TANGO: a placebo-controlled randomized phase 2 study of efficacy and safety of the anti-tau monoclonal antibody gosuranemab in early Alzheimer's disease

Abstract

In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.

Fig. 1. Participant disposition.

^aPlacebo-controlled period only. None of the participants completed the LTE period due to early study termination. Source data

Fig. 2. Longitudinal changes in a secondary efficacy outcome: CDR-SB scores from baseline to week 78.

The graph shows the adjusted mean changes in CDR-SB scores from baseline (±standard error (s.e.)) up to week 78. A greater positive change indicates a worsening of symptoms. Sample sizes for each group at each time point are listed. Analyses were two-sided at a 5% significance level. No adjustments were made for multiple comparisons. Source data

Fig. 3. Target engagement and pharmacodynamics.

a, Target engagement as measured by the adjusted mean change from baseline (±s.e.) in the CSF levels of unbound N-terminal tau. b, Pharmacodynamics as measured by the adjusted mean change from baseline (±s.e.) in the CSF levels of p-tau181. c, Pharmacodynamics as measured by the adjusted mean change from baseline (±s.e.) in the CSF levels of total tau. d, Pharmacodynamics as measured by the adjusted mean change from baseline (±s.e.) in the CSF levels of Aβ₄₂. Sample sizes for each group at each time point are listed for each panel. In a, the asterisks denote a significant difference from placebo for the group of the same color (***P < 0.0001). In b, the asterisks denote a statistically significant difference between the high-dose and placebo groups at week 76 (**P = 0.0022). In c, the asterisks denote a statistically significant difference between the 125 mg q4w low-dose group and the placebo group (*P = 0.0138) and between the intermediate-dose and high-dose groups at week 76 (***P < 0.0001). Analyses were two-sided at a 5% significance level. No adjustments were made for multiple comparisons. Source data

Fig. 4. Adjusted mean change in tau PET SUVR from baseline to week 78.

a–c, Adjusted mean change from baseline (±s.e.) in the tau PET SUVR in composite regions corresponding to Braak stages I–II (a), III–IV (b) and V–VI (c). Sample sizes are provided for each group at each time point and are the same for all panels. Analyses were two-sided at a 5% significance level. No adjustments were made for multiple comparisons. Source data

Extended Data Fig. 1. Longitudinal changes on secondary efficacy assessments from baseline to week 78.

Adjusted mean change from baseline (±SE) up to week 78 on the (a) ADAS-Cog13, (b) MMSE, and (c) ADCS-ADL scores. In panel A, a greater positive change indicates worsening of symptoms; in panels B and C, a greater negative change indicates worsening. Sample sizes for each group at each time point are listed for each panel. Asterisk denotes a significant difference between the high-dose placebo groups (P = 0.0378). Analyses were two-sided at 5% significance level. No adjustments were made for multiple comparisons. Source data

Extended Data Fig. 2. Longitudinal changes in the FAQ score from baseline to week 78.

Adjusted mean change from baseline (±SE) up to week 78 on FAQ score. A greater positive change indicates worsening of symptoms. Sample sizes for each group at each time point are listed for each panel. Analyses were two-sided at 5% significance level. No adjustments were made for multiple comparisons. Source data

Extended Data Fig. 3. Adjusted mean change in tau PET SUVR from baseline to week 78.

Adjusted mean change from baseline (±SE) in tau PET SUVR in brain regions corresponding to (a) medial temporal cortex, (b) lateral temporal cortex, and (c) frontal cortex. Sample sizes are provided for each group at each time point and are the same for all panels. Analyses were two-sided at 5% significance level. No adjustments were made for multiple comparisons. Source data

Extended Data Fig. 4. Brain volume changes as measured by structural MRI from baseline to week 78.

Adjusted mean change from baseline (±SE) in (a) whole brain volume, (b) hippocampus volume, and (c) lateral ventricle volume. Sample sizes for each group at each time point are listed for each panel. In panel C, the asterisk denotes a statistically significant difference in lateral ventricle volume between the high-dose and placebo groups at week 78 (P = 0.0481). Analyses were two-sided at 5% significance level. No adjustments were made for multiple comparisons. Source data