Tilavonemab in early Alzheimer’s disease: results from a phase 2, randomized, double-blind study

Abstract

Tau accumulation in patients with Alzheimer’s disease tracks closely with cognitive decline and plays a role in the later stages of disease progression. This phase 2 study evaluated the safety and efficacy of tilavonemab, an anti-tau monoclonal antibody, in patients with early Alzheimer’s disease.

In this 96-week, randomized, double-blind, placebo-controlled study (NCT02880956), patients aged 55–85 years meeting clinical criteria for early Alzheimer’s disease with a Clinical Dementia Rating-Global Score of 0.5, a Mini-Mental State Examination score of 22 to 30, a Repeatable Battery for the Assessment of Neuropsychological Status-Delayed Memory Index score of ≤85, and a positive amyloid PET scan were randomized 1:1:1:1 to receive one of three doses of tilavonemab (300 mg, 1000 mg, or 2000 mg) or placebo via intravenous infusion every 4 weeks. The primary end point was the change from baseline up to Week 96 in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Safety evaluations included adverse event monitoring and MRI assessments.

A total of 453 patients were randomized, of whom 337 were treated with tilavonemab (300 mg, n = 108; 1000 mg, n = 116; 2000 mg, n = 113) and 116 received placebo. Baseline demographics and disease characteristics were comparable across groups. The mean age was 71.3 (SD 7.0) years, 51.7% were female, and 96.5% were White. At baseline, the mean CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. The least squares mean change from baseline at Week 96 in the CDR-SB score with tilavonemab was not significantly different compared with placebo [300 mg (n = 85): −0.07 (95% confidence interval, CI: −0.83 to 0.69); 1000 mg (n = 91): −0.06 (95% CI: −0.81 to 0.68); 2000 mg (n = 81): 0.16 (95% CI: −0.60 to 0.93); all P ≥ 0.05]. The incidence of any adverse event and MRI findings were generally comparable across groups.

Tilavonemab was generally well tolerated but did not demonstrate efficacy in treating patients with early Alzheimer’s disease. Further investigations of tilavonemab in early Alzheimer’s disease are not warranted.

Tau accumulation accompanies cognitive decline in Alzheimer’s disease and plays a role in the later stages of disease progression. Florian et al. present the results of a phase 2 study examining the safety and efficacy of tilavonemab, a monoclonal antibody targeting extracellular tau, in patients with early Alzheimer’s disease.

See Younes and Sha (https://doi.org/10.1093/brain/awad151) for a scientific commentary on this article.

See Younes and Sha (https://doi.org/10.1093/brain/awad151) for a scientific commentary on this article.

Introduction

Alzheimer’s disease, which is pathologically marked by an abnormal accumulation and aggregation of extracellular amyloid-β (Aβ) and intracellular tau,^1,2 accounts for as many as 80% of dementia cases.³ Whereas Aβ levels accumulate decades before the onset of Alzheimer’s disease symptoms and plateau in symptomatic patients, tau pathology corresponds more closely with symptom onset, and tau levels are still rising in patients who have just started to show signs of cognitive decline.² Therefore, patients with early Alzheimer’s disease who are experiencing clinical symptoms could potentially benefit from therapies aiming to slow or stop tau accumulation.

Neurofibrillary tangles, a characteristic pathologic feature in Alzheimer’s disease and other neurologic disorders such as progressive supranuclear palsy (PSP), are formed inside neurons by insoluble aggregates of hyperphosphorylated tau.⁴ Tau fragments, or seeds, can be transmitted from one neuron to another by a range of mechanisms, including free fragments in the synapse, nanotubules, and exosomes.^4-7 However, while the neuroanatomical spread of tau is well known, the mechanism by which a tau seed initiates templating and aggregation is unclear. A preclinical study of transgenic mice carrying a mutated human tau gene that leads to early-onset frontotemporal dementia in humans found that targeting the N-terminus of tau blocked tau seeding activity from brain lysates.⁶ Continuous intracerebroventricular infusion of an anti-tau antibody reduced tau pathology in the mouse model as evidenced by biochemical, histopathologic, and functional/behavioural measures.^4,6 Similarly, intraperitoneal injections of the anti-tau antibody in the transgenic mice were highly effective at reducing accumulation of insoluble tau in the brain, reducing cortical and hippocampal atrophy and improving sensory motor function.⁴

Tilavonemab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the N-terminus of human tau and targets soluble extracellular tau in the brain.^8,9 This mechanism may block extracellular tau from propagating between cells and decrease the spread of tau pathology in brains with tauopathies.⁶ In a phase 1 single ascending–dose study (NCT02494024)⁸ and a phase 2, randomized, placebo-controlled trial (NCT02985879),¹⁰ tilavonemab was well tolerated but did not show efficacy in patients with PSP.¹⁰ Here, we report results from a phase 2 study investigating the efficacy of tilavonemab in slowing disease progression and the long-term safety of tilavonemab in patients with early Alzheimer’s disease.

