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The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early‐phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early‐phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. Highlights: Experts provided a framework to translate therapeutics (discovery to clinical trials).Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial).Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics)Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need. [ABSTRACT FROM AUTHOR]

Background: Bepranemab is a recombinant, humanized, full‐length IgG4 monoclonal antibody that binds to a central tau epitope (amino acids 235‐250). Here, we update on the progress of the TOGETHER study (AH0003; NCT04867616) with bepranemab in early Alzheimer's disease (AD). Method: TOGETHER is a global, multicenter, double‐blind, placebo‐controlled, parallel‐group study investigating the efficacy, safety and tolerability of bepranemab versus placebo. Patients with prodromal (National Institute on Aging‐Alzheimer's Association [NIA‐AA] Stage 3) or mild (NIA‐AA Stage 4) AD (target N = 450) will be randomized (1:1:1) to receive one of two doses of bepranemab or placebo (intravenous, every 4 weeks), over an 80‐week treatment period, followed by an optional 48‐week open‐label‐extension period. Participants will have a global Clinical Dementia Rating (CDR) score of 0.5 (prodromal AD) or 0.5–1.0 (mild AD) and a CDR‐Memory Box score ≥0.5 at screening and baseline, a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), mini‐mental state examination (MMSE) ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read positron emission tomography (PET) scan or a positive cerebrospinal fluid (CSF) pTau181/Aβ1‐42 ratio. The primary endpoint is change from baseline to Week 80 in CDR scale Sum of Boxes total score. Secondary endpoints include: pharmacokinetics; safety and tolerability; tau PET imaging and change from baseline in AD Assessment Scale‐Cognitive Subscale 14, Amsterdam Instrumental Activities of Daily Living questionnaire and MMSE at Weeks 56 and 80. Result: As of March 1, 2022, 56/125 planned centers have enrolled participants across 8 countries: Belgium, Canada, France, Netherlands, Poland, Spain, UK and USA. Of the 538 participants who entered screening, 62 have been randomized so far and 334 failed screening. Predominant reasons for screen failure include not meeting RBANS, MMSE or Aβ positivity (CSF or PET) criteria. Conclusion: This proof‐of‐concept study employs clinical outcome measures, imaging, pharmacokinetics, and biomarkers to assess the ability of bepranemab to slow progression of AD when administered in the early stages of disease. Enrollment and randomization are underway with nearly half of the study centers active. [ABSTRACT FROM AUTHOR]

Background: Bepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that binds to a central tau epitope (amino acids 235–250). Bepranemab is being developed to block or reduce the spread of tau pathology in people living with tau‐mediated diseases, like Alzheimer's disease (AD). Method: TOGETHER (AH0003; NCT04867616) is a global, multicenter, patient‐blind, investigator‐blind, placebo‐controlled, parallel‐group study, investigating the efficacy, safety, and tolerability of bepranemab (intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80‐week treatment period, followed by an optional 48‐week open‐label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14‐item Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog14), Amsterdam‐Instrumental Activities of Daily Living, and Mini‐Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long‐term safety and tolerability of bepranemab. Approximately 150 patients per arm will be enrolled across 3 study arms (low‐dose and high‐dose bepranemab, and placebo; randomized 1:1:1). Eligible patients will meet the National Institute of Aging‐Alzheimer's Association (NIA‐AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients will have a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR‐Memory Box score ≥0.5 at screening and baseline. Patients will have a score of ≤85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE ≥20 at screening and must meet the NIA‐AA 2018 definition of cerebral beta‐amyloid (Aβ) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTau181/Aβ1‐42 ratio. Result: Patient enrollment and assessment will begin in Quarter 2 2021. Conclusion: TOGETHER is a proof‐of‐concept study that will employ clinical outcome measures, imaging, PK, biomarkers, and safety to assess the ability of bepranemab to slow the progression of AD when administered in the prodromal/mild stages of disease. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease‐modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect.The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease‐modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS.To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial.The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival.Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]