Discover Biotrial’s Scientific publications & posters

There is a growing interest in the potential use of psychedelic compounds for the treatment of psychiatric and neurological disorders. As these programs move through early-stage clinical development, objective pharmacodynamic measures are needed to complement pharmacokinetic data to inform dose selection and dosing strategy. Resting-state EEG provides a non-invasive approach for measuring drug-related changes in brain activity. Conventional qEEG endpoints such as spectral power offers established measures of frequency-specific effects. Spectral power is a measure of how much of a signal’s activity occurs in different frequencies.
In parallel, entropy may function as a measure of the extent of complexity or randomness in the EEG signal. The entropic brain hypothesis suggests that psychedelic states may be associated with increased neural signal complexity, making entropy-based measures a potentially relevant EEG endpoints in this context.

LPH-5 is a novel next generation psychedelic. First in human (FIH) dosing was assessed in the LPH-5CS01 (ct.gov: NCT06722820) phase I study, with safety and pharmacokinetics (PK) as primary end points, enriched by numerous Central Nervous System (CNS) pharmacodynamics endpoints. This study was a unique opportunity to identify the potential range of therapeutic doses by assessing the dissociation between objective and subjective biomarkers (BMs) versus specific class-related Adverse Events (AEs).

Biosimilars are essential for expanding patient access to biologic therapies while reducing healthcare costs. Recent regulatory updates from the FDA, EMA, and MHRA reflect a shift toward a science-based, risk-proportionate approach that prioritizes analytical and functional characterization over routine comparative clinical efficacy studies.
Objective: To compare recent regulatory guidance and evaluate its impact on modern biosimilar developmen

Background Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei species. Fexinidazole, an oral treatment for HAT, has shown efficacy in both hemo-lymphatic and meningo-encephalitic stages of the disease. After oral administration, only a small fraction of fexinidazole is eliminated unchanged via the renal route; therefore, hepatic metabolic clearance represents a significant portion of the total clearance of fexinidazole. Consequently, in patients with hepatic impairment (HI), total clearance may be decreased, potentially resulting in overexposure of fexinidazole and could lead to modification of the exposures of its two metabolites. This study aims to evaluate the effect of mild and moderate HI on the pharmacokinetics (PK) of fexinidazole and its active metabolites compared with that in participants with normal hepatic function.
Methods This Phase I, multicentric, open-label, non-randomised study included 21 participants divided into three groups: mild HI (n = 7), moderate HI (n = 7) and normal hepatic function (n = 7). Each participant received a single oral dose of 1200 mg fexinidazole under fed conditions. PK parameters, including the maximum plasma concentration (Cmax), area under the plasma concentration–time curve (AUC inf) and terminal half-life (t½z), of fexinidazole and its metabolites M1 (sulfoxide metabolite) and M2 (sulfone metabolite) were assessed. Safety and tolerability were evaluated through adverse events, laboratory tests and vital signs.

Although deep learning methods for electroencephalogram (EEG) analysis are rapidly advancing,
architectures developed for human multichannel recordings may not be suited to animal EEG, where recordings typically involve substantially fewer channels. This study investigated whether deep learning could detect EEG alterations induced by the NMDAr antagonist MK-801 (dizocilpine), recorded in rats subjected or not to auditory stimulations, to determine the potential of this method for brain circuit-related efficacy and safety assessment.

The growing adoption of precision medicine has intensified the need for closer integration between medicinal products and the in vitro diagnostics used to identify eligible patient populations. In the European Union, however, clinical trials involving both a drug and an associated diagnostic have traditionally been regulated through two separate pathways: the Clinical Trials Regulation for the medicinal product and the In Vitro Diagnostic Regulation for the diagnostic component. This separation often results in duplicated submissions, unaligned assessment timelines, and increased operational burden for sponsors— particularly for complex multinational studies.
To address these challenges, the European Medicines Agency has launched COMBINE Project 1, a pilot testing a coordinated “all‑in‑one” assessment model for combined studies. The initiative aims to streamline EU regulatory procedures, improve predictability, and better support the development of drug–diagnostic combinations essential for precision medicine

There is a clear unmet need for therapies in SCLC. For several years, our team has been using circulating tumor cells (CTCs) to develop preclinical models of SCLC. To address current therapeutic challenges, we are developing a unique combination of humanized CTC-Derived Xenografts with controlled gut microbiota (MESHCAP model: Microbiote Exogene et Souris Humanisée pour le CAncer du Poumon).

Allopregnanolone, an endogenous neurosteroid, exhibits antidepressant and anxiolytic activity in patients with anxiety and depressive symptoms. Due to poor oral bioavailability, it has only received regulatory approval as an intravenous infusion to treat postpartum depression. GlyphAllo™ (SPT-300; Glyph™ Allopregnanolone), an oral prodrug of allopregnanolone, is designed to avoid first-pass metabolism and enhance oral bioavailability. Here, we assessed the ability of GlyphAllo to modulate electroencephalography (EEG) activity consistent with the known effects of allopregnanolone.

Safety pharmacology is a relatively young discipline dedicated to identifying adverse pharmacodynamic effects of new drugs that may impact human safety.
Since the publication of the ICH S7A guideline in 2000, the field has made significant efforts in implementing the 3Rs principles—Replacement, Reduction, and Refinement of animal use. This review provides a comprehensive overview of key milestones and innovations that have shaped the application of the 3Rs in safety pharmacology over the past 25 years. Typical examples are the use of non-invasive jacket telemetry for real-time cardiovascular monitoring in conscious freely moving animals and the introduction of the CiPA (Comprehensive in Vitro Proarrhythmia Assessment) paradigm in 2014. The review explores 3Rs-driven advances across core organ systems—cardiovascular, central nervous, and respiratory—as well as supplemental systems including gastrointestinal and renal.
Furthermore, it examines the evolving global regulatory landscape and the emergence of new approach methodologies (NAMs), such as artificial intelligence tools and complex microphysiological systems (MPS), and their integration into drug development pipelines. Finally, the review discusses future directions and potential challenges in achieving broader adoption of 3Rs-compliant strategies and NAMs in safety pharmacology.

Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as their underlying pathophysiology remain insufficient. Disinhibition in SZ patients’ cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent translational tools for drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them would constitute a major milestone. Here, we tested three different drugs whose features attract scientists for restoration of excitation/ inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT2A receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover, cariprazine normalized alpha and beta waves and LY379268 selectively corrected delta activity. Interestingly, only cariprazine mitigated the ASSR deficit. These differential normalization profiles, including cariprazine’s unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.

We are engaged in the setup of cancer preclinical models in order to test new therapies or new combinations of current therapies. Recently our work has focused on two highly lethal cancer
pathologies, Glioblastoma Multiforme (GBM) and Triple Negative Breast Cancer (TNBC).

Treating people with schizophrenia still represents a major challenge for neuropsychiatric drug development companies. While available atypical antipsychotics are mainly effective on positive symptoms of schizophrenia, their effects on cognitive and social-cognitive deficits remain insufficient and poorly characterized. For instance, a modest improvement of cognitive functions has been described following clozapine treatment. Nevertheless, it remains unclear whether this outcome is due to a direct effect on the neural circuits underlying cognition or to an indirect effect mediated by an overall reduction in positive symptoms. To address this question, we sought to measure mismatch negativity (MMN) responses in telemetered rats. MMN constitutes an electroencephalography-based biomarker of sensory, pre-attentional and predictive coding processes, functions whose disruptions highly influence certain aspects of patients’ cognitive symptoms. MMN was measured under N-methyl-D-aspartate receptor (NMDAr) pharmacological inhibition by MK-801 (dizocilpine), a model based on the glutamatergic hypothesis of schizophrenia, and we tested whether clozapine could improve MMN under this condition or not. We found that MK-801 dose-dependently reduced the MMN peak amplitude in rats, aligning with the MMN response deficit seen in schizophrenia patients. Strikingly, clozapine was able to mitigate this electrophysiological deficit, an unprecedented observation that has the potential to inspire new treatment strategies aimed towards unaddressed schizophrenia symptoms.

Genetic characterization of cell lines is essential for understanding and predicting sensitivity to anti-tumoral targeted therapies. A panel of genetically characterized cell lines from rare tumors (mucosal melanomas, histiocytic sarcomas, osteosarcomas, gliomas…) has been developed to test novel and repositioned anti-tumor therapies, focusing on mucosal melanoma (MM) models.

Ketamir-2 is a new molecular entity, and a novel ketamine analog designed to improve oral bioavailability, and offer a superior safety profile compared to existing ketamine treatments. It was found that Ketamir-2 is a low affinity NMDA receptor antagonist, that selectively binds to the PCP site. Its IC₅₀ on this receptor site is ∼100 µM. Ketamine acts as an NMDA receptor antagonist (0.5–1 µM affinity) and influences opioid receptors, monoaminergic systems (such as serotonin and dopamine). The selectivity of Ketamir-2 was evaluated across a broad range of receptors, transporters, and binding sites, but no activity was detected. Ketamir-2 is a lower affinity and selective PCP-site NMDA antagonist, compared with ketamine. Upon oral administration, Ketamir-2 does not induce hyperlocomotion in mice. Thus, it is different from Ketamine, which induces marked hyperlocomotion, a behavior which is thought to mimic the psychomotor agitation and disorganized behavior seen in schizophrenia, often linked to disruptions in brain neurotransmitter systems. Ketamir-2 was also evaluated via several pharmacological tests in mice to evaluate its anti-depressive and anxiolytic effects. These tests included the Open Field test (OFT), Elevated Plus Maze (EPM), and Forced Swimming Test (FST); all of which are commonly employed behavioral assays used to evaluate the efficacy of anxiety and depression medications. While showing significant effects in these tests at variable doses, ketamine, which was used as a positive control, did not differ from vehicle treatment or showed an opposite response to Ketamir in the majority of the tests studied.

The assessment of drug-induced QT interval prolongation and associated proarrhythmic risks, such as Torsades de Pointes (TdP), has evolved significantly over the past decades. This review traces the development of nonclinical QT evaluation, highlighting key milestones and innovations that have shaped current practices in cardiac safety assessment. The emergence of regulatory guidelines, including International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) S7B, established a nonclinical framework for evaluating drug effects on cardiac repolarization, addressing concerns raised by drug withdrawals in the 1990s. Advances in in vitro, in vivo, and in silico models have enhanced the predictive accuracy of nonclinical studies, with the hERG assay and telemetry-based animal models becoming gold standards. Recent initiatives, such as the Comprehensive in vitro Proarrhythmia Assay (CiPA) and the Japan iPS Cardiac Safety Assessment (JiCSA), emphasize integrating mechanistic insights from human-derived cardiomyocyte models and computational approaches to refine risk predictions. The 2020s mark a shift toward integrated nonclinical-clinical risk assessments, as exemplified by the ICH E14/S7B Questions and Answers. These highlight the need of best practices for study design, data analysis, and interpretation to support regulatory decision-making. Further more, the adoption of New Approach Methodologies (NAMs) and reinforced adherence to 3Rs principles (Reduce, Refine, Replace) reflect a commitment to ethical and innovative safety science. This review underscores the importance of harmonized and translational approaches in cardiac safety evaluation, providing a foundation for advancing drug development while safeguarding patient safety. Future directions include further integration of advanced methodologies and regulatory harmonization to streamline nonclinical and clinical risk assessments.