Discussion
AD
SEPARATION, SECONDARY, PATHOLOGY, DISEASE PROGRESSION
The TANGO study evaluated the safety and efficacy of gosuranemab in patients with AD. The participants tolerated gosuranemab well at all doses evaluated, and the safety outcomes were consistent with those reported in previous studies. However, no dose produced a favorable separation from placebo on a secondary endpoint: the change in the CDR-SB score from baseline at 78 weeks. Furthermore, none of the treatment groups exhibited an improvement over the placebo group in any of the exploratory efficacy endpoints. In one such assessment (ADAS-Cog13 scale), the high-dose group performed statistically significantly worse than the placebo group at week 78; however, this difference was not statistically significant in the LTE period. The lack of clinical efficacy observed in TANGO is consistent with the results of recent clinical trials investigating the N-terminal anti-tau antibodies semorinemab and tilavonemab in early ADTreatment with gosuranemab was associated with a robust reduction in the CSF levels of unbound N-terminal tau, confirming the target engagement of this antibody. In the treatment groups, the CSF levels of p-tau181 and total tau were lower at week 76 than at baseline. However, differences in p-tau181 and total tau levels among the treatment and placebo groups were significant only for some dose groups, and no dose–response was observed for either measure. Analysis of the tau PET substudy—the largest [Preclinical models of AD to date leave room for improved clinical translation. In several preclinical tau transgenic mouse models, the anti-tau antibodies tilavonemab, zagotenemab and semorinemab, which target N-terminal or conformational epitopes of tau, have demonstrated efficacy in reducing tau pathology and, in some cases, providing functional or behavioral improvementsAll groups exhibited comparable reductions in hippocampal and total brain volumes, consistent with disease progression. A statistically significant increase in the lateral ventricular volume, with unclear clinical significance, was observed in the high-dose treatment group relative to the placebo group.The pharmacodynamic data from the TANGO study are consistent with those from previous trials investigating gosuranemab. In a single-ascending-dose trial, gosuranemab doses of 70–4,200 mg decreased the CSF levels of unbound N-terminal tau by 67–97% at 4 weeksIn the TANGO study, gosuranemab was tested based on the hypothesis that extracellular seeding-competent tau species propagate tau pathology throughout the brain. This study is supported by preclinical data demonstrating the high binding affinity of gosuranemab to monomeric and aggregated forms of tau and its ability to remove seeding-competent forms of tau from AD brain lysate and interstitial fluid derived from tau transgenic miceIn addition to the biological and technical limitations discussed above, operational limitations should be considered when interpreting the study results. This study was affected by the COVID-19 pandemic. Many efforts were made to minimize the effect of the pandemic on the study participants. As a measure against study withdrawals, participants were allowed flexibility in scheduling their site visits. This flexibility made possible the low discontinuation rate observed in the study, at the expense of increased protocol deviations. However, these deviations were generally balanced across treatment groups, mitigating the potential effect of this limitation on the interpretation of the results. Limited data were collected during the LTE period due to the early termination of the study.