Materials and methods

Study design and participants

This was a phase 2, multiple-dose, randomized, double-blind, placebo-controlled study (Clinicaltrials.gov identifier: NCT02880956) conducted at 60 sites in 11 countries (Appendix 1 and Supplementary material). Eligible patients were adults aged 55–85 years who met the National Institute on Aging and the Alzheimer’s Association criteria for mild cognitive impairment or probable Alzheimer’s disease¹¹ and had a Clinical Dementia Rating (CDR) global score of 0.5 at screening Visit 1, a Mini-Mental State Examination (MMSE) score of 22 to 30, inclusive, at screening Visit 1, and a Repeated Battery for the Assessment of Neuropsychological Status-Delayed Memory Index (RBANS-DMI) score of ≤85; a positive amyloid PET scan; a Modified Hachinski Ischemic Scale score of ≤4; and who had a reliable study partner (e.g. family member) who could provide information on the patient’s cognitive and functional abilities. The CDR global score was limited to 0.5 because it was expected that treatment with an agent that stops tau spreading would be most beneficial prior to the onset of extensive spreading and neurodegeneration. In addition, tau PET was not available at the start of this study and could be implemented only after the study had commenced. Thus, we assumed patients with more extensive tau pathology could be excluded by limiting the CDR to 0.5. Patients were allowed to use medications to treat symptoms related to Alzheimer’s disease if they were receiving a stable dose for ≥12 weeks before randomization. Full inclusion and exclusion criteria can be found in Supplementary Table 1.

All patients and their respective study partners provided written informed consent before screening or before undergoing any study-specific procedures. All trial sites received approval from an independent ethics committee or institutional review board before authorization of drug shipment to a study site. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and adhered to the tenets of the Declaration of Helsinki. During the COVID-19 (Coronavirus disease 2019) pandemic, alternative safety measures were permitted by local regulations and the independent ethics committee/institutional review board to ensure the safety of participants, maintain protocol compliance, and minimize the risk to the integrity of the study.

Randomization and masking

Patients were randomized at the Day 1 visit through an interactive voice- or web-response system in a 1:1:1:1 ratio to receive one of three tilavonemab doses (300 mg, 1000 mg, 2000 mg) or placebo administered via intravenous infusion every 4 weeks. Randomization was stratified by site. Patients in Cohort 1 underwent more frequent pharmacokinetics (PK) sampling, safety monitoring by the data monitoring committee, and target engagement assessment based on measurements of CSF free tau. Patients who completed the 96-week double-blind period were eligible to enroll in an extension study for extended dose-blinded treatment (NCT03712787).

The investigator, study site personnel (except the unblinded pharmacist), and the patients were masked to treatment throughout the course of the study. The study sponsor remained masked. Patients’ identification numbers were changed for the PK analysis to maintain the masking of the sponsor.

Procedures

The study consisted of a 12-week screening period, 96-week double-blind treatment period, and a 20-week follow-up after administration of the last study drug. Tilavonemab (AbbVie Inc.) was administered via intravenous infusion every 4 weeks, with the infusion rate dependent on the patient’s weight at each visit. Patients returned to the study site every 4 weeks for their study drug infusion, blood collection, and various study procedures and assessments as described in Supplementary Table 2.

Outcomes

The primary efficacy end point was the change from baseline to Week 96 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Secondary efficacy endpoints are listed in Supplementary Table 3. Safety evaluations included monitoring of adverse events, vital signs, physical and neurologic examinations, ECGs, laboratory values, the Columbia-Suicide Severity Rating Scale, and MRI studies.

Exploratory outcomes assessed the effects of tilavonemab on potential markers of disease progression. Imaging biomarkers included volumetric MRI (vMRI) for the whole brain, medial temporal lobe, hippocampus, and lateral ventricles. Tau PET imaging was initiated during the trial at a limited number of sites and was therefore assessed in a subset of patients (n = 59 at baseline, n = 115 at Week 44, and n = 128 at Week 96). Imaging was obtained with tracer ¹⁸F-MK6240 and standardized uptake value ratio (SUVR) was analysed in Braak regions I-VI.¹² Fluid biomarkers included CSF neurofilament light chain (NFL), free tau and total tau, and plasma tau and NFL.

PK end points evaluated in Cohort 1 included maximum observed serum concentration (C_max), time to C_max (peak time, T_max), the area under the concentration-time curve from Day 0 to Day 28 (AUC_0–28) over the dosing interval after the first and fourth doses, and the observed serum concentration at the end of a dose interval (C_trough) after all doses.

