Study of the mechanism of action of Blarcamesine (ANAVEX®2‐73): Whole blood transcriptomics analysis identifies treatment impact on compensatory pathways by restoring key neurodegenerative pathways functionality, including Alzheimer’s disease pathway

作者: Afshar, Mohammad ; Kindermans, Martin ; Missling, Christopher U ; Hammond, Edward ; Parmentier, Frédéric ; Williams, Coralie ; Goodsaid, Federico

AbstractBackgroundBlarcamesine (ANAVEX®2‐73), a novel oral selective sigma‐1 receptor (SIGMAR1) agonist was investigated in a clinical Phase 2a study in Alzheimer’s disease in which blarcamesine resulted in a lower rate of cognitive (MMSE) and functional (ADCS‐ADL) decline. Following the positive results of this study, a translational approach led to investigating blarcamesine in an international, double‐blind, multicenter, placebo‐controlled Phase 2 clinical study of 14‐week duration in 132 patients with Parkinson’s disease dementia (PDD). Whole blood transcriptomics analysis (RNAseq) was performed for the PDD study at two timepoints: baseline and Week 14. After quality control filtering, 14,150 genes were retained for analysis.MethodsWeighted gene correlation network analysis (WGCNA) was used to identify clusters of genes that show a correlated expression change across patients and timepoints. Thus, a data‐driven gene network was generated. Associations between the identified clusters and treatment arms were explored in order to select clusters for which gene expression is significantly associated with the high blarcamesine dose. These associations were assessed using linear mixed effect models with three covariates: dose, patient and timepoint. Significance was assessed with Dunett’s test.ResultsBlarcamesine significantly restores functionality in key pathways of Alzheimer’s disease, Parkinson’s disease and Prion diseases. The analysis identified two clusters of genes that are significantly differentially expressed in treated patients and represent compensatory pathways to genes dysregulations induced by neurodegenerative diseases. In both clusters, majority of genes were confirmed to interact (STRING database). Amongst interacting genes, neurodegenerative pathways were identified as overrepresented (p < 0.01). Down‐regulation of genes involved with neurodegeneration was observed in the placebo arm, however, was compensated in the blarcamesine arm.ConclusionsThis analysis identified a gene network that is differentially expressed in patients treated with blarcamesine after 14 weeks of treatment, compared to placebo. The biological relevance of this gene network was assessed. Pathway analysis confirmed the impact of the treatment on pathways involved in neurodegenerative diseases The identification of a gene network as the blarcamesine response pathway lays the foundation to better understand the mechanism of action at the molecular level of blarcamesine, thus unlocking characterization of responders based on molecular profiling, as well as identification of new indications in the area of neurodegenerative and other disorders.

2023-06-01·Journal of Clinical Oncology

Artificial intelligence–based biomarkers of response to immunotherapy in patients with non–small-cell lung cancer considering previous lines of treatment.

作者: Michon, Lucas ; Bouaoud, Jebrane ; Boussageon, Maxime ; Boulahfa, Jawad ; Fayette, Jerome ; Swalduz, Aurélie ; Foy, Jean-Philippe ; Turcat, Thomas ; Perol, Maurice ; Ortiz-Cuaran, Sandra ; Iriso, Pablo ; Karabajakian, Andy ; Saintigny, Pierre ; Afshar, Mohammad ; Kindermans, Martin ; Parmentier, Frédéric ; Lantuejoul, Sylvie ; Attignon, Valéry

