Proposed system for food safety assessment. Scientific Committee, Food Safety Council.
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Animals↗
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Integrated functional genomics and safety assessment of plant-growth-promoting Caryophanales from post-maize-cultivation soils.
This study aimed to evaluate six environmental bacterial strains isolated from post-maize cultivation soils as candidates for agricultural biopreparation development, using an integrated functional genomic and safety assessment framework. Building on experimental validation of plant-growth-promoting activities, the analysis included: plant-growth-promoting traits (PGPT-Pred) using PLABase; carbohydrate-active enzymes (CAZymes) relevant for lignocellulosic crop residue degradation (dbCAN3); secondary metabolite profiles (antiSMASH); and screening for virulence factors and antibiotic resistance genes (ABRicate, BTyper3).All analyzed strains possess 1,449-1,617 predicted PGPT-encoding genes (24.1-35.9% of total genes), which are strongly shaped by taxonomic relatedness, as confirmed by congruence testing against ANI-based genomic divergence. Paenibacillus amylolyticus 5mez and Priestia megaterium 7psych showed distinct functional profiles compared to Bacillus spp., while Bacillus subtilis sensu lato strains were most similar to each other. Genomic predictions suggest involvement in nutrient acquisition (N, P, K, Fe) and stress mitigation. Secondary metabolite analysis revealed high biosynthetic potential, with non-Bacillus species harbouring a large proportion of unknown gene clusters, indicating underexplored metabolite diversity. CAZyme profiling identified P. amylolyticus 5mez as the most enzyme-rich strain, while B. cereus s.s. zielonkawy showed ligninolytic potential despite low overall CAZyme abundance. The safety assessment identified B. cereus s.s. zielonkawy as toxigenic and unsuitable for use. Of the remaining strains, P. amylolyticus 5mez and Pr. megaterium 7psych demonstrated the most favourable safety profiles, exhibiting no detectable virulence factors or antibiotic resistance genes, justifying their priority use in agricultural biopreparations, pending phenotypic validation. Given the high-dimensional, low-sample-size nature of multi-trait datasets in applied microbial genomics, tailored statistical approaches, including noise-reduction-validated PCA and distance-based congruence testing, were applied; their rationale and limitations are discussed.
Soil Microbiology↗
Isolation, genomic characterization, and safety assessment of an O-desmethylangolensin-producing Clostridium beijerinckii strain from Chinese Stinky Tofu.
The health benefits of dietary soy isoflavones are largely mediated by specific microbial metabolites, such as O-desmethylangolensin (O-DMA). However, the diversity and application potential of O-DMA-producing strains remain poorly explored, primarily due to the limited availability of isolated strains, narrow ecological sources, and a lack of practical applications. In this study, an O-DMA-producing bacterium, designated strain FRJF5, was isolated from Chinese stinky tofu under anaerobic conditions and was identified as Clostridium beijerinckii. The biosynthesized O-DMA exhibited an enantiomeric excess (e.e.) of 78.6%. Based on phylogenetic and average nucleotide identity analyses against 235 public C. beijerinckii genomes, the clustering of FRJF5 with strains from diverse habitats-including industrial fermentation settings, animal feces, and soil-highlights the broad ecological diversity within this species. Functional gene mining and intra-species comparative genomics revealed a unique flavonoid metabolism gene cluster in FRJF5. Using apigenin as a representative flavonoid, we confirmed the successful conversion to 3-(4-hydroxyphenyl)-propionic acid. Moreover, the strain was predicted and verified to possess a substantial butyrate-producing capacity. Genomic screening for virulence or antibiotic resistance genes, combined with phenotypic tests (hemolysis, antibiotic susceptibility, and mouse gavage), revealed a favorable safety profile for strain FRJF5. Finally, intervention experiments in a mouse model of colitis supported its potential in alleviating the disease. Collectively, this study identifies C. beijerinckii FRJF5 as a strain capable of simultaneously producing O-DMA and butyrate, highlighting its potential for future applications in functional foods.IMPORTANCESoy isoflavones require gut bacterial conversion into bioactive metabolites-such as the anti-inflammatory compound O-desmethylangolensin (O-DMA)-to exert health benefits. Yet O-DMA-producing strains remain scarce, largely confined to fecal sources, and poorly characterized. Here, we isolated Clostridium beijerinckii FRJF5 from Chinese stinky tofu, an unexplored ecological niche. This strain not only produces enantiomerically enriched O-DMA but also co-produces butyrate, a metabolite known to strengthen gut barrier function. Genomic mining uncovered a unique flavonoid metabolism gene cluster responsible for this dual activity. Combined with favorable safety profiles, FRJF5 emerges as a strong candidate for functional food applications. This work expands the known diversity of O-DMA producers and bridges traditional fermented foods with next-generation probiotic development.