Statistical analysis

A sample size of approximately 400 patients (roughly 100 patients in each of the three tilavonemab groups and 100 in the placebo group) was expected to provide ∼80% power to detect a tilavonemab treatment standardized effect size (versus placebo) of 0.45 for both the high dose and the middle dose and 0.28 for the low dose on CDR-SB score changes from baseline up to Week 96 using a one-sided test at the 2.5% significance level with Bonferroni method to adjust multiplicity.¹³ The sample size calculations assumed there would be a 25% dropout rate (i.e. no post-baseline data) and the calculation was conducted using Cytel EAST version 6.4 (Cytel).

Efficacy analyses were performed on the intent-to-treat (ITT) dataset, which included all randomized patients who received at least one study drug dose. Data collected more than 45 days after the last dose of the study drug were not included in the efficacy analyses. Efficacy data from the ITT dataset were analysed by treatment group assignment at the time of randomization, regardless of whether the patient received the correct treatment, was compliant with the protocol, or followed through with the study until completion. Interim efficacy analyses were also performed when 8 patients/group, 35 patients/group, and 55 patients/group, respectively, completed the Week 96 visit. The safety dataset included all randomized patients who received at least one study drug dose; however, safety analyses from the safety dataset were performed by actual treatment received rather than treatment assignment at the time of randomization.

The primary efficacy analysis used a likelihood-based, mixed-effects model repeated measures (MMRM) analysis of the change from baseline for each postbaseline visit using all observed data. The model included fixed, categorical effects for treatment, site, visit, Treatment × Visit interaction, and Baseline × Visit interaction with a continuous fixed covariate for baseline score. Satterthwaite’s approximation was used to estimate denominator degrees of freedom and the type III sum-of-squares for the least squares (LS) means was used to estimate treatment group differences. The MMRM analysis was also used to analyse secondary and exploratory variables. An analysis of covariance (ANCOVA) model was used for CDR-SB score subgroup analysis and CSF biomarkers for each scheduled visit. Owing to non-symmetry in the probability distribution, logarithmic transformation was employed on plasma and CSF biomarkers. Two sensitivity data analyses were performed on the primary efficacy end point, one excluding patients who did not meet the study selection criteria and missed or were underdosed for >2 doses; and the other excluding those who did not meet the study selection criteria and including those who had any available CDR-SB score, including patients who missed doses and those who completed a final assessment >45 days after the last dose. Missing data were handled using multiple imputation applied separately for each treatment group.

An external data monitoring committee was responsible for reviewing unblinded safety data after every 12th patient in Cohort 1 received their second dose of tilavonemab and had their MRI results available (approximately 2 weeks after the second dose). The committee also reviewed unblinded safety data after a total of approximately 100, 200, 300, and 400 patients were randomized, and every 6 months thereafter until study completion. Additionally, the data monitoring committee conducted efficacy data reviews during interim efficacy analyses, including changes from baseline to Week 96 on the CDR-SB score, Alzheimer’s Disease Assessment Scale (14-item) Cognitive Subscale total score, RBANS total scale score, and Functional Activities Questionnaire total score.

Data availability

AbbVie Inc. is committed to responsible data sharing regarding the clinical trials they fund. This commitment includes access to anonymized individual and trial-level data (analysis datasets) and other information (e.g. protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous independent scientific research and will be provided after review and approval of a research proposal and Statistical Analysis Plan and execution of a Data Sharing Agreement. Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit https://www.abbvieclinicaltrials.com/hcp/data–sharing/.

Results

Between October 2016 and May 2019, a total of 1360 patients were screened, of whom 453 were randomized to receive one of three doses of tilavonemab: 300 mg (n = 108), 1000 mg (n = 116), or 2000 mg (n = 113), or placebo (n = 116) (Fig. 1). A total of 392 (86.5%) patients completed the study. Overall, the number of patients who discontinued the study was similar across treatment groups [tilavonemab 300 mg (n = 15, 13.9%), tilavonemab 1000 mg (n = 11, 9.5%), tilavonemab 2000 mg (n = 18, 15.9%), placebo (n = 17, 14.7%)]. The primary reason for study discontinuation was an adverse event in the tilavonemab 300 mg group (n = 6), and withdrawal of consent in the tilavonemab 1000 mg (n = 6), tilavonemab 2000 mg (n = 11), and placebo (n = 9) groups.

Figure 1.

Patient disposition. ^aPatients may have more than one reason for exclusion. ^bIncludes all randomized patients who had ≥1 dose of study drug in the ITT and safety populations. ^cPrimary reasons for study discontinuation. AE = adverse event.

Baseline demographics, disease characteristics, and biomarker profiles were generally well balanced across treatment groups (Table 1 and Supplementary Tables 4 and 5) and were consistent with a patient population with early Alzheimer’s disease.¹

Table 1.

Baseline demographics and disease characteristics

Characteristic	Placebo n = 116	Tilavonemab			Total n = 453
		300 mg n = 108	1000 mg n = 116	2000 mg n = 113
Age, years	71.7 ± 6.7	71.6 ± 7.1	71.8 ± 7.1	70.3 ± 7.0	71.3 ± 7.0
Female, n (%)	70 (60.3)	45 (41.7)	60 (51.7)	59 (52.2)	234 (51.7)
Race, n (%)
White	111 (95.7)	102 (94.4)	113 (97.4)	111 (98.2)	437 (96.5)
Non-White	5 (4.3)	6 (5.6)	3 (2.6)	2 (1.8)	16 (3.5)
Age at onset of symptoms of cognitive impairment, years	67.5 ± 6.8	66.8 ± 7.2	67.4 ± 7.0	66.5 ± 7.1	67.1 ± 7.0
Education, years	14.9 ± 3.4	15.2 ± 4.0	14.3 ± 3.8	14.6 ± 3.6	14.7 ± 3.7
Symptomatic Alzheimer’s disease medication use, n (%)	78 (67.2)	72 (66.7)	87 (75.0)	83 (73.5)	320 (70.6)
ApoE4 carrier, n (%)	87 (75.0)	81 (75.0)	95 (81.9)	79 (69.9)	342 (75.5)
Amyloid PET, centiloid	99.7 ± 30.0	97.7 ± 30.6	97.7 ± 30.4	100.9 ± 33.6	99.0 ± 31.1
CDR-SB score	3.0 ± 1.2	3.0 ± 1.1	3.1 ± 1.2	2.9 ± 1.1	3.0 ± 1.2
ADAS-Cog14 total score	26.2 ± 7.4a	27.1 ± 8.2b	26.3 ± 7.4c	26.5 ± 6.7a	26.5 ± 7.4d
RBANS total scale score	71.7 ± 11.4c	72.4 ± 14.0	72.1 ± 12.2	70.6 ± 12.0	71.7 ± 12.4e
MMSE total score	24.0 ± 3.0	24.5 ± 2.9	24.5 ± 2.6	24.5 ± 3.0	24.4 ± 2.9
FAQ total score	8.1 ± 5.8	7.5 ± 5.3	8.4 ± 5.7c	7.3 ± 4.9	7.8 ± 5.4e
NPI total score	3.9 ± 6.0	3.7 ± 5.1	4.3 ± 5.9	4.0 ± 6.2	4.0 ± 5.8
UPSA-Brief score	60.1 ± 20.4	62.1 ± 18.1	60.1 ± 18.3f	60.8 ± 19.9g	60.7 ± 19.2h
ADCS-MCI-ADL-24 total score	54.2 ± 7.8f	54.6 ± 7.7	54.2 ± 7.1f	55.3 ± 6.8	54.6 ± 7.4i
ADCOMS score	0.4 ± 0.1a	0.4 ± 0.2j	0.4 ± 0.1g	0.4 ± 00.1k	0.4 ± 0.1l

Data are presented as mean ± standard deviation unless otherwise specified. ADAS-Cog14 = Alzheimer’s Disease Assessment Scale (14-Item) Cognitive Subscale; ADCOMS = Alzheimer’s Disease Composite Score; ADCS-MCI-ADL-24 = 24-item Alzheimer’s Disease Cooperative Study/Activities of Daily Living Scale Adapted for Patients With Mild Cognitive Impairment; FAQ = Functional Activities Questionnaire; NPI = Neuropsychiatric Inventory; UPSA-Brief = University of California San Diego Performance-Based Skills Assessment-Brief Version.

n = 111.

n = 106.

n = 115.

n = 443.

n = 452.

n = 114.

n = 112.

n = 450.

n = 449.

n = 105.

n = 108.

n =436.

At baseline, the mean (standard deviation) CDR-SB score was 3.0 (1.2), which worsened through Week 96 for all treatment groups. Change from baseline at Week 96 in the CDR-SB score was not significantly different between treatment groups (Fig. 2).

Figure 2.

Baseline mean and mean change from baseline over time in CDR-SB score. Data are from the ITT population and include all randomized patients who had ≥1 dose of study drug. The placebo-corrected LS mean (standard error) change in CDR-SB score from baseline at Week 96 was: tilavonemab 300 mg, −0.07 (0.39), P = 0.848; tilavonemab 1000 mg, −0.06 (0.38), P = 0.869; and tilavonemab 2000 mg, 0.16 (0.39), P = 0.679. Error bars represent minimum and maximum values.

