bradanicline (ATA-101) / CODA Biotherap - LARVOL DELTA

Dual Cholinergic Modulation in Dementia: Quinuclidine Carbamates Targeting Butyrylcholinesterase and α7 Nicotinic Receptor. (PubMed, Chem Biol Interact) - "Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism...The crystal structures confirmed non-covalent binding to the active site of human BChE, and the 6b-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Pain

The effects of task-specific home-based touchscreen training in people with Parkinson's disease: a pilot randomized controlled trial. (PubMed, J Neurol) - "Home-based, unsupervised touchscreen training is feasible and effective to improve movement time of the trained task, albeit without transfer to an untrained task. The heterogeneity and variability of the effects underscore the importance of personalizing rehabilitation programs in PD, according to baseline performance. Future studies should investigate a wider range of transfer tasks and clinical determinants that could impact the training response."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

MEDICATIONS FOR ALCOHOL USE DISORDER ARE INCREASINGLY PRESCRIBED IN PATIENTS WITH SEVERE ALCOHOL-RELATED LIVER DISEASE WITH A FAVORABLE SAFETY AND TOLERABILITY PROFILE (DDW 2024) - "Background/Aims: Alcohol use disorder (AUD) and alcohol-related liver disease (ALD) cause significant morbidity and mortality worldwide. 13 of 509 ALD patients met our inclusion criteria (156 excluded due to missing data 101 did not receive the AUD drug 39 miscoded). There were 11 Group 1 and 101 group patients. The number of ALD treated patients increased over time across both groups (Figure 1A/1B p=0."

Clinical • Addiction (Opioid and Alcohol) • Fibrosis • Hematological Disorders • Hepatology • Immunology • Inflammation

Diagnostic utility of HFLC% and IG% for acute Pancreatitis-A retrospective Case-Control study. (PubMed, Heliyon) - "We divided patients in the Non-MAP group with complete data(101 patients) into HFLC% ≥ 2.9 %(31 patients) and HFLC% < 2.9 %(70 patients) according to the threshold of 7th day HFLC%...HFLC% may be an independent laboratory marker for prognosis in AP. Combining HFLC% with IG%, CRP, and WBC helps evaluate AP patients' disease development and outcome."

Journal • Retrospective data • Hematological Disorders • Immunology • Infectious Disease • Inflammation • Pancreatitis • Systemic Inflammatory Response Syndrome • CRP

Chemogenetics for the Treatment of Spasticity (ASGCT 2024) - "Pharmacologic treatment with baclofen, alpha-2 agonists, and anticonvulsants can provide relief for some patients...However, the ability of chemogenetics approaches to regulate the activity of spinal motor neurons has not previously been evaluated.We hypothesized that an engineered chloride channel that opens upon binding of the ligand, bradanicline, could hyperpolarize motor neurons and inhibit their activity, resulting in changes in ambulation and grip strength...Thus, this approach may offer a safer and more effective treatment option for patients with spasticity. Future studies in animal models of spasticity may bear this out."

Cardiovascular • CNS Disorders • Gene Therapies • Movement Disorders • Orthopedics • Pain

Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig. (PubMed, Front Neuroimaging) - "Of particular significance, our in vivo investigations demonstrate that TC-5619 achieves substantial α7-nAChR occupancy, effectively blocking approximately 40% of α7-nAChR binding, whereas encenicline exhibits more limited α7-nAChR occupancy. This study underscores the importance of preclinical PET imaging and target engagement analysis in informing clinical trial strategies, including dosing decisions."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia

Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice. (PubMed, Nat Commun) - "Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy."

Journal • Preclinical • CNS Disorders • Epilepsy

ARTIFICIAL INTELLIGENCE IN THE CLINICAL SETTING OF THE RHEUMATIC DISEASES; A SYSTEMATIC REVIEW OF THE LITERATURE (EULAR 2023) - "The most common types of data used as training were demographic data in 114 articles followed by physical data 101, clinical test data 92, genomics data 40, image data 30 and pathological data 28...On the other hand, only a very small number of the study have examined the explainability of AI. The review indicates that research on the clinical implementation of AI applications is still at an early stage despite the great potential."

Clinical • Review • Ankylosing Spondylitis • Fibrosis • Immunology • Inflammatory Arthritis • Lupus • Myositis • Rheumatoid Arthritis • Rheumatology • Scleroderma • Seronegative Spondyloarthropathies • Spondylarthritis • Systemic Lupus Erythematosus • Systemic Sclerosis • Vasculitis

Optimizing Novel Chemogenetic Tools to Control Focal Seizures (AES 2022) - "Hippocampal ACh was monitored in vivo with 2‑P iAChSnFr sensor imaging. CODA71 chimeric chloride channels suppress hippocampal neuronal firing in acute slices after selective agonist TC-5619 application (TC-5619 rheobase: 368±39.7 pA; vehicle rheobase: 80±15.4 pA; p=0.002)... Our data show that chimeric chloride channels, like the CODA71 receptor, allow targeted focal seizure suppression, while avoiding potential pitfalls of systemic and DREADD-based therapies. We continue to explore how further restricting receptor expression to more select neuronal subsets or altering sensitivity to endogenous ACh signaling can further improve the potential of this approach to treat focal epilepsies."

CNS Disorders • Epilepsy • Immunology

Inhibition of neuronal activity using a novel chemogenetic platform developed for the treatment of neurological disorders (Neuroscience 2022) - "The dose-response relationship and current amplitudes of TC-5619 (TC) and acetylcholine (ACh) were assessed in CODA receptor-expressing HEK293 (HEK) cells and in primary neonatal mouse hippocampal (mHC) neurons... Optimization of engineered CODA receptors for desired properties can increase the safety and effectiveness of CODA Biotherapeutics’ chemogenetics-based therapeutic approach for neurological disorders."

CNS Disorders

Controlling focal seizures using novel chemogenetic tools (AES 2021) - "Our data demonstrate the potential of the Coda71 receptor, and other similar chimeric chloride channel variants, to allow targeted focal seizure suppression, while avoiding potential pitfalls of systemic and DREADD-based therapies. We aim to determine whether further restricting receptor expression to more select neuronal subsets or altering sensitivity to endogenous cholinergic signaling can further improve the potential of our approach to treat focal epilepsies."

CNS Disorders • Epilepsy • Immunology

Evidence for alpha nicotinic receptor activation during the cough suppressing effects induced by nicotine and identification of ATA-101 as a potential novel therapy for the treatment of chronic cough. (PubMed, J Pharmacol Exp Ther) - "We additionally observed that the αβ-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the α-selective agonist PHA 543613 dose-dependently inhibited evoked coughing. Significance Statement This study documents the antitussive actions of nicotine and identifies the α nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α nicotinic receptor selective agonists may be promising candidates for the treatment of chronic refractory cough."

Journal • Chronic Cough • CNS Disorders • Psychiatry • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] The Efficacy of Bradanicline in Refractory Chronic Cough (ERS 2020) - "Despite good tolerability, escalating doses of bradanicline did not reduce awake cough frequency in RCC patients compared with placebo."

Clinical • JAK3

Targacept lays off 46 percent of its workforce (Journalnow) - The next research updates for Targacept are expected in Q2-Q4 2012 for a P2 trial for the AZD1446 compound for Alzheimer's disease; Results from P2 trials of TC-5619 for attention-deficit hyperactivity disorder and schizophrenia are expected in H2 2012 and mid-2013, respectively

Anticipated P2 data • Alzheimer's Disease • Schizophrenia

Targacept and AstraZeneca amend collaboration (Businesswire) - "Targacept...announced that its collaboration with AstraZeneca has been restructured. Targacept now has the right to pursue development and commercialization of any alpha7 NNR modulator in any therapeutic area...without obligation to AstraZeneca. AstraZeneca now has the right to develop and commercialize the alpha4beta2 NNR modulators...including AZD1446, in any therapeutic area. AstraZeneca will return to Targacept all rights to the alpha4beta2 modulator TC-1734 (also known as AZD3480)...mild to moderate Alzheimer’s disease. TC-5619...top-line results from this study are expected by the end of 2013."

