befiradol (NLX-112) / Neurolixis, Pierre Fabre - LARVOL DELTA

Recent and on-going trials for the treatment of levodopa-induced dyskinesia: a review of the clinical trial databases. (PubMed, Neurodegener Dis Manag) - "Promising results were obtained in Phase II trials with the serotonin type 1A (5-HT1A) agonist befiradol, the dopamine D3 receptor antagonist mesdopetam and the phosphodiesterase inhibitor CPL500036. In contrast, the metabotropic glutamate 4 (mGlu4) receptor negative allosteric modulator foliglurax and JM-010 (a combination of the 5-HT1A partial agonist buspirone and the and the 5-HT type 1B and 1D [5-HT1B/1D] agonist zolmitriptan) did not meet their endpoints in Phase II studies. Lastly, robot-assisted Repetitive Transcranial Magnetic Stimulation (rTMS) of the pre-supplementary motor area may be a promising non-pharmacological approach to alleviate dyskinesia."

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

Discovery of a functionally selective serotonin receptor (5-HT1AR) agonist for the treatment of pain. (PubMed, Sci Adv) - "Cryo-electron microscopy structures of ST171 bound to 5-HT1AR in complex with the Gi protein compared to the canonical agonist befiradol bound to complexes of 5-HT1AR with Gi or Gs revealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein-coupled receptor drugs."

Journal • Pain

Functional MRI Analysis of Brain Activity in Rats With Diabetic Bladder Dysfunction. (PubMed, CNS Neurosci Ther) - "DBD rats exhibit heightened thalamic and PAG activity during micturition, potentially due to enlarged bladder capacity, with cortical activity serving as a compensatory mechanism. These findings highlight potential neural targets for DBD treatment."

Journal • Preclinical • Anesthesia • Diabetes • Metabolic Disorders • Urology

Neurolixis Publishes Positive Phase 2A Trial Results for NLX-112 in Parkinson’s Disease (Neurolixis Press Release) - P2a | N=27 | NCT05148884 | Sponsor: Neurolixis SAS | "Neurolixis today announced the publication of the results from its successful Phase 2A proof-of-concept clinical trial of NLX-112 (befiradol) in Parkinson’s disease. The findings, published in the prestigious journal 𝘔𝘰𝘷𝘦𝘮𝘦𝘯𝘵 𝘋𝘪𝘴𝘰𝘳𝘥𝘦𝘳𝘴, highlight NLX-112’s potential as a first-in-class, non-dopaminergic therapy with dual efficacy in addressing both levodopa-induced dyskinesia (LID) and motor impairment in Parkinson’s patients. The randomized, double-blind, placebo-controlled trial, supported by The Michael J. Fox Foundation and Parkinson’s UK, evaluated NLX-112 in patients with troubling LID. The study successfully met its primary endpoint of safety and tolerability, as well as its secondary endpoint of significantly reducing LID. Notably, NLX-112 also demonstrated anti-parkinsonian effects, significantly improving motor function in study participants."

P2a data • Parkinson's Disease

NLX-112 Randomized Phase 2A Trial: Safety, Tolerability, Anti-Dyskinetic, and Anti-Parkinsonian Efficacy. (PubMed, Mov Disord) - "These results support further clinical investigation of NLX-112 for treatment of PD LID."

Journal • P2a data • CNS Disorders • Movement Disorders • Parkinson's Disease

PET imaging of functional 5-HT1A receptors with [18F]F13640: From PET kinetics modeling to static Standardized Uptake Values Ratio. (PubMed, Neuroimage) - "This study confirms the feasibility of static acquisitions to facilitate clinical use of the [18F]F13640 radiopharmaceutical to image functional 5-HT1A receptors. This involves off-camera injection, 10 to 20 minutes static acquisition duration, and quantification using SUVR, while improving patient comfort."

Journal

Long-Term 5-HT1A Receptor Agonist NLX-112 Treatment Improves Functional Recovery After Spinal Cord Injury. (PubMed, Int J Mol Sci) - "Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT1A receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT1A receptors to treat SCI."

Journal • CNS Disorders • Orthopedics

Fentanyl dose-sparing in polyarthritic rats requires full agonism at 5-HT1A receptors: Comparison between NLX-112, (±)8-OH-DPAT, and buspirone. (PubMed, J Opioid Manag) - "These results suggest that oral FSA dose-sparing effect, in this rat polyarthritis pain model, requires high efficacy activation of 5-HT1A receptors, such as that afforded by NLX-112. By contrast, the agonist efficacy of (±)8-OH-DPAT and buspirone seems insufficient for FSA dose-sparing."