An ANCOVA subgroup analysis of CDR-SB mean score change from baseline revealed a numerical differential effect observed in male versus female patients and those aged younger than 65 years versus those aged 65 years and older (Supplementary Fig. 1). No differential treatment effect was observed for subgroups based on ApoE4 carrier status, patients’ geographic location, baseline Alzheimer’s disease medication use, or baseline amyloid burden measured by PET (Supplementary Fig. 1).

Similarly, through Week 96, there was no significant difference across treatment groups in any of the secondary outcomes assessed, including global clinical impact and decline in patient cognition (Supplementary Table 3).

Tilavonemab did not affect whole-brain volume over time (Supplementary Fig. 2A), nor was there any evidence of a treatment effect on medial temporal lobe or lateral ventricle volume as measured by vMRI (data not shown). Hippocampal volume was significantly less decreased at Week 28 in the tilavonemab 1000 mg group compared with placebo (−94.9 versus −121.6 mm³, respectively; P = 0.03) and was also significantly less decreased at Week 44 in the tilavonemab 2000 mg group compared with placebo (−127.9 versus −165.9 mm³, respectively; P = 0.01); however, these were the only time points with statistical significance between groups without multiplicity adjustment (Supplementary Fig. 2B). Similarly, there was no evidence of a treatment effect on plasma NFL or CSF NFL levels (Supplementary Figs 3 and 4), nor was there evidence of a treatment effect in the amount of tau deposits in any Braak regions based on the tau PET SUVR analyses that were completed in a subset of patients who had baseline and Week 96 scans (Supplementary Table 6).

There was evidence of target engagement among patients in Cohort 1. Assessments of target engagement including CSF and plasma tau concentration were conducted at Week 12 after the fourth dose of the study drug (Figs 3 and 4). Compared with placebo, CSF free tau levels were significantly lower at Week 12 in the tilavonemab 1000 mg (P = 0.028) and tilavonemab 2000 mg (P = 0.002) treatment groups (Fig. 4A). CSF total tau concentrations were significantly lower in the tilavonemab 300 mg group (P = 0.024 versus placebo) but were not different from placebo in the higher-dose groups (Fig. 4B). Plasma total tau levels were significantly increased in all treated patients compared with placebo (P < 0.001 for all comparisons; Fig. 3). Plasma total tau levels also increased in the placebo group although not to a significant degree, particularly when compared with the other treatment groups.

Figure 3.

Change from baseline through Week 96 in plasma total tau concentrations over time. Plasma concentrations (pg/ml) are from all treated patients. Estimate of the central value for the ratio of the measurement during treatment to the measurement at baseline where the logarithmic transformation was employed on the data. ***P ≤ 0.001 versus placebo.

Figure 4.

Estimates of the central value for the ratio of the measurement during treatment to the measurement at baseline at Week 12 in CSF free tau (A) and CSF total tau (B) concentrations. CSF data (pg/ml) are from patients in Cohort 1. Estimates of the central value for the ratio of the concentration during treatment to the concentration at baseline where the logarithmic transformation was employed on the data. *P ≤ 0.05 versus placebo, **P ≤ 0.01 versus placebo.

Preliminary exposure-response results showed no improvement in the primary or key secondary end points with increasing tilavonemab exposures (Supplementary Table 7). Tilavonemab serum exposure (C_max and AUC_0–28) increased in a dose-proportional manner from 300 mg to 2000 mg levels in study participants with Alzheimer’s disease with comparable dose normalized C_max and AUC_0–28 across the three dose levels (Supplementary Table 7). The median T_max was observed 2.3 to 3 h post start of infusion across the three dose levels and the mean half-life following the fourth dose was 19.6 to 37.5 days across the three dose levels. Tilavonemab CSF exposures also increased in a dose-proportional manner from 300 mg to 2000 mg levels (Supplementary Table 8). The geometric mean per cent CSF/serum penetration across the three dose levels was 0.28% to 0.38%.

Across the tilavonemab dose groups, two patients each had a single postbaseline titre that was positive for tilavonemab antidrug-antibodies (ADAs); these positive titres were not expected to affect the PK of tilavonemab. The subsequent titre was negative for both patients. No other detectable serum ADA titres were observed in any postbaseline sample in the tilavonemab dose groups.

