BAER-101 / AstraZeneca, Fortress - LARVOL DELTA

Nonsedating anxiolytics. (PubMed, Pharmacol Biochem Behav) - "This has rekindled the interest in the GABAA-receptor (GABAAR) positive allosteric modulator (PAM) compounds, which have a long history in treatment of anxiety beginning with diazepam, chlordiazepoxide, and alprazolam...Advances in molecular biology gave birth to a host of subtype selective GABAAR-PAMs which suffered from signs of sedation and motor impairment and only three compounds progressed to proof-of-concept studies (TPA-023, AZD7325 and PF-06372865)...In preclinical studies KRM-II-81 produced anxiolytic-like effects but with minimal sedation, respiratory depression, and abuse liability. Thus, KRM-II-81 is a newly discovered, non- BZD anxiolytic compound, which targets a selective population of GABAAR for improved therapeutic gain and reduced side effects."

Journal • Review • Anesthesia • CNS Disorders • Depression • Hepatology • Mood Disorders • Psychiatry

Avenue Therapeutics to Present BAER-101 Preclinical Data at American Society for Experimental Neurotherapeutics (ASENT) 2024 Annual Meeting (Fortress Biotech Press Release) - "Avenue Therapeutics, Inc...announced that Amy Chappell, M.D., FAAN will be presenting preclinical in vivo data evaluating BAER-101 using the SynapCell's Genetic Absence Epilepsy Rat from Strasbourg ('GAERS') model of epilepsy at the American Society for Experimental Neurotherapeutics (ASENT) 2024 Annual Meeting on Wednesday, March 13, 2024....In the model, BAER-101 demonstrated full suppression of seizure activity with a minimal effective dose of 0.3 mg/kg, PO. The effect was fast in onset and stable throughout the duration of testing."

Preclinical • Epilepsy

BAER-101, a selective potentiator of α2- and α3-containing GABAA receptors, fully suppresses spontaneous cortical spike-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). (PubMed, Drug Dev Res) - "BAER-101 was administered orally at doses of 0.3-100 mg/kg and diazepam was used as a positive control using a cross-over protocol with a wash-out period between treatments. This is the first report of an α2/3-selective GABA PAM suppressing seizures in the GAERS model. The data encourage proceeding to test BAER-101 in patients with epilepsy."

Journal • Preclinical • Absence Seizure Disorder • Anesthesia • CNS Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders

A Phase 2- Ready Potentiator of α2/3-Containing GABAA Receptors Potently and Fully Blocks Seizures in Rats with Genetic Absence Epilepsy (AES 2023) - "Diazepam was used as a positive control (2 mg/kg, IP). BAER-101 produced antiseizure effects with a minimal effective dose of 0.3 mg/kg, PO in GAERS confirming the antiseizure effects of this compound. The data are expected to translate into patients with seizures. BAER-101 has already been in over 700 patients with generalized anxiety disorders and Fragile X Syndrome where it was tolerated and safe."

P2 data • Preclinical • Absence Seizure Disorder • Anesthesia • Ataxia • CNS Disorders • Epilepsy • Fragile X Syndrome • General Anxiety Disorder • Genetic Disorders • Mood Disorders • Movement Disorders • Psychiatry

GABA Pathways in Autism Spectrum Disorder (ASD) (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: King's College London | Active, not recruiting ➔ Recruiting | N=28 ➔ 50 | Trial completion date: Aug 2023 ➔ Mar 2026 | Trial primary completion date: Feb 2023 ➔ Mar 2025

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date • Autism Spectrum Disorder • Genetic Disorders

Avenue Therapeutics Announces High Potency and Full Efficacy in a Model of Generalized Seizures for its Novel GABA-A Receptor Potentiator, BAER-101, Supporting Phase 2 Clinical Study (GlobeNewswire) - "Avenue Therapeutics, Inc...announced today that BAER-101...significantly suppressed seizures in a translational animal model of absence epilepsy....'These preclinical results demonstrate the potential of BAER-101 to improve the current treatment landscape of epilepsy with a differentiated approach designed to improve the safety profile compared to existing drugs, which are often not well-tolerated due to side effects including sedation, cognitive impairment, ataxia and addiction,'...As we advance toward potentially initiating a Phase 2a study in 2024..."

New P2 trial • Preclinical • CNS Disorders • Epilepsy

Molecular Variation in Fragile X Syndrome: Impact on Drug Target Engagement (ACNP 2022) - " In our single-dose challenge study, acamprosate, minocycline, and lovastatin dosing was not associated with any consistent changes in EEG signal... We have noted early evidence that FMRP status in fragile X syndrome (FXS) may represent a disease/disorder continuous molecular measure that impacts small molecule treatment response. The ability to effectively identify molecular patient subgroups based on peripheral FMRP analysis holds promise for use in larger Phase II and III studies to match patient groups to particular drugs under study. We believe FMRP levels will support future small molecule studies in FXS and potentially enable personalized medicine approaches in this field."

