PreClinical publications & posters

Afatinib-Bevacizumab and Osimertinib Halt Tumor Growth in NSCLC Models
Effects of aripiprazole on EEG and behavior in a rat model of SZ
Perianal Fistulizing Crohn’s Disease model
Orthotopic model of Lung Cancer
CD56+ circulating tumor cells in small cell lung cancer
Cognitive Impairments in Schizophrenia review
Ocular Administration of Palonosetron
Social housing of non-rodents during cardiovascular recordings
Microcirculation and NO-CO Studies of a Natural Extracellular Hemoglobin
Animal models for the treatment of post-traumatic stress disorder
Nigral dopaminergic lesion and repeated L-dopa exposure in Parkinson’s disease
Preclinical Pharmacology of BF2.649, a nonimidazole inverse agonist of H3 receptor
Arenicola marina extracellular hemoglobin
Validation of an automated system for measuring food intake in mice – APAS (FR)
Cutting-edge preclinical models to study response of Small Cell Lung Cancer to therapy
Development of canine tumoral cell lines as drug-testing models in comparative oncology: mucosal melanoma (MM)
Establishment of a new “Epithelial Ovarian Cancer” (EOC) syngeneic model in BALBc mice.
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Afatinib or Bevacizumab in combination with Osimertinib efficiently control tumor development in orthotopic murine models of non-small lung cancer

Lung cancer is one of the most common and deadliest cancers. Preclinical models are
essential to study new therapies and combinations taking tumor genetics into account. We
have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds,
commonly encountered in patients with pulmonary adenocarcinoma. We have
characterized these lines by testing their response to multiple drugs. Thus, we have developed
orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency.
These models allow the easy monitoring of tumor growth, particularly in response to treatment,
and of tumor cells dissemination in the body. We show that concomitant treatment with
osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab
(anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFRmutated
tumors. We also show that the addition of afatinib to osimertinib-treated tumors in
escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin.
These preclinical mouse models therefore make it possible to test innovative therapeutic
combinations and are also a tool of choice for studying resistance mechanisms.

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Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model

ABSTRACT:The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and
do not significantly modify SZ neurobiology. This has raised the question of the robustness and
translational value of methods employed during drug development. Electroencephalography (EEG)-
based measures like evoked and spontaneous gamma oscillations are considered robust translational
biomarkers as they can be recorded in both patients and animal models to probe a key mechanism
underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate
receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics
on such measures could therefore contribute to developing better therapies for SZ. Yet,
the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the
atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous
gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr
antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced
abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved
MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological
features underlying SZ symptoms, our results might explain aripiprazole’s inefficacy towards the
social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

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Molecular Science
A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn’s Disease

ABSTRACT: Fistulizing anoperineal lesions are severe complications of Crohn’s disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6 trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat
and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula
tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or
filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn’s disease.

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Orthotopic model of lung cancer: isolation of bone micro-metastases after tumor escape from Osimertinib treatment

ABSTRACT : Osimertinib is a third generation tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) in lung cancer. However, although this molecule is not subject to some of the resistance mechanisms observed in response to first generation TKIs, ultimately, patients relapse because of unknown resistance mechanisms. New relevant non-small cell lung cancer (NSCLC) mice models are therefore required to allow the analysis of these resistance mechanisms and to evaluate the efficacy of new therapeutic strategies.

Methods: Briefly, PC-9 cells, previously modified for luciferase expression, were injected into the tail vein of mice.

Tumor implantation and longitudinal growth, almost exclusively localized in the lung, were evaluated by bioluminescence. Once established, the tumor was treated with osimertinib until tumor escape and development of bone metastases.

Results: Micro-metastases were detected by bioluminescence and collected for further analysis.

Conclusion: We describe an orthotopic model of NSCLC protocol that led to lung primary tumor nesting and, after osimertinib treatment, by metastases dissemination, and that allow the isolation of these small osimertinib-resistant micro-metastases. This model provides new biological tools to study tumor progression from the establishment of a lung tumor to the generation of drug-resistant micro-metastases, mimicking the natural course of the disease in human NSCLC patients.

