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Background: Genetic‐driven deregulation of the amyloid pathway and overproduction of downstream amyloid‐β are known to cause early‐onset Alzheimer's disease (EOAD)1. ALN‐APP is an investigational intrathecally (IT) administered RNAi therapeutic designed to reduce upstream intracellular and extracellular amyloid precursor protein (APP) levels by lowering APP mRNA. As a result, we hypothesize that ALN‐APP may alter the cascade of events that result in neurodegeneration, potentially slowing, halting, or reversing Alzheimer's disease progression. Method: ALN‐APP‐001 (NCT05231785) Part A is an ongoing randomized, double‐blind, placebo‐controlled, Phase 1 single‐ascending dose study in patients with EOAD. Patients are required to have disease onset at age <65 years, Clinical Dementia Rating® global score of 0.5 or 1.0, and Mini Mental State Examination score >20. Patients are being evaluated over 6 months, with further follow‐up of up to 6 months as needed. The primary endpoint is the safety and tolerability of ALN‐APP. Secondary objectives include the evaluation of pharmacokinetics and pharmacodynamic effects of ALN‐APP. Result: 12 patients were enrolled and randomized 2:1 to receive ALN‐APP or placebo in 25mg and 75mg dose cohorts. Baseline characteristics are shown in Table 1. Mean (SD) duration on study was 6.7 (1.7) months for cohort 1 (25mg) and 2.0 (1.0) months for cohort 2 (75mg). Dose‐dependent reductions of soluble APPα and APPβ (sAPPα and sAPPβ) levels in cerebrospinal fluid (CSF) at day 15 were observed following a single dose of ALN‐APP, with mean reductions from baseline of 55% (sAPPα) and 69% (sAPPβ), and maximum reductions of 71% (sAPPα) and 83% (sAPPβ) in the 75mg cohort (n = 4) (Table 2). All adverse events (AEs) by data cut‐off on 01/17/2023 were mild or moderate (Table 3), with no AEs deemed related to study drug by the investigators. Additional cohort data will be presented at the meeting. Conclusion: This first clinical study of a CNS‐administered RNAi therapeutic demonstrates target engagement of APP, with reductions in CSF sAPPα and sAPPβ. To date, ALN‐APP remains generally well tolerated with all reported AEs mild or moderate. These interim results support further evaluation of ALN‐APP in patients with EOAD. Reference: 1. Hampel H et al. Molecular Psychiatry (2021). 26:5481‐5503. [ABSTRACT FROM AUTHOR]

Highlights • Drug resistant epilepsy is a common problem, especially in tertiary referral centers. • The proportion of patients that can be rendered seizure free is not well known. • We show that over 60% of patients have ongoing seizures despite adequate treatment. • Patients with ongoing seizures represent a severely affected population. • There is an ongoing need for further development of novel treatments for epilepsy. Abstract Purpose Despite the availability of a broad range of treatments for epilepsy, a significant proportion of patients have ongoing seizures. This study aims to characterize the drug resistant population and to report long-term outcomes of patients undergoing different types of pharmacological and surgical treatment. Methods Adult patients with drug resistant epilepsy (DRE) were identified from a largely retrospective database of 900 consecutive patients with epilepsy, recruited from two reference centers for DRE in Belgium. We report treatment trajectories and long-term seizure outcomes in the different treatment groups. Results 640 patients had DRE. 249 (38.9%) underwent presurgical assessment, followed by surgical treatment in 197 (30.8%), resulting in seizure freedom in 86 (13.4%). 443 patients (69.2%) were treated only with further AED trials, of which 163 (25.5%) became seizure free. In the 391 patients with ongoing seizures (61.1%), mean age was 43.2 years, mean disease duration 23 years and mean number of AED trials 6.9. 291 (74.4%) had tonic-clonic seizures, and 43 (11.0%) had one or more episodes of status epilepticus. Patients with hippocampal sclerosis were significantly more likely to be seizure free, while patients with malformation of cortical development and those with temporal lobe epilepsy of unknown etiology were more likely to have ongoing seizures. Conclusion Our findings demonstrate that – even with adequate access to surgical treatment and further AED trials – 61.1% of patients with DRE had ongoing seizures. This illustrates that there is a scope for ongoing development of novel treatments for DRE. [ABSTRACT FROM AUTHOR]

Purpose: Despite the availability of a broad range of treatments for epilepsy, a significant proportion of patients have ongoing seizures. This study aims to characterize the drug resistant population and to report long-term outcomes of patients undergoing different types of pharmacological and surgical treatment.Methods: Adult patients with drug resistant epilepsy (DRE) were identified from a largely retrospective database of 900 consecutive patients with epilepsy, recruited from two reference centers for DRE in Belgium. We report treatment trajectories and long-term seizure outcomes in the different treatment groups.Results: 640 patients had DRE. 249 (38.9%) underwent presurgical assessment, followed by surgical treatment in 197 (30.8%), resulting in seizure freedom in 86 (13.4%). 443 patients (69.2%) were treated only with further AED trials, of which 163 (25.5%) became seizure free. In the 391 patients with ongoing seizures (61.1%), mean age was 43.2 years, mean disease duration 23 years and mean number of AED trials 6.9. 291 (74.4%) had tonic-clonic seizures, and 43 (11.0%) had one or more episodes of status epilepticus. Patients with hippocampal sclerosis were significantly more likely to be seizure free, while patients with malformation of cortical development and those with temporal lobe epilepsy of unknown etiology were more likely to have ongoing seizures.Conclusion: Our findings demonstrate that - even with adequate access to surgical treatment and further AED trials - 61.1% of patients with DRE had ongoing seizures. This illustrates that there is a scope for ongoing development of novel treatments for DRE. [ABSTRACT FROM AUTHOR]