Anticipated P2 data • Licensing / partnership • Alzheimer's Disease • Schizophrenia

Targacept announces participation in upcoming conferences (Targacept) - Targacept is scheduled to present at the Deutsche Bank 2011 BioFEST and the Oppenheimer & Co. 22nd Annual Healthcare Conference

Anticipated conference • Schizophrenia

Targacept to report third quarter 2011 financial results on November 1, 2011 (Targacept) - Targacept announced that it will report financial results for the third quarter of 2011 on Tuesday, November 1, 2011, after the U.S. financial markets close

Anticipated quarterly results • Schizophrenia

Targacept: Annual Report 2012 (Targacept) - Anticipated patent expiry of composition of matter for a racemic mixture that includes TC-5619 in March 2019; Anticipated patent expiry of composition of matter for a family of racemic compounds that includes a racemic mixture that includes TC-5619 in August 2019; Anticipated patent expiry of composition of matter for a sub-family of racemic compounds that includes a racemic mixture that includes TC-5619 in Dec 2018; Anticipated patent expiry of composition of matter for salt forms, including the preferred salt in January 2029; Anticipated patent expiry of method of use of a racemix mixture that includes TC-5619 for schizophrenia in Feb 2023; Anticipated patent expiry of method of use of racemic mixture that includes TC-5619 for schizophrenia in Nov 2025; Anticipated patent expiry of commercial method and composition of matter for synthetic intermediates for manufacture of TC-5619 in Aug 2028

Anticipated patent expiry • Schizophrenia

Targacept announces negative top-line results from phase 2b clinical trial of TC-5619 in schizophrenia (Targacept Press Release) - P2b, N=603; NCT01488929; Sponsor: Targacept; "...TC-5619 did not meet the primary outcome measure, change from baseline on the Scale for the Assessment of Negative Symptoms (SANS) after 24 weeks versus placebo...TC-5619 did not demonstrate improvement on the key secondary measures of cognitive function...study was well conducted and provides a robust dataset upon which we have based our decision to not pursue further development of TC-5619 as a treatment for either schizophrenia or Alzheimer's disease"

Discontinued • P2b data • Alzheimer's Disease • Schizophrenia

A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia (Neuropsychopharmacology) - P2, N=185; NCT01003379; Pubmed ID: 23303043; "GMLT statistically favored...TC-5619 (p=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (p=0.030). No other secondary outcome measure demonstrated...a drug effect in the total population. There was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger...in favor of TC-5619 in tobacco users and occasionally better in the US than in India."

P2 data • Schizophrenia

Effects of alpha7 nicotinic receptor agonist TC-5619 in cognitive dysfunction in schizophrenia (ECNP 2011) - P2, N=185; Blinded analysis of Groton Maze Learning Test (GMLT) data showed positive skew; GMLT results favoring TC-5619 met the success criteria (adjusted p = 0.054); Scale for Assessment of Negative Symptoms (SANS), CGI – Global Impression (CGI-I), Subject Global Impression statistically favored TC-5619; TC-5619 was generally well tolerated, with no clinically significant change in any measures

P2 data • Schizophrenia

The alpha7 neuronal nicotinic receptor (NNR) modulator TC-5619 had beneficial effects and was generally well tolerated in a Phase 2 trial in cognitive dysfunction in schizophrenia (CDS) (ACNP 2011) - P2, N=185; GMLT results favored TC-5619 (Hochberg adjusted p=0.054) and met predefined success criteria (1-sided p<0.10). SANS, CGI-I and SGI-Cog results favored TC-5619 (unadjusted p<0.05) on a measurement date; TC-5619 was generally well tolerated and there were no noteworthy safety findings

P2 data • Schizophrenia

Targacept: Jefferies Global Healthcare Conference (Targacept) - "TC-5619: Completed Phase 2 Trial in Schizophrenia Patients"; "Statistical significance in primary endpoint (executive function test) and secondary endpoint for negative symptoms; other cognitive endpoints yielded mixed results"; "Results driven by tobacco users"; "Generally well tolerated at all dose levels"

P2 data • Schizophrenia

Targacept: Q3 2013 Results (Targacept) - Anticipated top-line data from P2b trial for negative symptoms and cognitive dysfunction in schizophrenia in Dec 2013/Jan 2014 

Anticipated P2b data • Schizophrenia

A Dose Escalation Study of Bradanicline in Refractory Chronic Cough (clinicaltrials.gov) - P2; N=46; Completed; Sponsor: Attenua, Inc.; Recruiting ➔ Completed; Trial completion date: Oct 2019 ➔ May 2019; Trial primary completion date: Sep 2019 ➔ May 2019

Clinical • Trial completion • Trial completion date • Trial primary completion date