O-desmethylangolensin↗
Whole-genome safety assessment of Loigolactobacillus coryniformis WBB05 and identification of a candidate gene for aerobic reuterin production.
This study reports on the safety profile of Loigolactobacillus coryniformis WBB05 for food industry applications and identifies glycerol-3-phosphate oxidase (GlpO) as a candidate gene associated with aerobic reuterin production. The safety of L. coryniformis WBB05 was evaluated through whole-genome sequencing, phenotypic analysis of haemolytic activity and determination of minimum inhibitory concentrations (MICs) of antibiotics. Comparative genomic analysis was performed to identify candidate genetic determinants for aerobic reuterin production. The draft genome (2.83 Mb, 179 contigs) harboured no known virulence factors, acquired antimicrobial resistance (AMR) genes or biogenic amine biosynthetic genes. Prophage analysis identified only one incomplete prophage region, and four CRISPR-Cas systems (212 spacers) were consistent with phage defence capacity. Secondary metabolite analysis revealed biosynthetic gene clusters encoding a coagulin-like bacteriocin. No β-haemolytic activity was observed. The MICs of all antibiotics tested were below the European Food Safety Authority cut-off values except for kanamycin (128 mg/L), although no acquired AMR genes were detected. Comparative genomic analysis revealed that L. coryniformis WBB05 possesses two putative copies of GlpO, a gene not detected in publicly available genomes of Limosilactobacillus reuteri, which produces reuterin only under anaerobic conditions. These findings support the use of L. coryniformis WBB05 as a safe adjunct culture for dairy applications and highlight GlpO as a candidate determinant of aerobic reuterin production. Further studies comparing GlpO-positive and GlpO-negative strains under aerobic and anaerobic conditions are warranted to confirm the role of GlpO.
Loigolactobacillus coryniformis↗
Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.
Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.
lentiviral vector↗
In silico analysis of metal resistance genes in Pseudomonas extremaustralis 2E-UNGS: Genomic insights and safety assessment for wastewater biotreatment.
Pseudomonas extremaustralis 2E-UNGS is a non-pathogenic strain isolated from the polluted Reconquista River basin (Buenos Aires Metropolitan Area, Argentina), with a 20-year history of study focused on its survival strategies that have enabled its application in various processes such as waste biotreatment and biosensing. Regarding bacterial-metal interactions, P. extremaustralis 2E-UNGS is capable of biosorbing Cd(II), Zn(II), and Cu(II), and biotransforming Cr(VI) to Cr(III), facilitating both the removal of these metals from aqueous systems and their use in biosensor development. The complete circular chromosome (6,372,594 bp) has been annotated in the NCBI GenBank under accession number NZ_CP091043.1. The aim of this work was to perform an in-depth exploration of the P. extremaustralis 2E-UNGS genome to support the optimization of sustainable bioprocesses within the One Health framework. To this end, the integration of experimental evidence with a detailed in silico analysis of key genes involved in metal-microorganism interactions, antibiotic resistance, and their interconnections provides valuable insights for the optimization of future biotechnological applications. Considering its antibiotic resistance profile, together with the activation of efflux pumps induced by metal stimuli-particularly observed under Zn(II) exposure-P. extremaustralis 2E-UNGS can be regarded as suitable for the design of confined bioreactor processes, minimizing the risk of potential accidental environmental releases. Therefore, modulation of gene expression emerges as a promising approach to enhance the efficiency of metal-loaded wastewater biotreatments.
Pseudomonas↗
Radiological safety assessment for a low-level radioactive solid waste storage facility: preliminary risk evaluation by reliability techniques.
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Accidents, Occupational↗
Assessing the Safety and Probiotic Potential of Bifidobacterium longum subsp. infantis BI45: A Comprehensive Study from Genomic Analysis to Randomized Controlled Clinical Trial in Healthy Adults.