CNS Disorders • Psychiatry • FMR1

Keynote — Clinical Trials in Fragile X Syndrome (NFXF-FXC 2022) - "Trials to be covered include: acamprosate, single dose EEG-focused challenge studies, AFQ056 (FXLEARN), ergoloid mesylates/5HTP, metformin, cannabidiol, BAER-101, BPN 14770, sulindac and Anavex 2-73. A basic explanation of how each medication works and results in trials previously conducted will be discussed. For each trial currently recruiting, requirements for participation, sites where patients can participate, and logistical information will be given, and presenters will answer any questions about trials."

Clinical • Fragile X Syndrome • Genetic Disorders

Pilot Study of BAER-101, a selective GABA A alpha 2,3 agonist in adults with fragile X syndrome (NFXF-FXC 2022) - "BAER-101, formerly AZD7325, is a GABA(A) alpha 2,3 receptor subunit selective agonist with significantly enhanced tolerability compared to broad GABA(A) agonists. Following initial laboratory study of BAER-101 in the FMR1 KO mouse in our lab where the drug demonstrated positive effects on memory, behavior, and audiogenic seizure, we moved to complete the first study of BAER-101 in humans with FXS."

Clinical • Anesthesia • CNS Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders

GABA Pathways in Autism Spectrum Disorder (ASD) (clinicaltrials.gov) - P=N/A | N=28 | Active, not recruiting | Sponsor: King's College London | Recruiting ➔ Active, not recruiting | N=100 ➔ 28 | Trial completion date: Sep 2021 ➔ Aug 2023 | Trial primary completion date: Feb 2020 ➔ Feb 2023

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Autism Spectrum Disorder • Genetic Disorders

GABA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome. (PubMed, Front Psychiatry) - "Other Fmr1 KO-specific phenotypes were not improved by the drug, such as increased hippocampal dendritic spine density, open field activity and marble burying. Overall, this work shows that BAER-101 improves select phenotypes in Fmr1 KO mice and encourages further studies into the efficacy of GABA-receptor subunit-selective agonists for the treatment of FXS."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Fragile X Syndrome • Genetic Disorders • Immunology • Mental Retardation

An Initial Study of AZD7325 in Adults With Fragile X Syndrome (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: Children's Hospital Medical Center, Cincinnati; Recruiting ➔ Completed; Trial completion date: Oct 2020 ➔ Jun 2020

Clinical • Trial completion • Trial completion date • Fragile X Syndrome • Genetic Disorders

The impact of radiochemistry in drug projects: The use of C-14 labeled in the AZD8529, AZD7325 and AZD6280 projects. (PubMed, J Labelled Comp Radiopharm) - "Understanding the metabolic transformations of a potential drug molecule is important to understanding the safety profile of a drug candidate. A quantitative whole body autoradiography study can detect covalent adducts in vivo as was the case with AZD5248 in which the compound bound to the aorta. Ultimately another compound free of aortic binding was developed, AZD7986."

Journal

Potentiating α subunit containing perisomatic GABA receptors protects against seizures in a mouse model of Dravet syndrome. (PubMed, J Physiol) - "Dravet syndrome mice (Scn1a ) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABA receptor α subunit expression The α / α subunit selective positive allosteric modulator (PAM) AZD7325 potentiates inhibitory postsynaptic currents (IPSCs) specifically in perisomatic synapses AZD7325 demonstrates stronger effects on IPSCs in the seizure resistant mouse strain consistent with higher α subunit expression AZD7325 demonstrates seizure protective effects in Scn1a mice without apparent sedative effects in vivo."

Journal • Preclinical • CNS Disorders • Epilepsy

An Initial Study of AZD7325 in Adults With Fragile X Syndrome (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Children's Hospital Medical Center, Cincinnati; Trial completion date: Jul 2018 ➔ Oct 2020; Trial primary completion date: May 2018 ➔ Jul 2020

Clinical • Trial completion date • Trial primary completion date

Synthesis of C-14 Labeled GABAA α2/α3 Selective Partial Agonists and the Investigation of Late-Occurring and Long-Circulating Metabolites of GABAA Receptor Modulator AZD7325. (PubMed, J Labelled Comp Radiopharm) - "A great number of AZD7325 metabolites were observed across species in vivo, whose identification was aided by [14 C]AZD7325. An interesting metabolic cyclization and aromatization pathway leading to the tricyclic core of M9 and the oxidative pathways to M10 and M42 are presented."

Journal