basmisanil (RG1662) / Roche - LARVOL DELTA

Ligand Binding and Functional Effect of Novel Bicyclic α5 GABAA Receptor Negative Allosteric Modulators. (PubMed, J Chem Inf Model) - "Starting from the published experimental structure of an engineered, homopentameric, basmisanil-binding GABAA receptor-like construct consisting of modified α5 subunits and an α1-containing GABAA structure, we created a new model of the ligand binding site at the α5/γ2 interface...In addition, calculations were able to explain the obtained structure-activity relationships, among others, the switch-like effect of the aromatic nitrogen position in the dihydro-naphthyridinone motif for the functional character, and suggest different binding poses for the ligands presenting silent versus negative allosteric effects in this set (SAMs vs. NAMs, respectively). We believe that our results can help design α5 selective GABAA negative allosteric modulators and better understand the GABAA receptor."

Journal • CNS Disorders

New Insights Into Pharmacology of GABAA Receptor Alpha Subunits-Selective Modulators. (PubMed, Am J Ther) - "Future drug discovery efforts are encouraged to focus on positive allosteric modulators that selectively target the α2, α3 subunits and negative/positive allosteric modulators that target the α5 subunit of the GABAA receptor. The pursuit of ligands possessing only anxiolytic effects or those enhancing cognition continues to be an important focus for future research, with promising advancements depicted in recent studies."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Epilepsy • Insomnia • Mood Disorders • Neuralgia • Pain • Psychiatry • Sleep Disorder

Basmisanil, an α5-GABAAR negative allosteric modulator, produces rapid and sustained antidepressant-like responses in male mice. (PubMed, Neurosci Lett) - "Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABAAR occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=7 | Terminated | Sponsor: Hoffmann-La Roche | Completed ➔ Terminated; The study was terminated due to slow recruitment and was not related to safety or tolerability.

Trial termination

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=7 | Completed | Sponsor: Hoffmann-La Roche | Terminated ➔ Completed

Trial completion

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=7 | Terminated | Sponsor: Hoffmann-La Roche | N=90 ➔ 7 | Trial completion date: Jan 2026 ➔ Mar 2024 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2026 ➔ Mar 2024; The study was terminated due to slow recruitment and was not related to safety or tolerability.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Hoffmann-La Roche | Active, not recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children Aged 2-14 Years With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed

Participation of lncRNAs in the development of diabetic complications: Systematic review and meta-analysis. I. Rat. (PubMed, Diabet Med) - "This review found a significant involvement of lncRNAs in the progression of pathologies associated with chronic hyperglycemia in rat models, and further studies are needed to establish their potential as biomarkers and therapeutic targets for diabetes."

Journal • Preclinical • Retrospective data • Review • Diabetes • Gestational Diabetes • Metabolic Disorders • Pain • Renal Disease • Retinal Disorders • MALAT1 • NEAT1

Quindecim, a Phase II, double-blind, randomized, placebo-controlled trial of basmisanil in children with Dup15q syndrome (EAN 2023) - P2 | "In the rare disease Dup15q Syndrome, with limited trial and natural history experience, this placebo- controlled Phase 2 study innovates beyond investigation of clinical safety and efficacy. By employing a physiological biomarker of disease pathologic processes, Quindecim will enable both timely decision making and potential future studies in Dup15q Syndrome."

Clinical • P2 data • CNS Disorders • Developmental Disorders • Psychiatry • Rare Diseases • UBE3A

Physiologically Based Biopharmaceutics Modeling of Food Effect for Basmisanil: A Retrospective Case Study of the Utility for Formulation Bridging. (PubMed, Pharmaceutics) - "However, there is need for further evaluation of the approach and a definition of what formulation changes are minor in this context. In addition, this work highlights some uncertainties in the handling of solubility in PBBM, in particular around temperature dependency of solubility and the parameterization of bile salt solubilization using measurements in biorelevant media."

Journal • Retrospective data

A 'middle-out approach' for the prediction of human drug disposition from preclinical data using simplified physiologically based pharmacokinetic (PBPK) models. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Three lipophilic bases were tested (diazepam, midazolam and basmisanil) for which intravenous PK data were available in rat, monkey and human. For basmisanil, the sparse preclinical data available could have affected the model performance for fitting and the subsequent extrapolation to human. Overall, this work provides a rational strategy to predict human drug distribution using preclinical PK data within the PBPK modelling strategy."

Journal • PK/PD data • Preclinical

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Safety and Efficacy of Basmisanil Treatment in Children With Dup15q Syndrome (clinicaltrials.gov) - P2 | N=90 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P2 trial

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome. (PubMed, J Neurodev Disord) - P2 | "Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome."

Clinical • Journal • P2 data • Cognitive Disorders • Developmental Disorders • Genetic Disorders • Mental Retardation • Pediatrics

The GABAA α5 Receptor as a Therapeutic Target for Dup15q Syndrome (ACNP 2021) - "The converging evidence reported here strongly suggests that excess GABAA receptor function contributes to the pathophysiology of Dup15q syndrome and points to the GABAA α5 receptor subtype as a novel and tractable target for the treatment of Dup15q syndrome. Roche is planning a randomized-controlled phase 2 trial in children with Dup15q syndrome to evaluate the effects of a GABAA α5 NAM (basmisanil) on core symptoms of Dup15q syndrome."

Alzheimer's Disease • CNS Disorders • Epilepsy

Basmisanil, a highly selective GABA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man. (PubMed, Sci Rep) - "At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABA-α5 receptor negative modulation."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Psychiatry • Schizophrenia

[VIRTUAL] Results of a 24- Week Phase 2 Trial with Basmisanil, a Potent Selective Negative Allosteric Modulator of Gabaa α5 Receptors, in Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2, P2b | "Discussion Overall, basmisanil did not improve cognitive deficits and functional impairment compared to placebo in a 24week study. However, subgroup analyses indicate that the cognitive subtype of patients may be associated with distinct profiles of treatment response."

P2 data • CNS Disorders • Schizophrenia

[VIRTUAL] Results of a 24- Week Phase 2 Trial with Basmisanil, a Potent Selective Negative Allosteric Modulator of Gabaa α5 Receptors, in Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2b | "Discussion Overall, basmisanil did not improve cognitive deficits and functional impairment compared to placebo in a 24week study. However, subgroup analyses indicate that the cognitive subtype of patients may be associated with distinct profiles of treatment response."

P2 data • CNS Disorders • Schizophrenia

[VIRTUAL] Results of a 24- Week Phase 2 Trial with Basmisanil, a Potent Selective Negative Allosteric Modulator of Gabaa α5 Receptors, in Cognitive Impairment Associated with Schizophrenia (CIAS) (SIRS 2021) - P2b | "Discussion Overall, basmisanil did not improve cognitive deficits and functional impairment compared to placebo in a 24week study. However, subgroup analyses indicate that the cognitive subtype of patients may be associated with distinct profiles of treatment response."

P2 data • CNS Disorders • Schizophrenia

Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits. (PubMed, Br J Anaesth) - "Basmisanil was markedly less potent than the other α5-NAMs, an unexpected result based on studies of recombinant α5 GABA receptors. Studying the effects of α5 GABA receptor-selective drugs on the tonic inhibitory current in neurones could inform the selection of compounds for future clinical trials."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Mental Retardation • Psychiatry

Preclinical and Early Clinical Pharmacological Profile of Basmisanil, a Gaba-A 5 Receptor Negative Allosteric modulator, Currently in a Phase 2 Clinical Trial for Cognitive Impairment Associated with Schizophrenia (SIRS 2019) - "Key aspects of the study design and baseline data will be presented. Discussion These data suggest basmisanil is a promising candidate drug with a unique pharmacological and safety profile for further clinical testing in conditions associated with cognitive impairment such as schizophrenia."

P2 data • CNS Disorders • Schizophrenia

Preclinical and Early Clinical Pharmacological Profile of Basmisanil, a Gaba-A 5 Receptor Negative Allosteric modulator, Currently in a Phase 2 Clinical Trial for Cognitive Impairment Associated with Schizophrenia (SIRS 2019) - "Key aspects of the study design and baseline data will be presented. Discussion These data suggest basmisanil is a promising candidate drug with a unique pharmacological and safety profile for further clinical testing in conditions associated with cognitive impairment such as schizophrenia."

P2 data • CNS Disorders • Schizophrenia

PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration. (PubMed, J Pharmacokinet Pharmacodyn) - "Plasma drug concentration and electrocardiogram (ECG) data from a drug-drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study."

Journal • CYP3A4

A Study of the Effect of RG1662 on Metformin in Healthy Volunteers (clinicaltrials.gov) - P1; N=17; Active, not recruiting; Sponsor: Hoffmann-La Roche; Recruiting -> Active, not recruiting

Enrollment closed • Biosimilar