While probiotics are increasingly consumed for health benefits, comprehensive safety assessments, particularly for novel strains, are imperative. This study aimed to conduct a holistic safety and efficacy assessment of Bifidobacterium longum subsp. infantis (B. infantis) BI45, spanning genomic analysis, in vitro tests, In vivo toxicity test, and a clinical trial. The safety of B. infantis BI45 was evaluated through: (1) whole-genome sequencing for antibiotic resistance and virulence genes; (2) in vitro phenotyping (hemolysis, cytotoxicity, gastrointestinal tolerance and antibiotic susceptibility); (3) an acute oral toxicity study in mice; and (4) a randomized, double-blind, placebo-controlled clinical trial. Forty-eight healthy adults were recruited and randomly assigned to receive either B. infantis BI45 or a placebo (n = 24/group) for 8 weeks. Hematological, biochemical, immunological, and gut microbiota parameters were assessed. Genomic analysis identified no transferable antibiotic resistance or virulence genes. In vitro assays confirmed the absence of hemolytic and cytotoxic activity, alongside high gastrointestinal tolerance. Antibiotic susceptibility testing showed that B. infantis BI45 is sensitive to a range of antibiotics. No adverse effects were observed in the murine toxicity study at 2 × 10¹⁰ CFU/kg. Importantly, the clinical intervention revealed no adverse events or significant alterations in hematological, hepatic, or renal function markers in the B. infantis BI45 group, demonstrating an excellent safety profile. Furthermore, B. infantis BI45 supplementation significantly increased serum levels of immunomodulatory markers Immunoglobulin A (IgA) and antimicrobial peptide LL-37 compared to the placebo (p < 0.05) and modulated the gut microbiota by enriching beneficial short-chain fatty acid producers. The multi-tiered evidence demonstrates that B. infantis BI45 is a safe probiotic strain that does not induce adverse reactions in healthy adults. Its consumption positively modulates host immunity and the gut microbiota.Trial Registration Number: NCT06863415 (ClinicalTrials.gov).
Adult↗
A Phase I Study Assessing the Safety, Tolerability, and Pharmacokinetics of Yinfenidone: A Novel, Potent Drug for Idiopathic Pulmonary Fibrosis Treatment in Healthy Chinese Subjects.
PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a median survival of only 2-3 years after diagnosis. Yinfenidone (HEC585) possesses the potential to inhibit the proliferation of pulmonary fibroblasts, making it a promising candidate for the treatment of IPF. This study assessed the safety, tolerability, pharmacokinetics, and metabolic profile of Yinfenidone hydrochloride capsule in healthy Chinese subjects. METHODS: This single-center, randomized, double-blind, placebo-controlled, single ascending-dose trial included seven dose groups(20, 50, 100, 200, 400, 600, and 800 mg). Each group enrolled8 healthy subjects: 6 received Yinfenidone hydrochloride capsules and 2 received matching placebo under fasting conditions. Serial pharmacokinetic (PK) blood samples were collected pre-dose and post-dose, liquid chromatography-tandem mass spectrometry was used to analyze the plasma concentrations of Yinfenidone. Additionally, metabolic biotransformation of Yinfenidone in plasma were conducted in the 100 mg dose group. Safety and tolerability endpoints were monitored via physical examinations, vital signs measurements, clinical laboratory tests, 12-lead electrocardiography (ECG), and adverse events (AEs) documentation throughout the trial. FINDINGS: Yinfenidone was rapidly absorbed, with a median maximum plasma concentration (Tmax) of 1.8-3.0 hours, and had a mean half-life (t1/2) ranging from 31.9 to 62.0 hours. Within the 20-100 mg dose range, systemic drug exposure generally increased with ascending dose, above 100 mg, exposure increased less than proportionally to dose. Metabolite profiling in the 100 mg group revealed that the parentcompound predominated in plasma, with metabolic pathways including mono-oxygenation and N-dealkylation. All reported AEswere mild, classified as Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1. No serious AEs observed; no subject discontinued the trial due to AEs. Single oral doses of 20-800 mg Yinfenidone hydrochloride capsules administered under fasting conditions demonstrated favorable safety and tolerability profiles in healthy Chinese subjects. IMPLICATIONS: Yinfenidone exhibited rapid absorption (median Tmax, 1.8-3.0 hours) and a long terminal t1/2 ranging from 31.9 to 62.0 hours in this single ascending-dose study, indicating that Yinfenidone can be taken once a day in subsequent clinical studies. Yinfenidone mainly exists in human plasma as the original drug and is metabolized through a variety of metabolic pathways. The AEs observed with Yinfenidone in this study, such as diarrhea, nausea, and dizziness, were similar to those reported with pirfenidone. Overall, Yinfenidone demonstrated a favorable safety and tolerability profile in this cohort of healthy subjects.