e14652 Background: Lung cancer is one of the most prevalent types of cancer worldwide: 250,000 new cases are diagnosed yearly in the US, amongst which 80% are non-small cell lung cancers (NSCLC). The optimal biomarker to select patients diagnosed with advanced disease and benefiting the most from immunotherapy is still to be identified. Herein, we used KEM (Knowledge Extraction and Management) explainable Artificial Intelligence (xAI) as a tool that systematically extracts and evaluates all association rules between all variables in a database, thus enabling the identification of subgroups of patients with advanced NSCLC treated with immunotherapy with higher chances of overall survival in the NIVOBIO cohort (Foy et al. Eur J Cancer 2023). We aimed to identify biomarkers linked to optimum response to immunotherapy considering previous lines of therapies. Methods: Data was retrieved from GEO warehouse (GSE161537) and aggregated into a consolidated database totaling 82 patients and 2,568 variables. A two-step analysis plan was then performed. First step relied on KEM xAI: rules between gene expression, number of previous treatment lines and survival were explored: 51,306 rules were generated. 19 rules involving 3 genes were retained using metrics such as Support (number of examples), Confidence (conditional probability) and Lift (relative probability) and focusing on genes with a consistent signal across rules. Second, Cox proportional hazards models were generated using these genes to test the interaction between their expression and the number of previous treatment lines the patient had undergone. Genes with a significant log-rank and interaction p-value were retained. Results: Our analysis identified 2 genes that were significantly associated with overall survival and previous lines of treatment: SOS2 (p < 0.001) and LIFR (p = 0.020) high expression was associated with improved survival among patients with at least two previous treatment lines, whereas it was associated with poor survival for other patients. Consistently, low expression values of these genes were associated with poor survival in patients with less than two previous treatment lines. SOS2 and LIFR gene expression was identified as having a significant interaction with the number of previous treatment lines in the Cox model with a hazard ratio of 0.08 and 0.39 respectively. Conclusions: Our analysis enabled the identification of biomarkers not obviously related to the immune microenvironment and associated with an improved or poor survival depending on when immunotherapy was administered. These findings are laying promising foundations for the development of dynamic biomarkers and their potential translation into therapeutic recommendations after further validation.

2023-05-24·BMC medicine

First-in-human, double-blind, randomized phase 1b study of peptide immunotherapy IMCY-0098 in new-onset type 1 diabetes.

Article

作者: Achenbach, Peter ; Ahangarani, Roxana R ; Kindermans, Martin ; Vanderelst, Luc ; Leslie, Richard David ; Boitard, Christian ; Ali, Mohammad Alhadj ; Parmentier, Frédéric ; Bovy, Nicolas ; Owen, Katharine R ; Gebruers, Evelien ; Vandepapelière, Pierre ; Dayan, Colin ; Carlier, Vincent ; Van Rampelbergh, Jean ; Keymeulen, Bart ; Van Mechelen, Marcelle

BACKGROUNDType 1 diabetes (T1D) is a CD4⁺ T cell-driven autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells by CD8⁺ T cells. Achieving glycemic targets in T1D remains challenging in clinical practice; new treatments aim to halt autoimmunity and prolong β-cell survival. IMCY-0098 is a peptide derived from human proinsulin that contains a thiol-disulfide oxidoreductase motif at the N-terminus and was developed to halt disease progression by promoting the specific elimination of pathogenic T cells.METHODSThis first-in-human, 24-week, double-blind phase 1b study evaluated the safety of three dosages of IMCY-0098 in adults diagnosed with T1D < 6 months before study start. Forty-one participants were randomized to receive four bi-weekly injections of placebo or increasing doses of IMCY-0098 (dose groups A/B/C received 50/150/450 μg for priming followed by three further administrations of 25/75/225 μg, respectively). Multiple T1D-related clinical parameters were also assessed to monitor disease progression and inform future development. Long-term follow-up to 48 weeks was also conducted in a subset of patients.RESULTSTreatment with IMCY-0098 was well tolerated with no systemic reactions; a total of 315 adverse events (AEs) were reported in 40 patients (97.6%) and were related to study treatment in 29 patients (68.3%). AEs were generally mild; no AE led to discontinuation of the study or death. No significant decline in C-peptide was noted from baseline to Week 24 for dose A, B, C, or placebo (mean change - 0.108, - 0.041, - 0.040, and - 0.012, respectively), suggesting no disease progression.CONCLUSIONSPromising safety profile and preliminary clinical response data support the design of a phase 2 study of IMCY-0098 in patients with recent-onset T1D.TRIAL REGISTRATIONIMCY-T1D-001: ClinicalTrials.gov NCT03272269; EudraCT: 2016-003514-27; and IMCY-T1D-002: ClinicalTrials.gov NCT04190693; EudraCT: 2018-003728-35.

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