Background: The hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs. Method: Here, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models. Results: Our RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid. Conclusion: Together, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies. [ABSTRACT FROM AUTHOR]

Background: The hyperphosphorylation and subsequent aggregation of the microtubule‐associated protein Tau (encoded by the MAPT gene) is one of the major histopathological hallmarks of numerous tauopathies, including Alzheimer's disease and progressive supranuclear palsy. The intracellular accumulation of aggregated Tau is associated with neuronal loss and disease progression in tauopathies. There is a high‐unmet need to identify strategies to target the intracellular accumulation of Tau aggregates with the aim of slowing tauopathy progression. Method: To model this, we used mice carrying multiple copies of a transgene with a prion promoter driving human MAPT with human tauopathy‐inducing mutation P301S. P301S‐Tau transgenic mice progressively accumulate neuroglial Tau aggregates associated with axonal damage, gliosis, body weight loss, and ambulatory dysfunction. Result: P301S mice treated with a single intracerebroventricular injection of Tau siRNA at eight months of age, had a sustainable decrease in MAPT mRNA and soluble Tau protein for three months following siRNA treatment (reduced ∼83% and ∼59%, respectively). siRNA treatment also prevented the progressive decrease in body weight and abrogated axonal damage, evidenced by decreased neurofilament light (NFL) chain in plasma and cerebrospinal fluid of eleven‐month‐old mice. Importantly, immunohistochemical analysis of misfolded Tau in vivo and HEK293‐4RD‐CFP/YFP Tau aggregate biosensor assay testing in vitro revealed a ∼97% decrease of Tau aggregates in the eleven‐month‐old mice, suggesting there exists a yet‐to‐be identified mechanism of Tau fibril clearance. Conclusion: Together, these results suggest an RNAi therapeutics approach targeting of MAPT mRNA may be sufficient to improve multiple parameters of tauopathy disease progression and a provide a compelling rationale for further development of Tau‐lowering strategies. [ABSTRACT FROM AUTHOR]

Background: The ε4 allele of the Apolipoprotein‐E (APOE) gene is the major genetic risk factor for late‐onset Alzheimer's disease (AD). APOE ε4 carriers represent around 45% of AD population, with each copy of APOE ε4 allele conferring increased risk for AD. Here, we aim to quantify disease progression during the early clinical stage of AD using imaging biomarkers to stratify patient populations for therapeutic interventions. Methods: Data used in the preparation of this abstract were obtained from the Alzheimer's Disease Neuroimaging Initiative. CDR some of boxes (CDR‐SB), PET (amyloid load; Florbetapir), MRI (hippocampal volume) and APOE4 genotype were collected. Only MCI patients were included (MMSE=27.6±1.8 and global‐CDR=0.5±0.05). Available follow up data with at least 10 participants were included in the analysis. Results: Data from 1021 participants with baseline MCI status were included in the study (110 ε4 homozygotes, 397 heterozygotes ε4). At baseline, CDR‐SB of non‐carriers and ε4 homozygotes was not different (p=0.24). The annual rate of cognitive decline in ε4 homozygotes (0.7 points per year; p=7e‐8) and heterozygotes ε4 (0.56 points per year; p=4e‐8) was 3.7 to 4.6 times greater than non‐carriers (0.15 points per year; p=0.00005). At baseline, hippocampal volume was significantly (p<0.01) lower in ε4 homozygotes (6.50 mL) and heterozygotes ε4 (6.76 mL) compared to non‐carriers (6.98 mL). The annual rate of hippocampal loss in ε4 homozygotes (0.09 mL; p=0.032) and heterozygotes ε4 (0.13 mL; p=0.0006) was faster than non‐carriers (0.03 mL; p=0.16). At baseline, amyloid load was significantly (p<0.0001) higher in ε4 homozygotes (SUVR=1.37) and heterozygotes ε4 (SUVR=1.31) compared to non‐carriers (SUVR=1.13). The rates of progression were not significantly different across groups. Conclusion: APOE ε4 carriers showed notably greater rate of progression on CDR‐SB compared to non‐carriers. Greater amyloid load and hippocampal atrophy were observed in APOE ε4 carriers compared to non‐carriers at baseline although the CDR‐SB scores were comparable. The amyloid deposition appeared to plateau at MCI. Hippocampal volume loss continued in all groups, with a fastest progression rate in ε4 carriers. Result suggests that detection of therapeutic changes from interventions may be more efficient in this population than the broader population of MCI patients. [ABSTRACT FROM AUTHOR]