Adult↗
Isolation, identification, and genomic characterization of Staphylococcus aureus phage vB_SauL_202595 and its bacteriostatic application in dairy products.
Staphylococcus aureus is an important pathogen associated with bovine mastitis and dairy product contamination, posing economic and public health risks through the food chain. In this study, a temperate phage, vB_SauL_202595, was isolated from a dairy farm environmental sample using S. aureus SHZ-0127 as the host, and its biological characteristics, genomic features, and antibacterial activity in dairy matrices were evaluated. vB_SauL_202595 lysed 18 of 66 tested S. aureus strains, with a lysis susceptibility rate of 27.3%, including 5 highly susceptible strains, indicating a relatively limited host range. The optimal multiplicity of infection was 0.01, the latent period was approximately 30 min, and the burst size was approximately 316 PFU/cell. The phage remained stable at 4°C-37°C and pH 6-10. Genome analysis showed that vB_SauL_202595 belongs to the class Caudoviricetes, has a genome of 44,503 bp with 33.59% GC content, and encodes 63 predicted proteins. No typical antibiotic resistance genes or major virulence factors were detected; however, integrase and repressor genes were identified, supporting its temperate nature. vB_SauL_202595 inhibited S. aureus SHZ-0127 growth, reduced mature biofilm biomass, and decreased viable bacterial counts in milk and yogurt, with reductions of 1.23 and 1.42 log10 CFU/mL under representative conditions, respectively. From a One Health perspective, these findings provide foundational evidence for reducing S. aureus contamination and related antimicrobial resistance risks along the dairy chain. Overall, vB_SauL_202595 represents a candidate phage resource for dairy-associated S. aureus biocontrol research, but its limited host range and lysogeny-related genes require further safety assessment before food-related applications.IMPORTANCEStaphylococcus aureus is a major pathogen associated with bovine mastitis and a common contaminant in dairy products, causing economic losses and public health risks through the food chain. Although phage-based biocontrol has emerged as a promising strategy for controlling S. aureus contamination in dairy products, systematic evidence regarding phage activity in actual dairy matrices remains limited. In this study, we isolated and characterized a dairy farm environment-derived temperate phage, vB_SauL_202595, and evaluated its biological characteristics, genomic features, host range, stability, biofilm removal ability, and antibacterial performance in milk and yogurt. These findings provide foundational experimental evidence for phage-based dairy biocontrol against S. aureus. However, due to its limited host range and lysogeny-related genomic features, vB_SauL_202595 should be considered a candidate phage resource for further study. Broader validation, including phage-cocktail testing, long-term storage assays, product quality assessment, and regulatory safety evaluation, is needed before practical application.
Staphylococcus aureus↗
Applications of metal-organic frameworks in smart packaging for food freshness indication: a comprehensive review.
Smart packaging is extensively studied for its multifunctional capabilities in antimicrobial activity, preservation, and atmosphere modification. Recently emerged metal-organic frameworks (MOFs) freshness-indicating packaging becomes a key research direction in smart packaging owing to its distinctive functions and physicochemical properties. As multifunctional materials, the unique porous structure and tunable properties of MOFs provide a distinctive approach for developing food packaging applications dedicated to food freshness indication. Existing MOFs-based smart packaging still faces potential safety risks and technical challenges in practical applications, and there remains a lack of integrated discussion that combines synthesis strategies, packaging design, optimization, and safety assessment. This review elaborates on the application of MOFs in freshness-indicating smart packaging, focusing on diverse MOFs synthesis strategies, the formats of smart packaging, types of indicator signals, and qualitative/quantitative analytical methods. It also delves into the methodology concepts of MOFs-based smart packaging and evaluates MOFs safety in food packaging by addressing potential risks. Studies show that MOFs-based smart packaging achieves qualitative and semi-quantitative analysis of food freshness through multiple signal modalities such as visible color change, fluorescence, and photothermal effects. This review emphasizes that safe MOFs design is critically important and should comply with the overall migration limit of <10 mg/dm2 specified in Regulation (EC) No 1935/2004, lanthanide element limit of <0.05 mg/kg, and FDA threshold of 1.5 μg/person/day. Comprehensive safety assessment and intelligent sensing platforms will constitute pivotal directions for advancing MOFs-based smart packaging toward practical application.
Food Packaging↗
[Unsuitability of the neurovirulence test for assessing the safety of vaccinal strains of the mumps virus].
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Animals↗
Screening of Fermentative Strains for Reducing the Allergenicity of a Whey Protein-Soy Protein System and Genomic Characterization of the Selected Strain.
Dual-protein systems combining whey protein isolate (WPI) and soy protein isolate (SPI) offer complementary nutritional benefits but are limited by the presence of major allergens. Lactic acid bacteria (LAB) fermentation provides a promising strategy to mitigate this limitation. In this study, Lacticaseibacillus paracasei JM053, selected from 13 LAB strains based on phenotypic screening, significantly reduced the in vitro allergenicity of the dual-protein system, increasing the IgE-binding inhibition rate to 48.75%. Whole-genome sequencing and characterization of JM053 revealed a comprehensive proteolytic system, including the proline-specific peptidase genes pepX and pepQ, which may contribute to the degradation of allergenic peptide sequences. Combined with in silico bioinformatic analysis, potential cleavage sites within the linear epitopes of the dual-protein system were predicted based on the substrate specificity of the identified proteases, offering a testable hypothesis for the strain's mechanism of action. In addition, in vitro safety assessment and genomic analysis supported the safety potential, stress tolerance, and probiotic characteristics of JM053. Collectively, this study provides a valuable candidate strain for the development of hypoallergenic dual-protein products and offers preliminary genomic insights into LAB-mediated allergenicity reduction.
Lacticaseibacillus paracasei↗
Nonclinical investigation of the potential of MHAA4549A, an anti-influenza A therapeutic antibody, to mediate antibody-dependent enhancement.
Antibody-dependent enhancement (ADE) of infection and disease is a theoretical safety risk for antiviral antibodies against seasonal viruses with antigenic drift, such as influenza. ADE of infection may occur if virus-specific antibodies at subtherapeutic, nonneutralizing concentrations facilitate virus uptake, thus potentially enhancing virus replication. In contrast, ADE of disease reflects exacerbation of viral disease severity through viral replication-dependent or -independent mechanisms. Because of the theoretical concern of ADE, nonclinical safety assessment of therapeutic anti-influenza antibodies includes a thorough evaluation of ADE potential. The current set of studies was conducted to investigate the potential of MHAA4549A-a broadly specific, neutralizing, therapeutic anti-influenza A antibody-to elicit ADE of infection and disease of influenza H3N2 A/Aichi/2/68 (X31) across a broad dose range. Assessment of ADE was based on totality of results from both in vitro and mouse influenza studies with integration across study endpoints. In vitro studies demonstrated that MHAA4549A can mediate increased X31 entry into human and murine monocytic cells, but increased uptake did not result in enhanced viral replication or release under physiologic conditions. In a mouse model of X31 infection, intravenous administration of MHAA4549A resulted in delayed body weight recovery, but no exacerbation in orthogonal endpoints including mortality, lung viral titers or genomes, lung weights, or severity of influenza pneumonia. Overall, the totality of nonclinical data did not demonstrate any clear indication of ADE of infection at nonneutralizing concentrations, suggesting a low risk for MHAA4549A to cause enhanced influenza A-mediated disease at subtherapeutic doses.
Animals↗
A novel genus of virulent phage targeting Acinetobacter baumannii: Efficacy and safety in a murine model of pulmonary infection.
Acinetobacter baumannii is a notable opportunistic pathogen responsible for severe hospital-acquired infections, with multidrug-resistant strains posing significant treatment challenges. Phage therapy, which employs bacteriophages as natural bacterial antagonists, has gained renewed attention as a promising solution to combat antibiotic-resistant infections. In this study, we isolated and characterized a novel virulent phage, vB_AbaS_qsb1, which specifically lyses A.baumannii. Phylogenetic and genomic analyses indicate that vB_AbaS_qsb1 is the founding member of a previously unreported genus, which we propose to name Acinibactriovirus, with Acinibactriovirus lysinus as the type species. vB_AbaS_qsb1 demonstrated robust stability across diverse temperature and pH ranges, a short latent period, and no known virulence or antibiotic resistance genes within its 54,713 bp dsDNA genome. Safety assessments showed that high-dose vB_AbaS_qsb1 induced no adverse effects in mice, with histopathology confirming its safety profile. Therapeutic experiments further indicated that vB_AbaS_qsb1 provided at least 50% protection against A.baumannii-induced pneumonia, significantly reducing bacterial loads and inflammation markers, while maintaining high phage titers in lung tissue.This study introduces vB_AbaS_qsb1 as a promising candidate for phage therapy against A.baumannii, offering both innovative insights and a valuable framework for future isolation, genomic characterization, and efficacy evaluation of phages targeting antibiotic-resistant bacteria.
Animals↗
Pharmacologic considerations in the design of toxicology experiments.
Final assessment of product acceptance must be based on value judgments that include (a) social, (b) economic, and (c) environmental factors as well as risk factors, and not on simple safety statements about the end product. The goal of toxicologic experiments should be to provide sufficient data to allow benefit-to-risk judgments about products. Benefit-to-risk judgments need to be made on a broad data base which includes: manufacturing, distribution, and use factors. Safety assessments begin with concerns associated with initial manufacture of raw materials and end with concerns related to disposal of the end products of use. Current experimental design needs to include biopharmaceutic considerations of the dose form, pharmacokinetic aspects, and pharmacodynamic factors as well as pathologic concerns. These factors stress the point that toxicology is a quantitative science because toxicity resides in the dose and dose form and not in the chemical entity.
Animals↗
Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.
BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33·5 years (SD 12·1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2·3 min (SD 2·7) for placebo, 24·0 min (8·7) for alixorexton 4 mg, 25·9 min (9·4) for 6 mg, and 28·2 min (11·4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22·2 min (95% CI 17·2-27·2) for alixorexton 4 mg, 24·1 min (19·0-29·1) for 6 mg, and 26·0 min (21·0-31·0) for 8 mg (adjusted p=0·0099 for 4 mg, adjusted p<0·0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.
Humans↗
Comparative Bioavailability of Trimodal (CTx-1301) Versus Bimodal Dexmethylphenidate Modified-Release Formulations in Adults with Attention-Deficit/Hyperactivity Disorder: A Randomized, Single-Dose, Crossover Study.
BACKGROUND AND OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder that often requires sustained symptom control throughout the day. Although bimodal extended-release dexmethylphenidate (d-MPH XR) formulations provide initial and intermediate drug release, they may not consistently maintain therapeutic exposure into the late afternoon and evening. Trimodal formulations with an additional delayed release component may extend drug exposure later in the day, although this remains to be established. To explore differences in pharmacokinetic (PK) profiles between trimodal (CTx-1301) and bimodal delivery of d-MPH XR, a comparative bioavailability study was conducted at the highest and lowest doses for both formulations. METHODS: In this randomized, 4-period, crossover study, adults with ADHD received single doses of CTx-1301 (50 mg and 6.25 mg) and d-MPH XR (40 mg and 5 mg). Comparative bioavailability was assessed through adjusted geometric mean ratios for exposure parameters (maximum observed plasma concentration [Cmax], area under plasma concentration-time curve to last measurable concentration [AUClast] and extrapolated to infinity [AUC0-inf]), with a prespecified bioequivalence range of 0.80 to 1.25. Secondary endpoints included partial AUCs and safety assessments. RESULTS: The study population (N = 45) was predominantly male (88.9%) and White (55.6%), with mean age of 29.6 ± 8.01 years. Adjusted geometric mean ratios comparing the primary exposure parameters (Cmax, AUClast, and AUC0-inf) for CTx-1301 versus d-MPH XR were within the bioequivalence range (0.80-1.25) at both the high and low doses. The CTx-1301-to-d-MPH XR partial AUC ratios were within the bioequivalence range from 0 to 9 hours post-dose. At later intervals (AUC9-12 and AUC12-16), adjusted geometric mean ratios exceeded the upper bioequivalence threshold, consistent with the expected contribution of the third medication release component. Dose proportionality was observed between the two CTx-1301 doses and two d-MPH XR formulations. CTx-1301 was generally well tolerated. The most commonly reported adverse events included tachycardia, insomnia, headache, nausea, and euphoric mood. The incidence of treatment-emergent adverse events was numerically lower with CTx-1301 than with d-MPH XR; however, no statistical analysis was performed. CONCLUSIONS: Key exposure parameters including Cmax, AUClast, and AUC0-inf for trimodal CTx-1301 were statistically bioequivalent to bimodal d-MPH XR. Interval‑specific PK analyses demonstrated higher exposure with CTx‑1301 during later post-dose intervals (9-16 h), consistent with the formulation's third release component. However, the clinical relevance of these PK differences requires further evaluation. CTx-1301 demonstrated dose proportionality and was well tolerated at high and low doses. REGISTRATION: ClinicalTrials.gov, NCT04138498; 19 September 2019.
Humans↗