Clinical • Journal • Preclinical • Immunology • Musculoskeletal Pain • Pain • DRD2

Preclinical investigation of the effect of stress on the binding of [18F]F13640, a 5-HT1A radiopharmaceutical. (PubMed, Nucl Med Biol) - "The present study demonstrated stress-induced cerebrometabolic activation or inhibition of various brain regions involved in stress model. Applying this model to our radiotracer, [18F]F13640 showed few influence of stress on its binding. This will enable to rule out any confounding effect of stress during imaging studies."

Journal • Preclinical • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry

Pharmacodynamic, pharmacokinetic and rat brain receptor occupancy profile of NLX-112, a highly selective 5-HT1A receptor biased agonist. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Co-administration of L-DOPA (6 mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16 mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound."

Journal • PK/PD data • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Levodopa-induced dyskinesia: do current clinical trials hold hope for future treatment? (PubMed, Expert Opin Pharmacother) - No abstract available

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

Altered brain serotonin 5-HT receptor expression and function in juvenile Fmr1 knockout mice. (PubMed, Neuropharmacology) - "Also, treatment with the selective 5-HTR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a central role for 5-HTRs in regulating AGS, compared to males, female Fmr1 knockout mice showed a lower prevalence of AGS and higher expression of antagonist-labeled 5-HTRs in the inferior colliculus, a neural system necessary for AGS. These results provide preclinical support that 5-HTR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli."

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

The neuroprotective properties of NLX-112 in MPTP treated mice are mediated by reactive gliosis and astrocytic GDNF (MDS Congress 2023) - "NLX-112 exhibits neuroprotective properties in MPTP treated mice by reversing the loss of nigral striatal TH-ir. NLX-112’s neuroprotective effects are likely mediated through reversal of MPTP induced inflammation as shown by attenuation of astrogliosis, inhibition of microgliosis but also upregulation of the neurotrophic factor, GDNF [3] in astrocytes."

Preclinical • CNS Disorders • Parkinson's Disease • GFAP

NLX-112 has favorable safety and tolerability and displays efficacy against levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) (MDS Congress 2023) - "NLX-112 was safe, well tolerated and significantly reduced LID in an apparently treatment-duration dependent manner, suggesting that NLX-112 could be a promising first-in-class serotonergic drug candidate for improved treatment of PD-LID."

Clinical • CNS Disorders • Parkinson's Disease

Multimodal imaging study of the 5-HT receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia. (PubMed, Neuroimage Clin) - "This neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson's disease."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Solid Tumor

Trial offers hope of a breakthrough in treatment for Parkinson’s disease (Yahoo News) - P2a | N=22 | NCT05148884 | Sponsor: Neurolixis SAS | "The findings from a phase 2a trial of the drug...have shown promising results that are being revealed at the World Parkinson’s Congress in Barcelona, Spain. In people taking the drug, there was significant reduction in movement symptoms, such as slowness, stiffness and tremor, the trial found....Those enrolled in the trial showed a significant reduction in movement symptoms – things like slowness, stiffness and tremor....People either received NLX-112 or the placebo in increasing doses during the initial four weeks, to minimise the potential side effects. They stayed on the maximum dose for two weeks and then were weaned off the drug over another fortnight. As well as finding that those who took the drug had improvements in the levodopa-induced dyskinesia and Parkinson’s symptoms, the trial also found the drug was well tolerated and safe."

P2a data • CNS Disorders • Parkinson's Disease

Re - Thinking Target Selectivity: How Biased Agonists At 5 - HT1A Sub - Populations in Specific Brain Regions Are Re - Shaping Drug Discovery for Serotonergic Disorders (CINP 2023) - "Several compounds have been identified that show promising profiles: NLX-101 preferentially activates 5-HT1A heteroreceptors in cortical regions associated with control of mood and cognition, whereas NLX-112 more strongly activates 5-HT1A autoreceptors in the Raphe nuclei associated with control of motor dysfunction and other mood disorders. A novel drug candidate, NLX-204 shows exceptional antidepressant-like properties in rodent models, equivalent to those of ketamine. Taken together, these findings suggest that a new generation of serotonin 5-HT1A receptor biased agonists will become available for improved treatment of disorders involving serotonergic neurotransmission and lead the way for targeting specific subpopulations of 5-HT1A receptors."

Clinical • Autism Spectrum Disorder • CNS Disorders • Depression • Genetic Disorders • Mood Disorders • Movement Disorders • Psychiatry

5-HT agonists for levodopa-induced dyskinesia in Parkinson's disease. (PubMed, Neurodegener Dis Manag) - "Clinical trials testing 5-HT agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD."

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

Neurolixis Announces Positive Ph2A Proof-of-Concept on NLX-112 in Levodopa-Induced Dyskinesia in Parkinson’s Disease (Neurolixis Press Release) - P2 | N=22 | NCT05148884 | Sponsor: Neurolixis SAS | "Neurolixis, Inc. today announced the positive results of its Phase 2A clinical trial with NLX-112 (befiradol), for treatment of levodopa-induced dyskinesias (LID) in Parkinson’s disease (PD). NLX-112...met the primary outcome of safety and tolerability and, in addition, showed statistically significant efficacy in reducing LID symptoms in Parkinson’s disease patients....22 patients (15 on NLX-112, 7 on PBO) completed the 8-week treatment according to the protocol. Safety was good and did not differ between NLX-112 and placebo groups....Beyond meeting the primary outcome of safety and tolerability, NLX-112 also achieved significant reductions in LID scores, whereas placebo group changes were not significant. Full analysis of efficacy measures is underway and will be disclosed in further announcements and at upcoming scientific conferences."

P2 data • CNS Disorders • Parkinson's Disease

Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia (clinicaltrials.gov) - P2 | N=27 | Completed | Sponsor: Neurolixis SAS | Recruiting ➔ Completed

Trial completion • CNS Disorders • Movement Disorders • Parkinson's Disease • CRP

[F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT receptors in humans. (PubMed, Eur J Nucl Med Mol Imaging) - "The favorable brain labeling and kinetic profile of [F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT receptors, unlike previous radiopharmaceuticals that act as antagonists. [F]F13640's kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry."

Journal • Psychiatry

Activating 5-HT1AReceptors to Correct Neuronal Hyperexcitability in FMR1 Knockout Mice (Neuroscience 2022) - "At the behavioral level, we tested the antiepileptic effects of the selective 5-HT1AR agonist, NLX-112 (0.25-2.5 mg/kg)...In vivo, Fmr1 KO mice showed significantly elevated 5-HT1AR-mediated behaviors when treated with the potent 5-HT1AR agonist (R)-8-OH-DPAT (1 and 2 mg/kg), an effect that was blocked by pretreatment with WAY-100635 (0.1 mg/kg). Collectively, these results suggest that upregulation of inhibitory 5-HT1ARs in the brains of Fmr1 KO mice may be a compensatory response to neuronal hyperexcitability, and that activating 5-HT1ARs may be pharmacotherapeutic for FXS."

Preclinical • CNS Disorders • Epilepsy • Mental Retardation • Mood Disorders • Psychiatry • FMR1

Befiradol treatment ameliorated the motor dysfunction of Spinocerebellar Ataxia Type 3 mouse model (ECNP 2022) - "elegans) SCA3 model [4], using as reference drug tandospirone (TD), a partial 5-HT1AR agonist, previously described to have transient anti-ataxia effects in SCA3 patients [5]. Contrarily, TD exhibited no therapeutic effect on motor function. Post-symptomatically, befiradol-treated animals’ coordination was improved in the MST early on the disease (lower dose - p=0.053), while minor impact was observed in other motor parameters. Conclusion : Overall, befiradol showed a beneficial effect in SCA3 mice motor function, reinforcing the potential role of serotonergic signaling modulation as a promising therapeutic target for SCA3, though further experiments should be conducted to clarify the optimal doses and the route of administration to be utilized for this drug."

Preclinical • Ataxia • CNS Disorders • Parkinson's Disease • ATXN3

Befiradol treatment ameliorated the motor dysfunction of Spinocerebellar Ataxia Type 3 mouse model (ECNP 2022) - "elegans) SCA3 model [4], using as reference drug tandospirone (TD), a partial 5-HT1AR agonist, previously described to have transient anti-ataxia effects in SCA3 patients [5]. Contrarily, TD exhibited no therapeutic effect on motor function. Post-symptomatically, befiradol-treated animals’ coordination was improved in the MST early on the disease (lower dose - p=0.053), while minor impact was observed in other motor parameters. Conclusion : Overall, befiradol showed a beneficial effect in SCA3 mice motor function, reinforcing the potential role of serotonergic signaling modulation as a promising therapeutic target for SCA3, though further experiments should be conducted to clarify the optimal doses and the route of administration to be utilized for this drug."

Preclinical • Ataxia • CNS Disorders • Parkinson's Disease • ATXN3

Improvement of urethral dysfunction by 5-HT  receptor agonist NLX-112 in diabetic rats. (PubMed, Neurourol Urodyn) - "Urethral dysfunction in T1D rats was improved by NLX-112. 5-HT receptors were upregulated in the dorsolateral nucleus of L6-S1 spinal cord in T1D rats. These findings suggest that NLX-112 may constitute a novel therapeutic strategy to treat diabetic urethral dysfunction."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus