Skip to main content

From Setback to Strategy: Rethinking Cognitive Schizophrenia Trials -Why the CONNEX trials Failed

Background  

Schizophrenia is a chronic, severe neuropsychiatric disorder characterised by disturbances in thought, perception, emotion, and cognition. It typically manifests in late adolescence or early adulthood, often between the ages of 15 and 35 years, and tends to follow a lifelong course with varying degrees of functional impairment. 

Schizophrenia has a multifactorial epidemiology. It is best understood as a neurodevelopmental disorder that arises from complex interactions between inherited vulnerability and environmental exposures across critical stages of brain development (World Health Organization, 2022). Genetics play a major role in schizophrenia. Family and twin studies consistently show high heritability—estimated at around 70–80% (Lichtenstein, P., 2009). 

Schizophrenia involves dysregulation of multiple neurotransmitter systems, most notably dopaminergic and glutamatergic pathways (Coyle, J.T., 2006). The dopamine hypothesis for example, describes hyperactivity in the mesolimbic pathway being the cause for associated positive symptoms in schizophrenia; hallucinations and delusions (Howes, O.D. 2009). 

Clinical and Functional Impact:  

The Three Symptom Domains of Schizophrenia 

 
Schizophrenia is a compelling example of a central nervous system (CNS) disorder that highlights the complex, multidimensional nature of neurodevelopmental conditions. Contemporary neuropsychiatric theory recognises that such disorders typically involve three interrelated symptom domains: positive, negative, and cognitive.  
 

Despite this understanding, clinical practice and the pharmacological industry have lagged in developing treatments that effectively address all three domains (Harvey et al., 2019). Schizophrenia is often narrowly associated with hallucinations and delusions, but these positive symptoms represent only one aspect of the condition (T.R. & Cuthbert, B.N. 2015).  

 Negative symptoms, such as social withdrawal and emotional blunting, alongside cognitive impairments affecting memory and executive function are equally significant and are linked to distinct neural circuits and neurochemical pathways. This multidimensional framework underscores the need for more comprehensive therapeutic approaches that reflect the disorder’s underlying neurobiological complexity. 

The Science Behind has been involved in a drug development pipeline for the treatment of schizophrenia specifically looking at cognitive performance. This drug has finished Phase I of its study and is now moving towards further development of its clinical trial (The Science Behind). 

Cardiff Universities Medicine Discovery Institute (MDI) set out to address these challenges by using pharmaco-magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI) as indices of target engagement in thePhase I of the clinical trial for the novel positive allosteric modulator (PAM) of the AMPA receptor - developed at Cardiff University. AMPA PAMS increase the conductance of AMPA and co-localised NMDA receptors and are proposed to improve cognitive via an increase in synaptic plasticity, particularly in conditions such as schizophrenia where NMDA receptor function is impaired (Hyder et al., 2023). 

 Schizophrenia affects –1% of the global population and though positive symptoms (eg hallucinations) can be relatively well managed, there are currently no treatments for the cognitive impairments that severely impar quality of life. Students targeting different receptors, including AMPARS, show the MEG can provide sensitive and time-resolved markers or pharmacological action.  

Current drug treatments  

Current drug treatments offered for schizophrenia are designed to reduce psychosis, however, are not yet capable of restoring cognitive or motivational symptoms.  

(+) They block dopamine (treat hallucinations/delusions). 

(-) They do not enhance cortical dopamine or glutamate (needed for cognition). 

Thus, cognitive and motivational impairment remains the largest untreated symptom in schizophrenia pharmacotherapy — drugs like iclepertin, are a first line attempt to tackle this.  

Overview of current clinical treatment success for treating all symptomologies associated with schizophrenia, from the lens of the modern neuropsychiatric theory:  

Iclepertin: The promising attempt at a “next generation” approach 

Iclepertin overview: 

  • Target: GlyT1 (glycine transporter-1) → increase synaptic glycine → enhance NMDA receptor activation. 

  • Intended role: Treatment of cognitive impairment in schizophrenia (CIAS), not positive or negative symptoms. 

  • Distinct from: Conventional D2/5-HT₂A antipsychotics. 

