed by volumetric MRI measurements is considered the most reliable structural biomarker of AD progression as noted in the recent draft guidances from both the US Food and Drug Administration (FDA) and European Medicines Agency. Tramiprosate, in the MRI sub-study of a phase 3 trial, showed a dose-dependent decrease in hippocampal atrophy [
32], providing the only evidence to date of a significant drug effect on preventing brain atrophy. The effects of ALZ-801 on fluid biomarkers and volumetric MRI measures will be evaluated in a phase 2 study in APOE4 carriers with early AD, as well as a phase 3 trial in APOE4/4 homozygotes with early AD.
The consistency of clinical and biomarker effects of these four anti-amyloid agents provides robust evidence for the role of Aβ oligomers as upstream initiator of AD pathogenesis that triggers tau pathology, neurodegeneration, and resultant cognitive impairment (Table
1). The recent development of sensitive plasma assays for p-tau and NfL applied across the clinical AD continuum provides additional support for the early, initiating role of Aβ in AD pathogenesis and will further facilitate the use of fluid biomarkers in clinical trials [
46‐
48].
Benefit-risk profiles of anti-amyloid agents in APOE4 carriers
APOE4 carriers, who are at higher risk of early AD progression and constitute ~ 65% of AD patients, provide an optimal group for clinical efficacy studies and initial approval for drugs targeting neurotoxic soluble Aβ oligomers, since these patients carry a several-fold higher burden of Aβ oligomers compared to noncarriers [
41]. APOE4 carriers also have higher levels of insoluble amyloid deposits in brain vessels, which increases their risk of ARIA-E and ARIA-H when treated with anti-amyloid antibodies [
33]. Therefore, careful evaluation of efficacy and safety of anti-amyloid agents in APOE4 carriers is important to determine the benefit-risk profile in this large subgroup of AD patients with increased risk and earlier onset of the disease. Due to the rapid removal of amyloid plaque deposits from brain vessels, treatment with antibodies aducanumab, gantenerumab, and BAN2401 is associated with a substantial risk of ARIA-E in APOE4 carriers. While the efficacy of aducanumab in APOE4 carriers has not yet been disclosed, the incidence of ARIA-E in APOE4 carriers was ~ 42% in this group versus ~ 35% in the overall population [
11,
19]. BAN2401 showed more robust clinical efficacy in APOE4 carriers [
23]; however, this was associated with a higher incidence of ARIA-E of ~ 15% versus 10% in the overall study population. In APOE4/4 homozygotes, ALZ-801/tramiprosate showed substantial cognitive and functional benefits with no events of ARIA-E [
31] and may offer an optimal benefit-risk profile in APOE4 carriers.
The next generation of selective anti-oligomer agents
The next generation of anti-oligomer therapeutics with improved selectivity and product profiles includes the following agents and mechanisms: (1) PMN310, an anti-amyloid antibody that selectively clears formed Aβ oligomers; (2) CT1812, a small molecule that inhibits Aβ oligomer binding to specific neuronal receptors that mediate neurotoxicity; and (3) PQ912 and ALZ-801, small molecules that prevent the formation of neurotoxic soluble Aβ oligomers. An example of an antibody designed to be highly selective to Aβ oligomers is PMN310 from ProMIS Neuroscience [
49], which is in preclinical development. CT1812 is an oral small molecule from Cognition Therapeutics that inhibits the binding of Aβ oligomers to sigma-2 receptors [
50], which is thought to mediate some of the oligomer-induced synaptic toxicity. CT1812 is currently being tested in phase 2 studies. PQ912 is an oral small molecule inhibitor of glutaminyl cyclase from Vivoryon Therapeutics that inhibits the formation of pyroglutamate forms of Aβ oligomers, which are thought to be highly toxic to synapses. In a small phase 2 study of 12-week duration, PQ912 showed promising effects on a biomarker of neuroinflammation in CSF [
51].
ALZ-801 is an oral agent, which efficiently crosses the blood-brain barrier, selectively interacts with Aβ monomers to inhibit misfolding, and blocks the formation of neurotoxic soluble Aβ oligomers in a dose-dependent manner, without affecting insoluble amyloid plaques or fibrils [
15‐
18]. ALZ-801 is a prodrug of tramiprosate with improved gastrointestinal absorption and tolerability, which achieved excellent brain penetration of ~ 40%, with low intersubject variability in over 130 elderly volunteers and AD patients [
30]. ALZ-801 is ready to enter phase 3 based on a large body of clinical data in AD patients, including (1) favorable safety profile from tramiprosate safety database of > 2000 AD patients treated for 18 months [
24,
31]; (2) well-defined target clinical dose that fully blocks the formation of Aβ oligomers in the brain based on clinical data from the phase 3 AD trials and from an in vitro Aβ oligomer inhibition assay [
15,
30]; and (3) precision medicine approach initially focusing on high-risk homozygous APOE4/4 patients with early AD [
1]. Oral ALZ-801 provides convenient at-home dosing for elderly patients and their caregivers, as well as potential preventive treatment of presymptomatic subjects with high risk for AD.