Citations

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

Abstract Background Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis. Repurposed posaconazole (PCZ) has demonstrated efficacy in vitro by targeting key metabolic pathways. The aim of this study was to determine the neuropharmacological profile of PCZ in patients with GBM through a Phase 0 first-in-human trial for this indication (NCT04825275). Methods We conducted an open-label, non-randomized, parallel-arm trial in participants with primary or recurrent GBM. Patients in the treatment arm received oral PCZ for 7-10 days presurgically to achieve steady-state concentrations. Microdialysis catheters were implanted to measure interstitial drug levels. Postoperative tissue and fluid samples were analyzed to evaluate PCZ pharmacokinetics (mass spectrometry) and pharmacodynamics, including vascular density, apoptosis, and metabolite concentrations (lactate and pyruvate) compared to controls. Results The trial was closed early due to slow accrual, enrolling 2 participants in the PCZ arm and three in the control arm. No drug-related safety issues were observed. Although PCZ was undetectable in microdialysate fluid, it accumulated in tumor tissue, with concentrations showing an association with CD31-measured endothelial content. PCZ-treated tumors exhibited trends toward lower BCL2 expression indicative of increased apoptosis, and significantly lower pyruvate levels in the tumor periphery compared to controls. Plasma lactate levels in treated patients normalized to control levels over 24 h. Conclusions Despite limited accrual, this trial provides the first clinical evidence that oral PCZ accumulates in human GBM tissue and shows preliminary signals of metabolic modulation. These findings provide biological rationale warranting further clinical investigation, potentially utilizing direct tissue sampling rather than microdialysis.

Abstract Importance Respiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8−19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season. Objectives To describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups. Design, Setting, and Participants Surveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV). Exposure Preexisting health conditions potentially increasing risk of severe RSV disease. Main Outcomes and Measures Patients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared. Results Among 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (p trend <0.001). Conclusions and Relevance Approximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations. Key Points Question What preexisting health conditions are present in children aged 8–<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ? Findings Among 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without. Meaning These findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.

Abstract Purpose: The addition of MEK inhibition (MEKi) to programmed cell death ligand 1 (PD-L1) blockade improves progression-free survival (PFS) in patients with advanced biliary tract cancer. Although MEK inhibitors may increase tumor cell immunogenicity, they can impair T-cell priming/effector function, limiting combination efficacy. We hypothesized that the addition of a CD27 agonist could restore T-cell function and enhance antitumor immunity in this combination. Patients and Methods: We conducted a randomized, phase II trial evaluating atezolizumab (840 mg, intravenously, days 1 and 15) in combination with the CD27 costimulatory monoclonal antibody [CDX-1127/varlilumab (3 mg/kg, intravenously, days 1 and 15)], with/without the addition of an MEK inhibitor [cobimetinib (60 mg, orally, daily, days 1–21, off days 22–28)] in unresectable biliary tract cancer following at least one metastatic therapy. Overall response rate (ORR) and PFS were coprimary endpoints. Treatment-related changes in CD8+ tumor-infiltrating lymphocytes (TIL) were the primary correlative outcomes. Results: The trial was closed early following interim preplanned ORR analysis. At closure, 57 patients had been enrolled [n = 29 in the cobimetinib + atezolizumab + varlilumab (CAV) arm; n = 28 in the atezolizumab + varlilumab (AV) arm]. A majority (67%) had intrahepatic cholangiocarcinoma, and 32% were immunotherapy experienced. Both regimens were well tolerated without new safety signals. Objective responses were rare [0% (CAV); 3.8% (AV)]. The median PFS (mPFS) was 2.40 (CAV) and 1.84 (AV) months [hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.38–1.18]. Among immunotherapy-experienced patients, the mPFS was 3.62 (CAV) and 1.84 (AV) months (HR, 0.54; 95% CI, 0.18–1.62). Treatment with CAV increased intratumoral CD8+ T-cell density compared with treatment with AV. Conclusions: The combinations of atezolizumab and varlilumab with/without cobimetinib were safe, but neither meaningfully improved outcomes in biliary tract cancer treated in the later lines. Correlative tissue studies validated preclinical work that MEKi increases CD8+ TILs.

ABSTRACT Background & Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is highly prevalent and increasingly recognized as a multisystem cardiometabolic disorder. The global burden, incidence and prognostic implications of coexisting chronic kidney disease (CKD) in MASLD remain uncertain. Methods In this meta‐analysis, we searched MEDLINE and EMBASE from inception through September 25, 2025, for observational studies reporting CKD prevalence and/or incidence among adults (≥ 18 years) with MASLD. The primary outcomes were pooled CKD prevalence, estimated using random‐effects models on the logit scale with the Hartung–Knapp adjustment, and pooled CKD incidence (per 1000 person‐years), estimated using random‐effects models with exact Poisson confidence intervals. Secondary outcomes included all‐cause mortality and cardiovascular, renal and cancer outcomes. Results From 2811 records, 36 observational studies met the inclusion criteria. Twenty‐three studies contributed prevalence estimates (575 615 participants; 56 248 CKD cases) and thirteen studies contributed incidence estimates (27 996 new events). The pooled global CKD prevalence among individuals with MASLD was 15.22% (95% CI 9.69–23.12). The pooled CKD incidence was 22.17 per 1000 person‐years (95% CI 11.44–32.89) in the MASLD population. Hypertension (OR 1.49, 95% CI 1.29–1.72), dyslipidaemia (OR 1.22, 95% CI 1.20–1.24) and diabetes (OR 1.94, 95% CI 1.69–2.22) were associated with higher odds of CKD in the MASLD population. All‐cause mortality rates were 18.28 per 1000 person‐years (95% CI 3.45–33.11) in coexistent MASLD and CKD, more than double those in the MASLD‐only population (7.26 per 1000 person‐years (95% CI 2.97–11.56)). Conclusions Coexistent CKD affects one in seven individuals with MASLD worldwide, conferring a more than two‐fold increased risk of all‐cause mortality compared with individuals with MASLD alone.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)–related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24–0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19–0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20–0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.