Keywords: Orthotopic lung tumor model, Metastasis, Bioluminescence, EGFR TK inhibitor, Tumor escape, Osimertinib

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Scientific Reports
Genomic characteristics and clinical signifcance of CD56+ circulating tumor cells in small cell lung cancer

ABSTRACT: Circulating tumor cells (CTC) have been studied in various solid tumors but clinical utility of CTC in small cell lung cancer (SCLC) remains unclear. The aim of the CTC-CPC study was to develop an EpCAM-independent CTC isolation method allowing isolation of a broader range of living CTC from SCLC and decipher their genomic and biological characteristics. CTC-CPC is a monocentric prospective non-interventional study including treatment-naïve newly diagnosed SCLC. CD56+ CTC were isolated from whole blood samples, at diagnosis and relapse after first-line treatment and submitted to whole- exome-sequencing (WES). Phenotypic study confirms tumor lineage and tumorigenic properties of isolated cells for the 4 patients analyzed with WES. WES of CD56+ CTC and matched tumor biopsy reveal genomic alteration frequently impaired in SCLC. At diagnosis CD56+ CTC were characterized by a high mutation load, a distinct mutational profile and a unique genomic signature, compared to match tumors biopsies. In addition to classical pathways altered in SCLC, we found new biological processes specifically affected in CD56+ CTC at diagnosis. High numeration of CD56+ CTC (> 7/ml) at diagnosis was associated with ES-SCLC. Comparing CD56+ CTC isolated at diagnosis and relapse, we identify differentially altered oncogenic pathways (e.g. DLL3 or MAPK pathway). We report a versatile method of CD56+ CTC detection in SCLC. Numeration of CD56+ CTC at diagnosis is correlated with disease extension. Isolated CD56+ CTC are tumorigenic and show a distinct mutational profile. We report a minimal gene set as a unique signature of CD56+ CTC and identify new affected biological pathways enriched in EpCAM-independent isolated CTC in SCLC.

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Molecular Science
Social-Cognitive Impairments of Schizophrenia

ABSTRACT: Schizophrenia (SZ) is a devastating psychiatric disorder affecting about 1% of the world’s population. Social-cognitive impairments in SZ prevent positive social interactions and lead to progressive social withdrawal. The neurobiological underpinnings of social-cognitive symptoms remain poorly understood, which hinders the development of novel treatments. At the whole- brain level, an abnormal activation of social brain regions and interregional dysconnectivity within social-cognitive brain networks have been identified as major contributors to these symptoms. At the cellular and subcellular levels, an interplay between oxidative stress, neuroinflammation and N-methyl-D-aspartate receptor hypofunction is thought to underly SZ pathology. However, it is not clear how these molecular processes are linked with interregional dysconnectivity in the genesis of social-cognitive symptoms. Here, we aim to bridge the gap between macroscale (connectivity analyses) and microscale (molecular and cellular mechanistic) knowledge by proposing impaired myelination and the disinhibition of local microcircuits as possible causative biological pathways leading to dysconnectivity and abnormal activity of the social brain. Furthermore, we recommend electroencephalography as a promising translational technique that can foster pre-clinical drug development and discuss attractive drug targets for the treatment of social-cognitive symptoms in SZ.

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Ocular Administration of Palonosetron in the Prevention of Cisplatin-Induced Nausea and Vomiting

ABSTRACT: Cancer treatments are frequently associated with nausea and vomiting despite greatly improved preventive medication. Administration of antinausea agents as eye drops might provide easy and rapid access to the systemic circulation for prevention of nausea and vomiting and for the treatment of breakthrough nausea, but the ocular administration route has rarely been evaluated. Palono- setron is a second-generation 5-hydroxytryptamine 3 receptor antagonist approved for prevention and treatment of chemotherapy induced nausea and vomiting. We compared ocular administration of palonosetron to non-active vehicle eye drops and to intravenous palonosetron in the prevention of cisplatin-induced nausea and vomiting in beagle dogs. Palonosetron ocular drops at the dose of 30 mg/kg reduced cumulative nausea over time as measured with the area under the visual analog scale curve by 98% compared with the vehicle and reduced nausea-associated dog behavior by 95%. Vomiting was completely prevented with repeated palonosetron ocular dosing. Hydroxypropyl-b-cyclodextrin (HP-b-CD) palonosetron formulation was well tolerated locally at the palonosetron concentration of 3 mg/ml. Absorption of palonosetron from eye drops was fast. Ten minutes after ocular administration, palonose- tron plasma concentrations were similar compared with intravenous administration, and remained similar for six hours. We conclude that palonosetron is rapidly absorbed into the systemic circulation from eye drops. Ocularly administered palonosetron was well tolerated in the HP-b-CD formulation and was highly effective in the prevention of cisplatin-induced nausea and vomiting. Evaluation of the safety and efficacy of ocular administration of palonosetron is warranted in the prevention and treatment of chemotherapy-induced nausea and vomiting in clinical trials.

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Social housing of non-rodents during cardiovascular recordings in safety pharmacology and toxicology studies

ABSTRACT: Introduction: The Safety Pharmacology Society (SPS) and National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) conducted a survey and workshop in 2015 to define current industry practices relating to housing of non-rodents during telemetry recordings in safety pharmacology and toxicology studies. The aim was to share experiences, canvas opinion on the study procedures/designs that could be used and explore the barriers to social housing.

Methods: Thirty-nine sites, either running studies (Sponsors or Contract Research Organisations, CROs) and/or outsourcing work responded to the survey (51% from Europe; 41% from USA).

Results: During safety pharmacology studies, 84, 67 and 100% of respondents socially house dogs, minipigs and non-human primates (NHPs) respectively on non-recording days. However, on recording days 20, 20 and 33% of respondents socially house the animals, respectively. The main barriers for social housing were limitations in the recording equipment used, study design and animal temperament/activity. During toxicology studies, 94, 100 and 100% of respondents socially house dogs, minipigs and NHPs respectively on non-recording days.

However, on recording days 31, 25 and 50% of respondents socially house the animals, respectively. The main barriers for social housing were risk of damage to and limitations in the recording equipment used, food consumption recording and temperament/activity of the animals.

Conclusions: Although the majority of the industry does not yet socially house animals during telemetry recordings in safety pharmacology and toxicology studies, there is support to implement this refinement. Continued discussions, sharing of best practice and data from companies already socially housing, combined with technology improvements and investments in infrastructure are required to maintain the forward momentum of this refinement across the industry

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Microcirculation and NO-CO Studies of a Natural Extracellular Hemoglobin Developed for an Oxygen Therapeutic Carrier

ABSTRACT: Extracellular soluble hemoglobins (Hbs) have long been studied for their possible use as safe and effective alternatives to blood transfusion. While remarkable progress has been made in the use of cell-free Hb as artificial oxygen carrier, significant problems remain, including susceptibility to oxidative inactivation and propensity to induce vasoconstriction. Hemarina-M101 is a natural giant extracellular hemoglobin (3600 kDa) derived from marine invertebrate (poly- chaete annelid). Hemarina-M101 is a biopolymer composed of 156 globins and 44 non-globin linker chains and formulated in a product called HEMOXYCarrier® . Prior work has shown Hemarina-M101 to possess unique anti-oxidant activity and a high oxygen affinity. Topload experiment with this product into rats did not revealed any effect on heart rate (HR) and mean arterial pressure (MAP). A pilot study with the hamster dorsal skinfold window chamber model showed absence of microvascular vasoconstriction and no significant impact on mean arterial blood pressure. In vitro nitric oxide (NO) and carbon monoxide (CO) reaction kinetics measurements show that Hemarina-M101 has different binding rates as compared to human Hb. These results revealed for the first time that the presence of this marine hemoglobin appears to have no vasoactivity at the microvascular level in comparison to others hemoglobin based oxygen carriers (HBOCs) developed so far and merits further investigation

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A perspective on the contribution of animal models to the pharmacological treatment of posttraumatic stress disorder

ABSTRACT: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, disabling disorder that may develop following exposure to a traumatic event. This review summarizes currently used animal models of PTSD and their potential role in the development of better therapeutics. Heterogeneity is one of the main characteristics of PTSD with the consequence that many pharmacological approaches are used to relieve symptoms of PTSD. To address the translational properties of the animal models, we discuss the types of stressors used, the rodent correlates of human PTSD (DSM-5) symptoms, and the efficacy of approved, recommended and off-label drugs used to treat PTSD in ‘PTSD-animals’.

Conclusions: Currently available animal models reproduce most PTSD symptoms and are validated by existing therapeutics. However, novel therapeutics are needed for this disorder as not one drug alleviates all symptoms and many have side effects that lead to non-compliance among PTSD patients. The true translational power of animal models of PTSD will only be demonstrated when new therapeutics acting through novel mechanisms become available for clinical practice.

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Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

ABSTRACT: This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson’s disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with L-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with L-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic L-dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic L-dopa exposure in the context of partial nigral cell loss.

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BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride], a Nonimidazole Inverse Agonist/Antagonist at the Human Histamine H3 Receptor: Preclinical Pharmacology

ABSTRACT: Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity 50% higher than that of ciproxifan. Its in vitro potency was 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders

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biotechnologies journal
Arenicola marina extracellular hemoglobin: a new promising blood substitute

ABSTRACT: The need to develop a blood substitute is now urgent because of the increasing concern over Europe’s BSE outbreak and the worldwide HIV/AIDS epidemic, which have cut blood supplies. Extracellular soluble hemoglobin has long been studied for its possible use as a safe and effective alternative to blood transfusion, but this has met with little success. Clinical trials have revealed undesirable side effects–oxidative damage and vasoconstriction–that hamper the application of cellfree hemoglobin as a blood substitute. We have addressed these problems and have found a new promising extracellular blood substitute: the natural giant extracellular polymeric hemoglobin of the polychaete annelid Arenicola marina. Here we show that it is less likely to cause immunogenic response; its functional and structural properties should prevent the side effects often associated with the administration of extracellular hemoglobin. Moreover, its intrinsic properties are of interest for other therapeutic applications often associated with hemorrhagic shock (ischemia reperfusion, treatment of septic shock and for organ preservation prior to transplantation). Moreover, using natural hemoglobin is particularly useful since recombinant DNA techniques could be used to express the protein in large quantities.

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Clinical publications

Pharmacodynamics of ALG-055009, a THR-β Agonist, in Hyperlipidemic Subjects
Neural Circuits in Anxiety Disorders
Defensive Behavior in Anxiety Disorders
Cenerimod No Impact on Oral Contraceptive, PK
Safety and Effectiveness of OTS and PGE-E as Bowel Cleansers
Eryaspase and Chemotherapy for Advanced Pancreatic Cancer Phase IIb Trial
Metopimazine Is Primarily Metabolized by a Liver Amidase in Humans
TRC150094 in Overweight and Obese Subjects: Phase-I Trial
The Immune Factors Driving DNA Methylation Variation in Human Blood
Receptor Inhibition – Cannabis Use Disorder Phase I, II trials
Pharmacodynamics of Multiple Ascending Oral Doses of ALG-055009, a THR-β Agonist, in Hyperlipidemic Subjects

Thyroid hormone receptor-beta (THR-β) is the primary THR expressed in
liver and plays an important role in lipid metabolism. Therapeutics targeting
THR-β represent a promising approach to treating patients with metabolic
dysfunction-associated steatohepatitis (MASH) by decreasing hepatic fat
content and improving liver histology, as evidenced by recent Phase 3 data
for the THR-β agonist resmetirom.
ALG-055009 is a THR-β agonist that in preclinical models had:
• High selectivity for THR-β over THR-α
• Nanomolar potency (EC50 = 50 nM) in cell-based assays that is 5-50x
more potent than other THR-β agonists in development
• High efficacy (i.e., reductions in total cholesterol and/or low-density
lipoprotein cholesterol (LDL-C)) in diet-induced obese rat and mouse
• A favorable pharmacokinetic (PK) profile with low plasma clearance,
metabolic stability, high oral bioavailability and a long plasma half-life

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Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder

ABSTRACT: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxietyrelated networks in humans have not been investigated.

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Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

ABSTRACT: Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

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Molecular Science
Lack of Effect of Cenerimod, a Selective S1P1 Receptor Modulator, on the Pharmacokinetics of a Combined Oral Contraceptive

ABSTRACT: Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10–25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction.

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Comparison of the efficacy and safety of oral trisulphate solution (OTS) and polyethylene glycol electrolyte (PGE-E) as bowel cleansing agent

ABSTRACT: Polyethylene Glycol Electrolyte (PEG-E) is the primary recommended
bowel cleansing agent in current Chinese bowel preparation guidelines. Patient
compliance might be influenced by poor taste and large volume (3-4L), which can
impact on the clinical outcome. Oral Trisulphate Solution (OTS) is a bowel cleansing
agent with fruit favor and lower volume (3L) required. Aim: To compare the efficacy
and safety of OTS and PGE-E on bowel cleansing before routine colonoscopy.
Methods: This was a Phase III, multicenter, randomized, controlled, non-inferiority,
investigator/assessor-blinded trial (NCT03562884). 294 subjects were included and
randomized and 283 subjects (mITT, figure 1) received OTS (Eziclen, nZ143) or
PEG-E (Fortrans, nZ140) via 2-days split-dosing regimen. The primary outcome
was the proportion of subjects with successful preparation (global BBPS score  6
by central assessment). The secondary outcomes included BBPS global score, BBPS
score by segment, lesion detection rate, proportion of fully compliant, patient
satisfaction (6-questions questionnaire, lower score indicated better satisfaction)
investigator satisfaction score (5-point Likert scale score) and safety evaluations.
Farrington-Manning method was used to comparison the difference between