  • Clinical status: Phase II positive, Phase III negative (didn’t meet endpoints). 

  • Take-home: Novel mechanism, promising ideation, but so far real-world benefit not confirmed. 

The next generation approach  

Rather than targeting dopamine or serotonin like current schizophrenic pharmacological interventions, iclepertin acts on the glutamatergic system, specifically modulating NMDA receptor function through glycine transporter (GlyT1) inhibition (Bauminger, H. & Gaisler-Salomon, I. 2022). This represents a novel and more nuanced approach to addressing the neurophysiological underpinnings of schizophrenia (Nakagome, K. 2022).  

This reflects a deeper appreciation of the extracellular environment, receptor density, and the spatial and temporal dynamics that govern synaptic signalling and plasticity (Mothet, J.-P., 2015). Research into the tripartite synapse, involving neurons, astrocytes, and the surrounding glial network, has gained increasing attention, yet remains relatively novel within neuropsychopharmacology.

Preclinical studies, such as investigations into MK-801–induced deficits in animal models, have provided valuable insights into the pathophysiology of cognitive and behavioural impairments in schizophrenia, supported by translatable EEG biomarkers (Rosenbrock, H., 2022).  

  The next step—and the focus of this discussion—is understanding why these promising mechanistic insights failed to translate successfully in clinical trials for iclepertin, such as the CONNEX trials. 

CONNEX trails protocol  

The largest clinical investigation of iclepertin to date was the CONNEX programme, conducted by the German pharmaceutical company Boehringer Ingelheim. The programme enrolled approximately 1,840 patients across threerandomised, double-blind, placebo-controlled trials—CONNEX-1, CONNEX-2, and CONNEX-3 (ClinicalTrials.gov, 2021) —involving individuals with schizophrenia who were receiving stable antipsychotic treatment (Blahova Z., 2024). Each study aimed to recruit around 586 participants, with roughly 293 patients assigned to iclepertin (10 mg once daily) and 293 to placebo (Reuteman-Fowler C., 2024). 

Key Changes Across Clinical Phases of Iclepertin Development:  

Phase I–III Translational Design Continuity Table (IND-Focused) 

Purpose: Showing how early-phase clinical strategy decisions propagate into late-phase success or failure, and where early advisory input can mitigate risk.  



Table references: Harvey et al. (2024), Rosenbrock, H., Desch, M. & Wunderlich, G. (2023), Schultheis et al. (2022) EEG biomarkers 

Key Message for Early-Phase Advisory Positioning: 

  • Phase I design decisions lock in Phase III success probability.

  • Failure in CONNEX was not just Phase III execution—it reflects missed opportunities to build a translational bridge from Phase I to pivotal design. 

  • Early clinical advisory can materially reduce Phase III risk by embedding: 

  • Translational biomarker strategy 

  • Model-informed dose optimisation 

  • Population enrichment hypotheses 

  • Scalable endpoint and site standardisation frameworks 

Why CONNEX Likely Failed — Key Translational and Protocol Lessons 

Core Risk Factors Identified 

1. Lack of Structured Cognitive Training (CCT) 
GlyT1/NMDA modulation supports neuroplasticity, but behavioural engagement is often required to translate synaptic changes into measurable cognition gains. Phase III did not include standardised CCT, potentially limiting clinical signal translation. 

2. Population Heterogeneity and Signal Dilution 
Phase III enrolled a large, multinational, cognitively heterogeneous population. Inclusion of near-normal and severely impaired patients likely diluted treatment effects compared with more enriched Phase II cohorts. 

3. Mechanism–Endpoint Sensitivity Gap 
Early development demonstrated target engagement (e.g., EEG/MMN paradigms), but Phase III relied on MCCB, a distal and variable cognitive endpoint. Mechanistic biomarkers were not used for enrichment or adaptive decision-making (Giordano et al. 2021). 

4. Fixed-Dose, Long-Duration Pivotal Design 
A single 10 mg dose was selected despite Phase II dose–response signals at 10 and 25 mg. The 6‑month endpoint increased attrition, practice effects, and operational variability, reducing drug–placebo separation. 

