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Industry | Biopharmaceuticals |
---|---|
Founded | 2011 |
Headquarters | |
Key people | Mark A. Varney, Adrian Newman-Tancredi |
Website | https://www.neurolixis.com/en/ |
Neurolixis is a biopharmaceutical company focused on novel drugs for the treatment of human central nervous system diseases.
Neurolixis Inc. was founded in 2011 by Mark A. Varney, PhD, and Adrian Newman-Tancredi, PhD, DSc.. The company's therapeutic focus is on CNS disorders including Parkinson's disease, neurological orphan disorders, depression and cognitive deficits. [1] The company has offices in USA and in France. [2]
In September 2013, Neurolixis in-licensed two clinical-phase drugs, befiradol and F-15599 from Pierre Fabre Laboratories, a French pharmaceutical company. [3] Befiradol (also known as NLX-112) is targeted to the treatment of movement disorders, notably dyskinesia in Parkinson's disease, whereas F-15599 (also known as NLX-101) is intended for the treatment of autism spectrum disorders including Rett syndrome and Fragile X syndrome. In addition, Neurolixis is developing its own novel chemical entities (NCEs), notably NLX-204 (see below).
Neurolixis has been awarded a series of research grants by the Michael J. Fox Foundation and by Parkinson's UK. Neurolixis undertook research examining the effects of novel, highly selective and efficacious serotonergic drugs targeting 5-HT1A receptors in brain regions relevant to therapeutic properties in Parkinson's disease. [4] The Michael J. Fox Foundation subsequently announced that it was supporting proof-of-principle studies on befiradol (also known as NLX-112) in models of Parkinson's disease [5] and showcased Neurolixis in its Partnering Program. [6] In January 2018, the British charity Parkinson's UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients. [7] In March 2019, Neurolixis announced that the US Food and Drug Administration (FDA) gave a positive response to Neurolixis' Investigational New Drug (IND) application for befiradol to be tested in a Phase 2 clinical study in Parkinson's disease patients with troublesome Levodopa-induced dyskinesia. [8] Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg. [9] [10]
On 22 November 2020, The Sunday Times reported that the two charities, Parkinson's UK and Michael J. Fox Foundation, were jointly investing $2 million to support a clinical trial on befiradol in Parkinson's disease patients with troublesome Levodopa-induced dyskinesia, a potentially "life changing" drug. [11] On 23 November 2020, Parkinson's UK and Michael J. Fox Foundation, confirmed their funding in an official announcement. [12] Neurolixis announced on 30 November 2021 the start of patient recruitment in a Phase 2A clinical trial to investigate the safety, tolerability and preliminary efficacy of NLX-112 versus placebo in L-dopa-induced dyskinesia in Parkinson's disease patients. [13] On 20 March 2023, Neurolixis, Parkinson's UK and Michael J. Fox Foundation announced that the clinical trial had met its primary endpoint of safety and tolerability, and also the secondary endpoint of efficacy in reducing Levodopa-induced dyskinesia. [14]
In other studies, befiradol showed pro-motility activity in a transgenic nematode worm model of spinocerebellar ataxia type 3 [15] (also known as SCA3 or Machado-Joseph disease), an orphan disorder. Befiradol also reversed depression-like behavior and catalepsy induced by tetrabenazine, a drug used for the treatment of Huntington's disease. [16]
F-15599 (also known as NLX-101) was awarded Orphan Drug Status by the United States Food and Drug Administration (FDA) in October 2013 [17] and Orphan Medicinal Product designation by the European Medicines Agency in March 2014. [18] In collaboration with researchers at the University of Bristol, Neurolixis has been awarded a grant by the International Rett Syndrome Foundation to study F-15599 in animal models of Rett syndrome. [19] In June 2015, Neurolixis was awarded a grant by the Rett Syndrome Research Trust to advance F-15599 to clinical development. [20] Subsequent studies on F-15599 investigated its functional selectivity (also referred to as 'biased agonism') at cortical serotonin 5-HT1A receptors using brain imaging techniques in rat: functional magnetic resonance imaging [21] and positron emission tomography. [22] The functional selectivity of F-15599 was considered to underlie its rapid-acting antidepressant-like activity in the 'chronic mild stress' (CMS) model of depression. F-15599 reversed CMS-induced anhedonia (measured as a deficit in sucrose solution consumption) after a single day of treatment. [23] More recently, Neurolixis has broadened its characterization of F-15599 to other autism spectrum disorders, notably Fragile X syndrome. Researchers at the University of California, Riverside showed that F-15599 protected transgenic Fragile X syndrome mice from audiogenic seizures and death. [24]
In addition to developing befiradol and F-15599, Neurolixis is also developing its own novel chemical entities (NCEs) in collaboration with a team at Jagiellonian University in Krakow, Poland. Scientists from Neurolixis and Jagiellonian University filed a patent application on the NCEs in 2016, [25] and it issued in the USA under patent number US10562853B2. [26] The NCEs are selective serotonin 5-HT1A receptor agonists that show functional selectivity for either extracellular signal-regulated kinases activation [27] or for beta arrestin activation. [28] It has been suggested that such compounds may have utility for treatment of distinct CNS disorders. [29] In particular, NLX-204 shows preferential activation of extracellular signal-regulated kinases [30] and exhibits rapid-acting antidepressant-like activity in rodent models. [31]
Mirtazapine, sold under the brand name Remeron amongst others, is an atypical tetracyclic antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine activity in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.
Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.
Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.
Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.
Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.
Flesinoxan (DU-29,373) is a potent and selective 5-HT1A receptor partial/near-full agonist of the phenylpiperazine class. Originally developed as a potential antihypertensive drug, flesinoxan was later found to possess antidepressant and anxiolytic effects in animal tests. As a result, it was investigated in several small human pilot studies for the treatment of major depressive disorder, and was found to have robust effectiveness and very good tolerability. However, due to "management decisions", the development of flesinoxan was stopped and it was not pursued any further.
Vilazodone, sold under the brand name Viibryd among others, is a medication used to treat major depressive disorder. It is classified as a serotonin modulator and is taken by mouth.
Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis and is also being studied for the treatment of Alzheimer’s disease psychosis, schizophrenia, agitation, and major depressive disorder. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist.
S-15535 is a phenylpiperazine drug which is a potent and highly selective 5-HT1A receptor ligand that acts as an agonist and antagonist at the presynaptic and postsynaptic 5-HT1A receptors, respectively. It has anxiolytic properties.
Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Eptapirone (F-11,440) is a very potent and highly selective 5-HT1A receptor full agonist of the azapirone family. Its affinity for the 5-HT1A receptor was reported to be 4.8 nM (Ki), and its intrinsic activity approximately equal to that of serotonin.
Pardoprunox (INN) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued. It was also being investigated for the treatment of depression and anxiety but these indications appear to have been abandoned as well.
Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.
F-15,599, also known as NLX-101, is a potent and selective 5-HT1A receptor full agonist. It displays functional selectivity by strongly activating 5-HT1A receptors in the postsynaptic prefrontal cortex while having little effect on somatodendritic autoreceptors in the raphe nucleus. As a result, it has been touted as a preferential postsynaptic 5-HT1A receptor agonist and has been investigated as a novel potential antidepressant.
Sarizotan (EMD-128,130) is a selective 5-HT1A receptor agonist and D2 receptor antagonist, which has antipsychotic effects, and has also shown efficacy in reducing dyskinesias resulting from long-term anti-Parkinsonian treatment with levodopa.
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