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Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme
- P. Falkai, C. Reuteman-Fowler, Z. Blahova, S. Ikezawa, S. R. Marder, J. H. Krystal
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S637
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Introduction
Cognitive impairment (CI) is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signalling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signalling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-wk, Phase II trial (NCT02832037) in 509 patients (pts) with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition.
ObjectivesThe Phase III CONNEX programme aims to confirm the efficacy, safety and tolerability of iclepertin in improving cognition and functioning in a larger cohort of pts.
MethodsCONNEX consists of three replicate randomised, double-blind, placebo-controlled parallel-group trials in pts with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 pts, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 wks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities and interact ≥1 hr per wk with a designated study partner. Pts with CI due to developmental, neurological or other disorders, or receiving cognitive remediation therapy within 12 wks prior to screening, will be excluded. Pts will be recruited from 39 countries in Asia, Australia, New Zealand, North and South America and Europe, and randomised 1:1 to receive either oral iclepertin 10 mg (n=293) or placebo (n=293) once daily over 26 wks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).
ResultsThe studies are currently recruiting (first pts enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures and the experience of collecting these data as part of a large multicountry, multicentre study.
ConclusionsTo date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III programme would provide important insight into the role of glutamate in cognitive symptoms, that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for CI associated with schizophrenia.
Disclosure of InterestP. Falkai Consultant of: Advistory board Boehringer Ingelheim Pharma GmBH & Co. KG, C. Reuteman-Fowler Employee of: Boehringer Ingelheim Pharma GmBH & Co. KG, Z. Blahova Employee of: Boehringer Ingelheim Pharma GmBH & Co. KG, S. Ikezawa Consultant of: Financial agreements with Boehringer Ingelheim Pharma GmbH, Merck, Biogen and Sunovion, S. Marder Grant / Research support from: Boehringer Ingelheim, GW Pharma, Consultant of: Boehringer Ingelheim, Merck, Sunovion, J. Krystal Shareolder of: Co-founder of Freedom Biosciences, Inc Investments in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences and Tempero Bio., Consultant of: Aptinyx, Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Taisho Pharmaceutical Co Advistory board: Biohaven Pharmaceuticals, BioXcel Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, Delix Therapeutics, EpiVario, Eisai, Jazz Pharmaceuticals, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio and Terran Biosciences;
Physiological evidence of a deficit to enhance the empathic response in schizophrenia
- S. Corbera, S. Ikezawa, M.D. Bell, B.E. Wexler
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- Journal:
- European Psychiatry / Volume 29 / Issue 8 / October 2014
- Published online by Cambridge University Press:
- 15 April 2020, pp. 463-472
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Empathy is crucial for maintaining effective social interactions. Research has identified both an early-emotional sharing and a late-cognitive component of empathy. Although considered a functionally vital social cognition process, empathy has scarcely been studied in schizophrenia (SZ). We used event-related potentials (ERPs) to study the temporal dynamics of empathic response in 19 patients with SZ and 18 matched healthy controls (HC) using an empathy for physical pain paradigm. Participants responded to pictures of hands in neutral and painful situations in an active empathic condition and one manipulated by task demands. Additionally, subjective ratings of the stimuli and empathic self-reports were collected. People with SZ had (1) decreased early-emotional ERP responses to pictures of others in pain; (2) decreased modulation by attention of late-cognitive ERP responses; (3) lower ratings of perspective taking and higher ratings of personal distress which were both related to decreased modulation of late-cognitive empathic responses; (4) a significant relationship between high affective overlap between somebody else's pain and their own pain and decreased modulation of late-cognitive empathic responses; (5) a distinct relationship between regulatory deficits in late-cognitive empathy and functioning. Patients had present but reduced early and late empathy-related ERPs. Patients also reported increased personal distress when faced with distress in others. The late ERP responses are thought to be associated with self-regulation and response modulation. The magnitude of these late responses was inversely associated with reported levels of personal distress in both patients and controls. Additionally, regulatory deficits in cognitive empathy were highly related with deficits in functioning. Decreased ability to regulate one's own emotional engagement and response to emotions of others may be an important source of distress and dysfunction in social situations for patients with schizophrenia.
Propagation of the higher-order Landau modes of electron plasma wave
- S. Ikezawa, Y. Kawai, T. Hara, Y. Nakamura, T. Itoh, T. Kawabe
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- Journal:
- Journal of Plasma Physics / Volume 17 / Issue 2 / April 1977
- Published online by Cambridge University Press:
- 13 March 2009, pp. 251-257
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Propagation of electrostatic electron waves whose frequency is smaller than the electron plasma frequency in a large unmagnetized plasma is investigated both experimentally and theoretically. When a receiver is close to a transmitter, free-streaming electrons are detected owing to their large capacity for excitation. When the distance between the receiver and the transmitter becomes large, the third-order Landau mode is observed due to its smaller damping than that of free-streaming electrons. Finally, a dip in amplitude of the wave, caused by interference by the higher-order Landau modes, is seen. The results are in reasonable agreement with numerical calculation assuming a dipole excitation for the wave.