5. Phase II Effect Size Inflation (“Winner’s Curse”) 
Small proof-of-concept studies often overestimate efficacy. Modest Phase II signals may not have been robust enough to replicate at global scale. 

Where TSB Creates Value in IND and Early Clinical Development 

The Science Behind (TSB) focuses on designing Phase I–II programmes to maximise Phase III success probability through: 

  • Translational biomarker and endpoint co-development 

  • Model-informed dose optimisation and adaptive trial design 

  • Population enrichment strategies to reduce heterogeneity 

  • Scalable cognition and CNS endpoint operational frameworks

  • Regulatory-aligned translational development narratives 

Practical Protocol Enhancements TSB Would Implement 

Phase I Translational Addendum 
Randomised proof-of-mechanism cohort in patients (n≈30–50): CSF PK/PD, EEG/MMN or P300, cognitive microtasks to confirm CNS target engagement and mechanistic efficacy. 

Phase II Mechanism-Aligned Design 
Factorial design incorporating structured CCT (drug × CCT interaction testing) to define behavioural co-intervention requirements for Phase III (Fornacon-Wood et al. 2022) 

Biomarker-Responder Enrichment 
Short PD run-in with EEG/MMN or cognitive microtasks; randomise biomarker responders to reduce heterogeneity and increase effect size. 

Operational Standardisation 
Centralised cognitive assessment platforms, certified raters, harmonised language/culture protocols, and digital endpoints to minimise site variance before global scale-up. 

Summary for IND-Phase Sponsors 

CONNEX scaled a modest Phase II signal into a large multinational Phase III programme without equivalent translational enrichment, behavioural co-intervention, or operational standardisation. These design choices increased variability and reduced sensitivity to detect efficacy. 

TSB embeds translational rigour from IND onward—linking mechanism to endpoints, optimising dose and population selection, and building scalable operational frameworks—to materially reduce late-phase clinical failure risk. 

References:   

  1. Bauminger, H. & Gaisler-Salomon, I. (2022) ‘Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia’, International Journal of Molecular Sciences, 23(15), p. 8617. doi: 10.3390/ijms23158617. 

  1. Blahova, Z., Ikezawa, S., Falkai, P., Krystal, J.H. & Rangan, T. (2024) ‘CONNEX, a Phase III Randomized Trial Program Assessing Efficacy and Safety of Iclepertin in Schizophrenia: Recruitment and Baseline Characteristics’, BJPsychOpen, 10(Suppl 1), pp. S72–S73. doi: 10.1192/bjo.2024.230. 

  1. ClinicalTrials.gov (2021) ‘A Phase III Randomized, Double-blind, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of BI 425809 Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-3)’ [online]. Available at: https://clinicaltrials.gov/ct2/show/NCT04860830  

  1. Cardiff University (2023) First Phase schizophrenia clinical trial completes initial studies successfully, Cardiff University, 19 June. Available at: https://www.cardiff.ac.uk/news/view/2727463-clinical-trial-launches-for-new-schizophrenia-drug 

  1. Coyle, J.T. (2006) ‘Glutamate and schizophrenia: beyond the dopamine hypothesis’, Cellular and Molecular Neurobiology, 26(4–6), pp. 365–384. doi: 10.1007/s10571-006-9062-8. 

  1. Fornacon-Wood, I. et al. (2022) ‘Understanding the differences between Bayesian and frequentist statistics’, International Journal of Radiation Oncology, Biology, Physics, 112(5), pp. 1076–1082. doi: 10.1016/j.ijrobp.2021.09.007. 

  1. Giordano, A.L., Smith, D.D. & Harris, E.L. (2021) ‘Challenges in CNS drug development and the role of imaging’, Psychopharmacology, 238(2), pp. 343–358. doi: 10.1007/s00213-021-05838-3. 

  1. Harvey, P.D. et al. (2019) ‘Domain-based treatment approaches in neuropsychiatry: cognition and functioning in schizophrenia’, CNS Spectrums, 24(2), pp. 154–162. doi: 10.1017/S1092852918001189. 