Through Week 96 of the study, a treatment-emergent adverse event was reported for 414 (91.4%) patients. Of these, 124 (27.4%) patients experienced an adverse event with a reasonable possibility of being treatment related as assessed by the investigator. The incidence of any adverse event was generally comparable across the tilavonemab treatment groups and placebo (Table 2). Serious adverse events were reported for 84 (18.5%) patients, with the most common being pneumonia, fall, and syncope (each occurring in four patients total). In total, 20 (4.4%) patients discontinued study drug due to an adverse event. There were six deaths during the study (Table 2); none were considered related to treatment. The most common (>10.0%) adverse events among patients receiving tilavonemab (any dose) were fall (19.0%), headache (12.2%), dizziness (11.0%), upper respiratory tract infection (11.0%), nasopharyngitis (10.4%), urinary tract infection (10.4%), and diarrhoea (10.1%). Infusion-related reactions were minimal across all treatment groups (tilavonemab 300 mg, n = 1; tilavonemab 1000 mg, n = 0; tilavonemab 2000 mg, n = 2; placebo, n = 0). MRI safety findings (e.g. microhaemorrhages and cerebral oedema) were comparable among the tilavonemab and placebo groups (Table 2).

Table 2.

Treatment-emergent adverse events through Week 96

Adverse events, n (%)	Tilavonemab
	Placebo (n = 116)	300 mg (n = 108)	1000 mg (n = 116)	2000 mg (n = 113)
Any adverse event	108 (93.1)	94 (87.0)	108 (93.1)	104 (92.0)
Adverse event related to study druga	28 (24.1)	32 (29.6)	31 (27.6)	33 (29.2)
Serious adverse event	26 (22.4)	19 (17.6)	22 (19.0)	17 (15.0)
Adverse event leading to discontinuation of study drug	4 (3.4)	6 (5.6)	6 (5.2)	4 (3.5)
Deathb	1 (0.9)	2 (1.9)	2 (1.7)	1 (0.9)
Most common adverse events by preferred term c , n (%)
Fall	25 (21.6)	21 (19.4)	17 (14.7)	26 (23.0)
Headaches	12 (10.3)	10 (9.3)	11 (9.5)	20 (17.7)
Dizziness	10 (8.6)	14 (13.0)	9 (7.8)	14 (12.4)
Upper respiratory tract infection	9 (7.8)	7 (6.5)	12 (10.3)	18 (15.9)
Nasopharyngitis	11 (9.5)	11 (10.2)	12 (10.3)	12 (10.6)
Urinary tract infection	15 (12.9)	11 (10.2)	13 (11.2)	11 (9.7)
Diarrhoea	9 (7.8)	12 (11.1)	10 (8.6)	12 (10.6)
Depression	11 (9.5)	10 (9.3)	8 (6.9)	12 (10.6)
Arthralgia	9 (7.8)	7 (6.5)	12 (10.3)	10 (8.8)
Anxiety	11 (9.5)	3 (2.8)	9 (7.8)	16 (14.2)
Adverse events of interest, n/N (%) d
Microhaemorrhaged	9/116 (7.8)	10/107 (9.3)	15/116 (12.9)	9/111 (8.1)
Cerebral oedemad	3/116 (2.6)	3/107 (2.8)	2/116 (1.7)	2/111 (1.8)
Infusion-related reaction, n (%)	0	1 (0.9)	0	2 (1.8)

Safety population included all randomized patients who had ≥1 dose of study drug. Data include all treatment-emergent adverse events with onset on or after the first dose date of study drug and within 20 weeks after the last dose date of study drug.

As assessed by the investigator.

Causes of death are stroke (placebo), pneumonia, and myocardial infarction (tilavonemab 300 mg); congestive heart failure and delirium (tilavonemab 1000 mg); and most likely atherosclerotic coronary artery disease and ischaemic heart disease (tilavenumab 2000 mg).

Occuring in >10.0% of patients by primary Medical Dictionary for Regulatory Activities v23.1 preferred term.

MRI findings where data are n/N where n = the number of patients with new postbaseline MRI findings and N = the number of patients with non-missing postbaseline values.

Patients who completed the 96-week treatment period were eligible to enroll in a long-term extension study (NCT03712787). The extension study was terminated when the primary efficacy analysis did not achieve the study objectives. Patient disposition and summary safety data are shown in Supplementary Fig. 5 and Supplementary Table 9, respectively. The overall safety findings in the extension study were consistent with those reported in the main study.

Discussion

This phase 2 study of tilavonemab, a monoclonal antibody that binds to the N-terminus of human tau, did not demonstrate efficacy for slowing disease progression in patients with early Alzheimer’s disease; the mean CDR-SB score worsened through Week 96 in all treatment groups and there was no significant reduction in decline of patient cognition or function with tilavonemab treatment compared with placebo when measured by secondary end points. While there was no evidence that tilavonemab had an effect on plasma or CSF NFL levels, or on whole-brain or medial temporal lobe volume, there was some evidence that it had a positive effect on hippocampal volume at higher dose levels, with less decrease from baseline at certain time points.

