Table 3 Overview fluid-based endpoint results in trials

The TRAILBLAZER-ALZ study, investigating donanemab (target class: amyloid β), showed no significant changes in plasma Aβ42/40 ratio levels [27]. There was a significant decrease in plasma pTau217 and GFAP reported in patients receiving donanemab. These changes also correlated with change in brain amyloid plaques as visualized by PET. Donanemab slowed cognitive decline compared to placebo. 

Lecanemab (target class: amyloid β) showed a significant increase in CSF Aβ42 after 12 and 18 months in people receiving the drug [26]. There was no change in the Aβ40 measurements between placebo and treatment. Furthermore, levels of CSF tTau, pTau181, and NRGN were reduced after 12 and 18 months. No change in CSF NFL was reported between the two groups. In plasma, Aβ42/40 ratio increased reported and plasma pTau181 and GFAP decreased following lecanemab treatment compared to placebo. Patients receiving lecanemab showed reduced rates in cognitive decline compared to placebo. 

Gantenerumab and crenezumab (target class: amyloid β) both showed insignificant treatment effects. There was no significant effect on cognition for patients receiving gantenerumab [33]. CSF pTau181, tTau, and NRGN decreased in the patients receiving gantenerumab. However, different responses in fluid biomarkers were found for men and women [34]. Crenezumab did not show changes in the core AD biomarkers measured: CSF Aβ42, Aβ40, tTau, and pTau181 [35].

Semorinemab, gosuranemab, and tilavonemab (target class: Tau) are all monoclonal antibodies investigated in phase 2 trials which showed no clinical benefit. Semorinemab showed dose-dependent increase in plasma mid-domain tau, which is indicated as their target engagement marker and a lowering in CSF pTau181, pTau217 and tTau [36, 37]. Gosuranemab also showed target engagement by lower CSF N-terminal tau. However, there was no effect on Tau PET [38]. Tilavonemab reduced CSF free Tau in a dose-dependent manner after 12 weeks and increased plasma tTau, also indicating target engagement [39]. MAPT_rx is an antisense oligonucleotide (target class: Tau) that has shown a dose-dependent effect on CSF tTau concentrations [40].

Neflamapimod (target class: inflammation), a p38α kinase inhibitor, showed reduced CSF levels of pTau181 and tTau compared to placebo and a positive trend for NRGN. No significant effects were seen for NFL, Aβ42, and Aβ40 levels [41]. There was no effect reported on episodic memory performance (HVLT-R).

A trial with rifaximin (target class: antiviral/anti-bacterial), which is an antibiotic that reduces neurotoxic microbial drivers of inflammation by changing gut flora composition, also measured several fluid-based markers. However, there were no significant changes in the BTE inflammatory cytokines. NFL was significantly lower following treatment [42].

S-equol (target class: growth factors and hormones), an estrogen receptor β agonist inducing mitochondrial activity, used cytochrome oxidase (COX) and citrate synthase (CS) activity in platelet-derived mitochondria as target engagement marker. COX/CS activity increased for 11/15 patients following two weeks of study drug administration [43].