  1. Harvey, P.D., McDonald, S., Fu, E. & Reuteman-Fowler, C. (2024) ‘Efficacy and safety of iclepertin (BI 425809) with adjunctive computerized cognitive training in patients with schizophrenia’, Schizophrenia Research: Cognition, 40, p. 100340. doi: 10.1016/j.scog.2024.100340. 

  1. Hyder, R., Jones, N., Swettenham, J., Harrison, N. and Singh, K. (2023) 1.41 – Using Magnetoencephalography to accelerate CNS drug discovery. In: MEG UKI 2023 Conference Booklet. Poster session 1, MEG UKI, Trinity College Dublin, 27–28 October, p. 41. Available at: https://meguk.ac.uk/wp-content/uploads/2023/10/MEGUKI-2023-Conference-Booklet-complete.pdf 

  1. Howes, O.D. & Kapur, S. (2009) ‘The dopamine hypothesis of schizophrenia: version III—the final common pathway’, Schizophrenia Bulletin, 35(3), pp. 549–562. doi: 10.1093/schbul/sbp006. 

  1. Insel, T.R. & Cuthbert, B.N. (2015) ‘Brain disorders? Precisely: why our current definitions fail us and how to move forward’, Neuron, 88(1), pp. 18–31. doi: 10.1016/j.neuron.2015.09.017. 

  1. Lichtenstein, P., Yip, B.H., Björk, C., Pawitan, Y., Cannon, T.D., Sullivan, P.F. & Hultman, C.M. (2009) ‘Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study’, JAMA Psychiatry, 66(7), pp. 748–755. doi: 10.1001/archgenpsychiatry.2009.94. 

  1. Mothet, J.-P., Le Bail, M. & Billard, J.-M. (2015) ‘Time and space profiling of NMDA receptor co-agonist functions’, Journal of Neurochemistry, first published 19 June. doi: 10.1111/jnc.13204. 

  1. Nakagome, K. (2022) ‘Plain language summary of the effects of iclepertin (BI 425809) on cognition in patients with schizophrenia’, Future Neurology, 17(3). doi: 10.2217/fnl-2022-0008. 

  1. Reuteman-Fowler, C., Blahova, Z., Ikezawa, S., Marder, S., Falkai, P. & Krystal, J.H. (2024) ‘The Phase III CONNEX programme assessing the efficacy and safety of iclepertin in patients with schizophrenia: Trial design and recruitment update’, European Psychiatry, 67(S1), pp. S87–S88. doi: 10.1192/j.eurpsy.2024.224. 

  1. Rosenbrock, H., Desch, M. & Wunderlich, G. (2023) ‘Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia’, European Archives of Psychiatry and Clinical Neuroscience, 273(7), pp. 1557–1566. doi: 10.1007/s00406-023-01576-z. 

  1. Rosenbrock, H., Dorner-Ciossek, C., Giovannini, R., Schmid, B. & Schuelert, N. (2022) ‘Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia’, Journal of Pharmacology and Experimental Therapeutics, 382(2), pp. 223–232. doi: 10.1124/jpet.121.001071. 

  1. The Science Behind: A Promising New Drug for Treating Cognitive Decline in Schizophrenia. The Science Behind. Available at: https://thesciencebehind.com/news/a-promising-new-drug-for-treating-cognitive-decline-in-schizophrenia 

  1. Schultheis, C., Rosenbrock, H., Mack, S.R. et al. (2022) ‘Quantitative electroencephalography parameters as neurophysiological biomarkers of schizophrenia-related deficits: A Phase II substudy of patients treated with iclepertin (BI 425809)’, Translational Psychiatry, 12, p. 329. doi: 10.1038/s41398-022-02096-5. 

  1. Simbec-Orion (2023) First Dose Administered in Phase I Trial of Novel Treatment for Cognitive Impairment Associated with Schizophrenia, 9 March. Available at: https://www.simbecorion.com/news/first-dose-administered-in-phase-i-trial-of-novel-treatment-for-cognitive-impairment-associated-with-schizophrenia/ 

  1. World Health Organization (WHO) (2022) ‘Schizophrenia: Key Facts’, Geneva: World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/schizophrenia