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Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial

ABSTRACT: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line
advanced pancreatic adenocarcinoma.
Methods: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.
Results: 141 patients were randomized (eryaspase arm, n Z 95; control arm, n Z 46). Median
OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1e8.8) in the
eryaspase arm versus 4.9 months (3.1e7.1) in the control arm (HR, 0.63; 95% CI, 0.39e1.01; P Z 0.056) and 2.0 months (95% CI, 1.8e3.4) in the eryaspase arm versus 1.8 months (1.4 e3.8) in the control arm (HR, 0.67; 95% CI, 0.40e1.12; P Z 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P Z 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37 e0.84; P Z 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n Z 93) were gamma glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).
Conclusion: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway

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Metopimazine is primarily metabolized by a liver amidase in humans

ABSTRACT: Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first-pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin-monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall
MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP.

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Safety, Tolerability, and Pharmacokinetics of a Novel Mitochondrial Modulator, TRC150094, in Overweight and Obese Subjects: A Randomized Phase-I Clinical Trial

ABSTRACT: TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n= 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (−2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects.

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The immune factors driving DNA methylation variation in human blood

ABSTRACT: Epigenetic changes are required for normal development, yet the nature and respective contribution of factors that drive epigenetic variation in humans remain to be fully characterized. Here, we assessed how the blood DNA methylome of 884 adults is affected by DNA sequence variation, age, sex and 139 factors relating to life habits and immunity. Furthermore, we investigated whether these effects are mediated or not by changes in cellular composition, measured by deep immunophenotyping. We show that DNA methylation differs substantially between naïve and memory T cells, supporting the need for adjustment on these cell-types. By doing so, we find that latent cytomegalovirus infection drives DNA methylation variation and provide further support that the increased dispersion of DNA methylation with aging is due to epigenetic drift. Finally, our results indicate that cellular composition and DNA sequence variation are the strongest predictors of DNA methylation, highlighting critical factors for medical epigenomics studies.

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Signaling-specific inhibition of the CB1 receptor for cannabis use disorder: phase 1 and phase 2a randomized trials

ABSTRACT: Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the frst of a new pharmacological class, is a signaling-specifc inhibitor of the cannabinoid receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular efects resulting from Δ9 – tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing signifcant adverse efects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 signifcantly reduced cannabis’ positive subjective efects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efcacious treatment for CUD. identifers: NCT03325595, NCT03443895 and NCT03717272

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Core lab publications & posters

Vortioxetine Escitalopram EEG Study – Randomized Crossover Trial
Sensory Dysfunction in Schizophrenia and Alzheimer’s Dementia
Optimizing Behavioral Paradigms for Anhedonia
Brain Disease Assessment Workflow for Multiple Sclerosis
Mismatch Negativity as EEG Biomarker in CNS Drug Development
Transdiagnostic Perspective: Impulsivity and Compulsivity in Obesity and Diabetes
Safety and PK of Fosgonimeton in Alzheimer’s patients
Poster: EEG Implementing An Objective Biomarker
Poster: RTOC Pre-Competitive Consortium
Mismatch Negativity as EEG Biomarker in CNS Drug Development
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Effects of Vortioxetine and Escitalopram on Electroencephalographic Recordings – A Randomized, Crossover Trial in Healthy Males