Despite lack of treatment efficacy, there was evidence of target engagement. The decrease of CSF free tau (i.e. tau not bound by antibodies) indicates that the doses assessed were sufficient to engage CSF tau. The magnitude of decrease in CSF tau necessary for clinical benefit is unknown; however, even though the CSF free tau reduction from baseline increased with increasing tilavonemab exposures, this effect seems to plateau at higher doses. In a study on the safety and efficacy of tilavonemab in PSP by Höglinger et al.,¹⁰ the higher dose of 4000 mg was included. The estimated effect on CSF free tau (per cent difference from placebo) was −38.0% for tilavonemab 2000 mg and −46.3% for tilavonemab 4000 mg. Therefore, it seems unlikely that higher doses of tilavonemab will show clinical benefit. The increase in plasma total tau levels seen across all treatment groups may be due to the extended plasma half-life of detectable tau in the presence of anti-tau antibodies, as suggested by prior studies.⁹ Tilavonemab was generally well tolerated, and no significant safety signals were observed. Missing infusions or delayed efficacy visits due to COVID-19 did not significantly impact the study results as suggested by sensitivity analyses.

There was a numerical differential effect observed on an ANCOVA subgroup analysis of CDR-SB mean score change from baseline in male versus female patients and those aged younger than 65 years versus those aged 65 years and older (Supplementary Fig. 1); however, the Treatment × Gender interaction term in the ANCOVA model is not statistically significant (P = 0.227) at the 0.1 level. For the age subgroup analysis, even though the Treatment × Age group interaction term in the ANCOVA model is statistically significant at the 0.1 level (P = 0.064), after adjusting multiple comparisons among three tilavonemab dose groups and placebo group, the statistical significance was not achieved for any tilavonemab dose group. In addition, the small sample size (ranges from 15 to 28 patients) for each tilavonemab dose group in the younger than 65 years group contributes to the uncertainty of the observed treatment effect in this age group.

The negative findings reported in this trial are consistent with results reported from other clinical trials investigating N-terminal anti-tau antibodies for the treatment of early Alzheimer’s disease. In separate trials, gosuranemab and semorinemab, IgG4 monoclonal antibodies that target the N-terminal of extracellular tau, failed to slow disease progression in patients with mild cognitive impairment due to Alzheimer’s disease and mild Alzheimer’s disease but were well tolerated.^14-16 Of note, both gosuranemab and tilavonemab also failed to show efficacy in phase 2 trials of patients with PSP, despite evidence of target engagement.^10,17

A possible reason that N-terminal anti-tau antibodies have been unsuccessful in treating early Alzheimer’s disease could lie in the mechanism driving neurodegeneration and clinical symptoms. While tau aggregates are considered a key contributor in the pathogenesis of Alzheimer’s disease’s cognitive decline, they are not the only mechanism, and other misfolded proteins such as amyloid-β, transactive response DNA-binding protein 43, α-synuclein,¹⁸ as well as processes such as neuroinflammation and gliosis,¹⁹ also play a role. Thus, targeting tau alone might not be sufficient to slow disease progression, at least at symptomatic stages.

Another reason for the lack of efficacy could be because anti-tau antibodies, such as tilavonemab, may be unable to bind tau if its aggregates in the brain are released in exosomes, as has been shown in cultured primary neurons and cells expressing mutant human tau.⁵ Exosomes may also provide an important link between the propagation of tau protein and the activation of microglia.²⁰ Further research is needed to understand the cellular mechanisms involved in the secretion and spreading of tau aggregates between cells.⁷

Additionally, there is a lack of clarity regarding which specific tau species is responsible for driving Alzheimer’s disease pathology.²¹ Even though tilavonemab binds most tau species, including normal tau, it is possible that tilavonemab may not recognize certain tau species that lack an N-terminal and may be important in Alzheimer’s disease pathology. In support of this, antibodies targeting the N-terminus of tau did not detect truncated forms of tau in vitro, while those antibodies directed to the central region of tau recognized all species.²² The mid-domain region also drives tau aggregation and antibodies that bind here may better prevent the spreading of aggregated pathologic forms of tau.²³ This suggests that anti-tau antibodies directed against the N-terminus may be less effective than those that target the mid-domain region.²⁴ To this point, several anti-tau antibodies targeting the mid-domain region are currently in development.^25-27

A key limitation to this study is the natural history of the disease as it presents in the study population. Because Alzheimer’s disease begins before symptoms manifest, it is possible that even patients clinically diagnosed with early Alzheimer’s disease are already too advanced pathologically to benefit from treatment with an anti-tau antibody.² Furthermore, tau imaging was not available at the time the trial began, and, therefore, the effect of tilavonemab on tau accumulation could be assessed only in a small subset of patients. An additional limitation is the lack of diversity in the study population, as most of the participants were White and well educated.

Although generally well tolerated, tilavonemab did not demonstrate efficacy in treating patients with early Alzheimer’s disease. Overall, data from this phase 2 study do not support further investigations of tilavonemab for the treatment of early Alzheimer’s disease.

Appendix I

Aware study investigators

Full details are available in the Supplementary material.

Lealani Acosta, Thomas Ala, Sanka Amadoru, Jeffrey Apter, Steven Arnold, Merce Boada-Rovira, Anne Boerjesson-Hanson, Wendy Bond, Michael Borrie, Gabriella Bottini, Bruce Brew, Mark Brody, James Burke, Jeffrey Burns, Annalisa Chiari, Roger Clarnette, Sharon Cohen, Martin Farlow, Simon Fishman, Norman Foster, Kristian Frederiksen, Giovanni Frisoni, Nigel Gilchrist, Darren Gitelman, Ira Goodman, Marc Gordon, Neill Graff-Radford, Merja Hallikainen, Adrian Ivanoiu, Gregory Jicha, Michael Jonsson, Diana Kerwin, Dineke Koek, James Lah, Ayesha Lall, Elly Lee, Gabriel Léger, Peter Ljubenkov, Camillo Marra, Pablo Martinez-Lage, Joseph Masdeu, Scott McGinnis, Patrizia Mecocci, Philip Morris, Marshall Nash, Allison Perrin, Aimee Pierce, Robert Riesenberg, Juha Rinne, Raquel Sanchez Del Valle, Elio Scarpini, Paul Schulz, Ronald Schwartz, Amanda Smith, Bryan Spann, Sylvie Van Snick, Rik Vandenberghe, Cherian Verghese, Alberto Villarejo, Chuang-Kuo Wu.

Funding

AbbVie Inc. funded the research for this study and participated in the study design; study research; collection, analysis, and interpretation of data; and writing, reviewing, and approving this manuscript for publication. All authors had access to the data, participated in the development and review of the document, and in the decision to submit this manuscript for publication. No honoraria or payments were made for authorship.

Competing interests

S.E.A. has received fees for serving on advisory boards for Allyx Therapeutics, Inc., Bob’s Last Marathon, Cassava, Cortexyme, Inc., Sage Therapeutics, Inc., vTv Therapeutics, Inc., and for consulting to AbbVie Inc., Boyle Shaughnessy Law, Cognito Therapeutics, Inc., Eisai, EIP Pharma, Inc., M3 Biotech, Inc., Orthogonal Neuroscience, Inc., and Risen Pharmaceutical Technology Co, Ltd. He has received sponsored research grant support from the following commercial entities: AbbVie Inc., Amylyx, Inc., Athira Pharma, Inc., Chromadex, Inc., EIP Pharma, Inc., Janssen Pharmaceuticals, Inc., Novartis AG, Seer Biosciences, Inc. and vTv Therapeutics, Inc. He has received sponsored research grant support from the following non-commercial entities: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Challenger Foundation, John Sperling Foundation, and the National Institutes of Health. M.B. has received consulting fees from Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, and Zambon. She has served on advisory boards for Grifols, Roche, Lilly, Araclon Biotech, Merck, Zambon, Biogen, Novo-Nordisk, Eisai, and Schwabe Pharma, and has given lectures for Roche, Biogen, Grifols, Nutricia, Araclon Biotech, and Novo-Nordisk. She has received funding from Life Molecular Imaging, Bioiberica, Grifols, Araclon Biotech, Roche, and Janssen, and grants from CIBERNED (Instituto de Salud Carlos III [ISCIII]), EU/EFPIA Innovative Medicines Initiative Joint Undertaking, ADAPTED Grant No. 115975, from EXIT project, EU Euronanomed3 Program JCT2017 Grant No. AC17/00100, MOPEAD, Innovative Medicine Initiative, Grant. No. 115985, PreDADQoL, ERA-NET (call 2015) Grant No. AC15/00082, TARTAGLIA, Red federada para accelerar la aplicación de la inteligencia artificial en el sistema sanitario español, dentro del marco del Programa Misiones IA (2021), PREADAPT Project, Joint Program for Neurodegenerative Diseases (JPND) Grant No. AC19/00097, and from grants PI13/02434, PI16/01861 BA19/00020, and PI19/01301, European Marie Sklodowska Curie. Acción Estratégica en Salud, integrated in the Spanish National RCDCI Plan and financed by Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—‘Una manera de Hacer Europa’), by Fundación bancaria ‘La Caixa’ and Grífols SA (GR@ACE project). H.F., D.W., Q.G., Z.J., H.Z., N.F., H.V.K., and M.G. are employees of AbbVie Inc., and may hold AbbVie stock and/or stock options. B.R.-M. is an employee of AbbVie Deutschland GmbH. K.B. is a former employee of AbbVie Inc., currently employed by Harmony Biosciences.

Supplementary material

Supplementary material is available at Brain online.