tilavonemab (ABBV-8E12) / C2N Diagnostics, AbbVie - LARVOL DELTA

APPLICATIONS OF DIGITAL TWINS OF ALZHEIMER'S DISEASE (AD) PARTICIPANTS FOR DESIGNING EFFICIENT TRIALS AND IMPROVING CONFIDENCE IN DECISION-MAKING (ADPD 2025) - P2 | "The trained AD model generated digital twins of participants post-hoc using the baseline data of participants enrolled in a completed phase 2 trial (AWARE trial, N=453, NCT02880956), which tested tilavonemab, an anti-tau monoclonal antibody, in subjects with early AD...Conclusions Digital twins can be seamlessly integrated into AD studies to enhance efficiency in the design and conduct while remaining aligned with regulatory guidance. Furthermore, digital twins increase confidence in decision-making during the trial."

Alzheimer's Disease • CNS Disorders

Comparative the efficacy and safety of Gosuranemab, Semorinemab, Tilavonemab, and Zagotenemab in patients with Alzheimer's disease: a systematic review and network meta-analysis of randomized controlled trials. (PubMed, Front Aging Neurosci) - "Further studies are needed to confirm these findings, assess long-term effects, and refine treatment protocols. https://www.crd.york.ac.uk/prospero/#myprospero, CRD42024583388."

Journal • Retrospective data • Review • Alzheimer's Disease • CNS Disorders • Dementia • Infectious Disease • Nephrology

Drug Development. (PubMed, Alzheimers Dement) - P2 | "Depending on correlations between prognostic scores and actual trial outcomes, a potential overall sample size reduction of 5-10% could be achieved using DT methodology (PROCOVATM) while maintaining statistical power, based on Δ CDR-SB and Δ ADAS-Cog 14 in the AWARE study. Sample size savings could enable shortening of the recruitment period and reduce the number of patients on placebo, encouraging greater patient participation."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Efficiency of multivariate tests in trials in progressive supranuclear palsy. (PubMed, Sci Rep) - "We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial...The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases."

Journal • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Limitations and potential strategies of immune checkpoint blockade in age-related neurodegenerative disorders. (PubMed, J Physiol Sci) - "Lately, disease-modifying therapies (DMTs) that can alter the pathophysiology that underlies AD with anti-Aβ monoclonal antibodies (MAbs) (e.g., aducanumab, lecanemab, gantenerumab, donanemab, solanezumab, crenezumab, tilavonemab). Similarly, in Parkinson's disease (PD), DMTs utilizing anti-αSyn (MAbs) (e.g., prasinezumab, cinpanemab,) are progressively being developed and evaluated in clinical trials. These therapies are based on the hypothesis that both AD and PD may involve systemic impairments in cell-dependent clearance mechanisms of amyloid-beta (Aβ) and alpha-synuclein (αSyn), respectively, meaning the body's overall inability to effectively remove Aβ and αSyn due to malfunctioning cellular mechanisms. In this review we will provide possible evidence behind the use of immunotherapy with MAbs in AD and PD and highlight the recent clinical development landscape of anti-Aβ (MAbs) and anti-αSyn (MAbs) from these clinical trials in order to better investigate..."

Checkpoint block • Checkpoint inhibition • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease

Proteostasis as a fundamental principle of Tau immunotherapy. (PubMed, Brain) - "Therefore, by phage display, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralises proteopathic seeding activity in multiple cell lines, and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab)...Gene set over-representation analysis (ORA) further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced restoration of proteostasis links target engagement and treatment efficacy."

Journal • Alzheimer's Disease • CNS Disorders • MAPT

Assessment of AI-generated digital twin (DT) methodology on reduction of treatment effect variance and potential clinical trial sample size saving using a Phase 2 trial dataset from patients with Alzheimer’s disease (AD) (AAIC 2024) - P2 | "We assessed these properties using data from a Phase 2 clinical trial of tilavonemab in patients diagnosed with early AD (NCT02880956) and digital twin (DT) methodology (PROCOVA TM )... Depending on correlations between prognostic scores and actual trial outcomes, a potential overall sample size reduction of 5–10% could be achieved using DT methodology (PROCOVA TM ) while maintaining statistical power, based on Δ CDR-SB and Δ ADAS-Cog 14 in the AWARE study. Sample size savings could enable shortening of the recruitment period and reduce the number of patients on placebo, encouraging greater patient participation."

Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Language impairment associated with prognosis in progressive supranuclear palsy (AAIC 2024) - " One hundred-forty-six patients with a diagnosis of possible or probable PSP from the Tilavonemab (ABBV-8E12) clinical trial were evaluated at baseline and week 32 using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the PSP rating scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL)... language impairment at baseline, in contrast to memory and executive functions, was predictive of functional decline as measured by PSPRS. Atrophy in language areas at baseline predicted language decline. Language impairment may be an independent prognostic factor in PSP."

Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Assessing tilavonemab efficacy in early Alzheimer's disease via longitudinal item response theory modeling. (PubMed, Alzheimers Dement (N Y)) - "While tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

COMPARATIVE ANALYSIS OF TAU N-TERMINAL ANTIBODIES IN VITRO AND IN A MOUSE MODEL OF TAUOPATHY (ADPD 2024) - " We generated a novel pan-Tau antibody, RNJ1, which binds to a region in Tau's N-terminus adjacent to the epitope of the clinically tested HJ8.5 (murine version of tilavonemab), which we used here as a benchmark for comparison of therapeutic efficacy... Our study presents RNJ1 as a promising Tau antibody with enhanced therapeutic potential and underscores the importance of exploring Tau's N-terminus in pathology and as a therapeutic target."

Preclinical • Alzheimer's Disease • CNS Disorders • MAPT

A Novel Tau Staging Scheme Using [18F]MK-6240 PET Visual Read Extent Scores (CTAD 2023) - P2 | " This work includes data from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) and from the phase 2 study evaluating the efficacy and safety of tilavonemab in patients with early AD (NCT02880956)... This study shows the potential advantages of the current visual read algorithm for patient selection by tau load. Future analyses will focus on the relationship between visual extent scores and plasma biomarkers."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model. (PubMed, Sci Rep) - "Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease

A tau-directed monoclonal antibody could alter the tau pathology of progressive supranuclear palsy (MDS Congress 2023) - "Our study suggests that a tau-directed monoclonal antibody could alter the tau pathology of PSP and might promote microglia/macrophage-mediated phagocytosis."

CNS Disorders • Parkinson's Disease • Progressive Supranuclear Palsy • CD68

Passive tau-based immunotherapy for tauopathies. (PubMed, Handb Clin Neurol) - "At present, 12 anti-tau antibodies have entered clinical trials, and 7 of them are still in clinical testing for primary tauopathies and AD (semorinemab, bepranemab, E2814, JNJ-63733657, Lu AF87908, PNT00, and APNmAb005). Two other anti-tau monoclonal antibodies have been discontinued for the treatment of primary tauopathies, i.e., gosuranemab and tilavonemab. Further evidence will come from ongoing Phase I/II trials on passive immunotherapeutics for treating primary and secondary tauopathies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Frontotemporal Lobar Degeneration • Movement Disorders • Progressive Supranuclear Palsy

A polygenic risk score (PRS) predicts cognitive decline in the APOE3 population in an early Alzheimer’s disease clinical trial cohort (AAIC 2023) - "We utilized PRS ( geno SCORE™) to predict cognitive function decline in a cohort of 280 AD patients in a Ph2 clinical trial for Tilavonemab, a monoclonal antibody targeting the N-terminus of human tau...Conclusions : The results of these analyses demonstrate that geno SCORE™ may be helpful to enrich for APOE3 individuals most susceptible to cognitive decline over time. Since the majority of genetic risk studies have focused on an APOE4 population, this method provides a novel tool to enrich for individuals at high risk for cognitive decline over time in a less studied population in which there is difficulty with prediction of disease progression."