ABSTRACT: The antidepressant drug vortioxetine has a multimodal action modulating neurotransmission through inhibition of the serotonin transporter and modulation of serotonin receptors. Vortioxetine has also been shown to alleviate cognitive symptoms in preclinical studies and in patients with depression. However, it is largely unclear how vortioxetine affects the brain processing in humans. The present study was conducted in 32 healthy males in a randomized, double-blinded, placebo-controlled, active comparator, four-way crossover design. Treatments were 10 and 20 mg/day vortioxetine, 15 mg/day escitalopram, and placebo, administered orally once daily for three days. Results were compared to placebo. Treatment effect was assessed by recording spontaneous electroencephalography (EEG) and 40 Hz auditory steady state responses. For the spontaneous EEG, both vortioxetine and escitalopram decreased the frequency content in the theta band (4–8 Hz) and increased power in the beta (12–32 Hz) and gamma (32–45 Hz) bands. Vortioxetine and escitalopram decreased connectivity during rest in the theta band and increased connectivity in the gamma bands. Finally, both treatments caused decreased power in the evoked gamma band in response to 40 Hz auditory stimulation. Although the global EEG changes were comparable between vortioxetine and escitalopram, subtle differences between treatment effects on the EEG in terms of effect size and regional distribution of the EEG changes were apparent. To our knowledge, the current results are the first data on how vortioxetine affects EEG in humans. The present study calls for further investigations addressing the possible electrophysiological and cognitive effects of vortioxetine.   2019 IBRO.Published by Elsevier Ltd. All rights reserved

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Electrophysiological assessment methodology of sensory processing dysfunction in schizophrenia and dementia of the Alzheimer type

ABSTRACT: Schizophrenia and Alzheimer’s disease impacts on various sensory processings are extensively reviewed in the present publication. This article describes aspects of a research project whose aim is to delineate the neurobiology that may underlie Social Withdrawal in Alzheimer’s disease, Schizophrenia and Major Depression. This is a European-funded IMI 2 project, identified as PRISM (Psychiatric Ratings using Intermediate Stratified Markers). This paper focuses specifically on the selected electrophysiological paradigms chosen based on a comprehensive review of all relevant literature and practical constraints. The choice of the electrophysiological biomarkers were fundamentality based their metrics and capacity to discriminate between populations. The selected electrophysiological paradigms are resting state EEG, auditory mismatch negativity, auditory and visual based oddball paradigms, facial emotion processing ERP’s and auditory steady-state response. The primary objective is to study the effect of social withdrawal on various biomarkers and endophenotypes found altered in the target populations. This has never been studied in relationship to social withdrawal, an important component of CNS diseases.

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Optimizing Behavioral Paradigms to Facilitate Development of New Treatments for Anhedonia and Reward Processing Deficits in Schizophrenia and Major Depressive Disorder: Study Protocol

ABSTRACT: Behavioral tasks focusing on different subdomains of reward processing may provide more objective and quantifiable measures of anhedonia and impaired motivation compared with clinical scales. Typically, single tasks are used in relatively
small studies to compare cases and controls in one indication, but they are rarely included in larger multisite trials. This is due to limited systematic standardization as well as the challenges of deployment in international studies and stringent adherence to the high regulatory requirements for data integrity. The Reward Task Optimization Consortium (RTOC) was formed to facilitate operational implementation of reward processing tasks, making them suitable for use in future large-scale, international, multisite drug development studies across multiple indications. The RTOC clinical study aims to conduct initial optimization of a set of tasks in patients with major depressive disorder (MDD) or schizophrenia (SZ).

Methods: We will conduct a multicenter study across four EU countries. Participants (MDD = 37, SZ = 37, with ≤80 age- and gender-matched healthy volunteers) will attend a study visit comprising screening, self-report and clinically rated assessments of anhedonia and symptom severity, and three reward processing tasks; specifically, the Grip Strength Effort task, the Doors task, and the Reinforcement Learning
Working Memory task. The Grip Strength Effort and Doors tasks include simultaneous Bilderbeck et al. Optimizing Reward-Related Biomarkers electroencephalography/event-related potential recordings. Outcomes will be compared using a two-way group design of MDD and SZ with matched controls, respectively. Further analyses will include anhedonia assessment scores as covariates. Planned analyses will assess whether our findings replicate previously published data, and multisite deployment will be evaluated through assessments of quality and conduct. A subset of participants will complete a second visit, to assess test–retest reliability of the task battery.

Discussion: This study will evaluate the operational deployment of three reward processing tasks to the regulatory standards required for use in drug development trials. We will explore the potential of these tasks to differentiate patients from controls and to provide a quantitative marker of anhedonia and/or impaired motivation, establishing their usefulness as endpoints in multisite clinical trials. This study should demonstrate where multifaceted reward deficits are similar or divergent across patient populations. Registration: (NCT04024371).

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A Clinically-Compatible Workflow for Computer-Aided Assessment of Brain Disease Activity in Multiple Sclerosis Patients

ABSTRACT: Over the last 10 years, the number of approved disease modifying drugs acting on the focal inflammatory process in Multiple Sclerosis (MS) has increased from 3 to 10. This wide choice offers the opportunity of a personalized medicine with the objective of no clinical and radiological activity for each patient. This new paradigm requires the optimization of the detection of new FLAIR lesions on longitudinal MRI. In this paper, we describe a complete workflow—that we developed, implemented, deployed, and evaluated—to facilitate the monitoring of new FLAIR lesions on longitudinal MRI of MS patients. This workflow has been designed to be usable by both hospital and private neurologists and radiologists in France. It consists of three main components: (i) a software component that allows for automated and secured anonymization and transfer of MRI data from the clinical Picture Archive and Communication System (PACS) to a processing server (and vice-versa); (ii) a fully automated segmentation core that enables detection of focal longitudinal changes in patients from T1-weighted, T2-weighted and FLAIR brain MRI scans, and (iii) a dedicated web viewer that provides an intuitive visualization of new lesions to radiologists and neurologists. We first present these different components. Then, we evaluate the workflow on 54 pairs of longitudinal MRI scans that were analyzed by 3 experts (1 neuroradiologist, 1 radiologist, and 1 neurologist) with and without the proposed workflow. We show that our workflow provided a valuable aid to clinicians in detecting new MS lesions both in terms of accuracy (mean number of detected lesions per patient and per expert 1.8 without the workflow vs. 2.3 with the workflow, p = 5.10−4 ) and of time dedicated by the experts (mean time difference 2′ 45′′ , p = 10−4 ). This increase in the number of detected lesions has implications in the classification of MS patients as stable or active, even for the most experienced neuroradiologist (mean sensitivity was 0.74 without the workflow and 0.90 with the workflow, p-value for no difference = 0.003). It therefore has potential consequences on the therapeutic management of MS patients.

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Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study

ABSTRACT: The lack of translation from basic research into new medicines is a major challenge in CNS drug development. Theneed to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer’s disease (AD) patients, and age-matched healthy controls. To evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease evaluation of the MMN response. Our findings suggest further investigations to support the identification of neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and clinical stages of SZ drug development

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Transdiagnostic Perspective of Impulsivity and Compulsivity in Obesity: From Cognitive Profile to Self-Reported Dimensions in Clinical Samples with and without Diabetes

ABSTRACT: Impulsive and compulsive behaviors have both been observed in individuals with obesity. The cooccurrence of obesity and type 2 diabetes (T2D) is more strongly associated with impulsivity, although there are no conclusive results yet. A multidimensional assessment of impulsivity and compulsivity was conducted in individuals with obesity in the absence or presence of T2D, compared with healthy, normal-weight individuals, with highly impulsive patients (gambling disorders), and with highly compulsive patients (anorexia nervosa). Decision making and novelty seeking were used to measure impulsivity, and cognitive flexibility and harm avoidance were used for compulsivity. For impulsivity, patients with obesity and T2D showed poorer decision-making ability compared with healthy individuals. For compulsivity, individuals with only obesity presented less cognitive flexibility and high harm avoidance; these dimensions were not associated with obe sity with T2D. This study contributes to the knowledge of the mechanisms associated with diabetes and its association with impulsive–compulsive behaviors, confirming the hypothesis that patients with obesity and T2D would be characterized by higher levels of impulsivity.

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer’s Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial

ABSTRACT: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer’s disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss.

Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton.

Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4 ± 6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8 ± 4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2 ± 7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement.

Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo.

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EEG: Implementing An Objective Biomarker In Clinical Research

ABSTRACT: Electroencephalography (EEG) is an electrophysiological technique used to measure and record the electrical activity of the brain. By directly recording this activity, EEG provides an unbiased representation of
the brain’s function and its response to pharmacological agents or stimuli. These recordings can be performed in several different ways (resting or not, together with various types of simulations) and with a
variety of devices. Here we aim to explain the different types of EEG recordings possible and show a few examples of how they can be used in Drug Development.

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Driving paradigm optimization for clinical trials: the RTOC pre-competitive consortium and validation of reward processing tasks.
Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study

ABSTRACT: The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The
need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology
and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation
from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN)
response in schizophrenic (SZ) patients, Alzheimer’s disease (AD) patients, and age-matched healthy controls. To
evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of
MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN
attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation
of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in
APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease
evaluation of the MMN response. Our findings suggest further investigations to support the identification of
neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we
provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and
clinical stages of SZ drug development.

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