Clinical • Alzheimer's Disease • CNS Disorders • Dementia • APOE

VISUAL ASSESSMENT OF [18F]MK-6240 PET SCANS IN EARLY ALZHEIMER'S DISEASE (ADPD 2023) - "[18F]MK -6240 tau PET scans were included in a substudy of the Phase 2 study of tilavonemab in early Alzheimer's disease (AD) (NCT0288095) at baseline, week 44, and week 96... Our visual assessment of [18F]MK -6240 PET scans showed good agreement between readers. The use of a novel extent score may allow us to select AD patients by Braak stage using solely a visual read."

Alzheimer's Disease • CNS Disorders • Immunology

MODELING PHARMACODYNAMIC EFFECTS OF PUBLISHED CLINICALLY TESTED ANTI-TAU AND ANTISYNUCLEIN ANTIBODIES TO IMPROVE CLINICAL TRIAL DESIGN (ADPD 2023) - "We si mulated clinical trials of gosuranemab, tilavonemab, semorinemab, cinpanemab and prasinezumab using published clinical profiles. The current model suggests that the antibodies' effect on accessible biomarkers in CSF is quite different from changes in other brain compa rtments, notably in the synaptic cleft and neuronal uptake which are proxies for disease progression."

Clinical • PK/PD data • Immunology

Tilavonemab in early Alzheimer's disease: results from a phase 2, randomized, double-blind study. (PubMed, Brain) - P2 | "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."

Clinical • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Dementia

An Extension Study of ABBV-8E12 in Early Alzheimer's Disease (AD) (clinicaltrials.gov) - P2 | N=364 | Terminated | Sponsor: AbbVie | Completed ➔ Terminated; Discontinued because of lack of efficacy in the parent study (Study M15-566; NCT02880956).

Trial termination • Alzheimer's Disease • CNS Disorders

AbbVie acquires Syndesi Therapeutics in $1bn deal (PMLive) - “The deal will allow AbbVie to access Syndesi’s research into the potential treatment of cognitive impairment and other symptoms associated with neurodegenerative and neuropsychiatric disorders, including major depressive disorder and Alzheimer's disease. AbbVie has been heavily involved in various Alzheimer’s projects, including an amyloid-beta drug the company believes could work against the degenerative disease. However, AbbVie’s R&D team has also been hindered by setbacks, including a decision to scrap a phase 2 tau-focused drug, ABBV-8E12, after failing to record efficacy….According to the terms of the $1bn agreement, Abbvie will pay Syndesi an upfront payment of $130m, with milestone payments of up to $870m.”

Licensing / partnership • Alzheimer's Disease • CNS Disorders

An Extension Study of ABBV-8E12 in Early Alzheimer's Disease (AD) (clinicaltrials.gov) - P2; N=364; Completed; Sponsor: AbbVie; Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders

Phase 2 Study of Tilavonemab, an Anti-tau Antibody, in Early Alzheimer’s Disease (CTAD 2021) - P2 | "Although generally safe and well tolerated among patients in the study, tilavonemab did not demonstrate efficacy in treating patients with early AD."

P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • Infectious Disease • Nephrology • Pain • Respiratory Diseases • Amyloid PET • APOE • MRI • Plasma NfL

Characteristics of subjects with discordant amyloid status between visual read and centiloid from the Phase 2 clinical study of Tilavonemab in early Alzheimer’s disease (CTAD 2021) - P2 | "Visually-negative CL-positive amyloid patients had a significantly lower mean CL value than visually-positive (randomized) patients and were significantly less impaired as measured by MMSE and CDR-SB. Using a quantitative threshold (CL) as an inclusion criterion appears to be a valid strategy but is more sensitive to lower levels of amyloid, which may result in an earlier or less impaired AD population."

Clinical • P2 data • Alzheimer's Disease • Amyloidosis • CNS Disorders • Dementia • Amyloid PET

Neuropathology of progressive supranuclear palsy after treatment with tilavonemab. (PubMed, Lancet Neurol) - No abstract available

Journal • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Neuropathology of progressive supranuclear palsy after treatment with tilavonemab - Author's reply. (PubMed, Lancet Neurol) - No abstract available

Journal • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy