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'''Neurolixis''' is a biopharmaceutical company focused on novel drugs for the treatment of human [[central nervous system]] diseases.
'''Neurolixis''' is a biopharmaceutical company focused on novel drugs for the treatment of human [[central nervous system]] diseases.


Neurolixis Inc. was founded in 2011 and is managed by two pharmaceutical industry professionals, Mark A. Varney, PhD (Chief Executive Officer) and Adrian Newman-Tancredi, PhD, DSc (Chief Scientific Officer). The company's therapeutic focus is on CNS disorders including Parkinson's disease, neurological orphan disorders, depression and cognitive deficits of schizophrenia.<ref>{{cite web |url=http://neurolixis.com/home.html |title=neurolixis.com |publisher=neurolixis.com |date= |accessdate=2014-05-17 |deadurl=yes |archiveurl=https://web.archive.org/web/20140517172109/http://neurolixis.com/home.html |archivedate=2014-05-17 |df= }}</ref> The company has offices in Southern California and in France.<ref>[http://www.castres-mazamet.com/html/poles-sud/50/#7/z ]{{dead link|date=June 2019}}</ref>
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.<ref>{{cite web |url=http://neurolixis.com/home.html |title=neurolixis.com |publisher=neurolixis.com |accessdate=2014-05-17 |url-status=dead |archiveurl=https://web.archive.org/web/20140517172109/http://neurolixis.com/home.html |archivedate=2014-05-17 }}</ref> The company has offices in USA and in France.<ref>{{Cite web |url=http://www.castres-mazamet.com/html/poles-sud/50/#7/z |title=Pôles Sud n°50 - le magazine de l'agglomération de Castres-Mazamet |access-date=2015-06-25 |archive-url=https://web.archive.org/web/20150626143506/http://www.castres-mazamet.com/html/poles-sud/50/#7/z |archive-date=2015-06-26 |url-status=dead }}</ref>


In September 2013, Neurolixis announced that it had in-licensed two clinical-phase drugs from [[Pierre Fabre Group|Pierre Fabre Laboratories]], a French pharmaceutical company. The drugs ([[befiradol]] and [[F-15599]]) are targeted to the treatment of dyskinesia in [[Parkinson's disease]] and to breathing deficits in [[Rett syndrome]], respectively.<ref>{{cite web|url=http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf |title=NEUROLIXIS ANNOUNCES IN-­‐LICENSING OF TWO CLINICAL COMPOUNDS FROM PIERRE FABRE MEDICAMENT |date=September 23, 2013 |website=neurolixis.com |access-date=2019-06-05}}</ref>
In September 2013, Neurolixis in-licensed two clinical-phase drugs, [[befiradol]] and [[F-15599]] from [[Pierre Fabre Group|Pierre Fabre Laboratories]], a French pharmaceutical company.<ref>{{cite web|url=http://neurolixis.com/images/stories/nlx_pf_license_23sept13.pdf |title=NEUROLIXIS ANNOUNCES IN-LICENSING OF TWO CLINICAL COMPOUNDS FROM PIERRE FABRE MEDICAMENT |date=September 23, 2013 |website=neurolixis.com |access-date=2019-06-05}}</ref> [[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).


== Development of [[befiradol]] (NLX-112) for movement disorders ==
⚫
Neurolixis has been awarded a series of research grants by the [[Michael J. Fox Foundation]] to undertake research examining the effects of novel, highly selective and efficacious serotonergic drugs targeting [[5-HT1A receptor]]s in brain regions relevant to therapeutic properties in Parkinson's disease.<ref>{{cite web|url=https://www.michaeljfox.org/foundation/funded-grants.php?institution=Neurolixis,%20Inc |title=Parkinson's Disease Grants funded by the Michael J. Fox Foundation &#124; The Michael J. Fox Foundation |publisher=Michaeljfox.org |date=2012-10-26 |accessdate=2014-05-17}}</ref> 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<ref>{{cite web|url=https://www.michaeljfox.org/grant/predicting-efficacious-dose-selective-5-ht1a-agonist-nlx-112|title=Predicting the Efficacious Dose of the Selective 5-HT1A Agonist NLX-112|website=The Michael J. Fox Foundation for Parkinson's Research - Parkinson's Disease}}</ref> and showcased Neurolixis in its Partnering Program.<ref>[https://www.michaeljfox.org/research/opportunities-for-industry/partnering-program.html ]{{dead link|date=June 2019}}</ref> 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.<ref>{{cite web|url=https://www.parkinsons.org.uk/news/investing-new-treatment-dyskinesia|title=Investing in a new treatment for dyskinesia - Parkinson's UK|website=www.parkinsons.org.uk}}</ref> 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]].<ref>{{cite web|url=https://www.prlog.org/12758787-fda-approves-neurolixis-ind-application-for-clinical-trial-with-nlx-112-in-parkinsons-disease.html|title=FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease|first=Neurolixis|last=Inc|website=PRLog}}</ref>


⚫
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 receptor]]s in brain regions relevant to therapeutic properties in Parkinson's disease.<ref>{{cite web|url=https://www.michaeljfox.org/foundation/funded-grants.php?institution=Neurolixis,%20Inc |title=Parkinson's Disease Grants funded by the Michael J. Fox Foundation &#124; The Michael J. Fox Foundation |publisher=Michaeljfox.org |date=2012-10-26 |accessdate=2014-05-17}}</ref> 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<ref>{{cite web|url=https://www.michaeljfox.org/grant/predicting-efficacious-dose-selective-5-ht1a-agonist-nlx-112|title=Predicting the Efficacious Dose of the Selective 5-HT1A Agonist NLX-112|website=The Michael J. Fox Foundation for Parkinson's Research - Parkinson's Disease}}</ref> and showcased Neurolixis in its Partnering Program.<ref>{{Cite web |url=https://www.michaeljfox.org/research/opportunities-for-industry/partnering-program.html |title=Partnering Program of the Michael J. Fox Foundation for Parkinson?s Research &#124; Parkinson's Disease Information |access-date=2015-06-25 |archive-url=https://web.archive.org/web/20150626140243/https://www.michaeljfox.org/research/opportunities-for-industry/partnering-program.html |archive-date=2015-06-26 |url-status=dead }}</ref> 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.<ref>{{cite web|url=https://www.parkinsons.org.uk/news/investing-new-treatment-dyskinesia|title=Investing in a new treatment for dyskinesia - Parkinson's UK|website=www.parkinsons.org.uk|date=24 January 2018 }}</ref> 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]].<ref>{{cite press release |url=https://www.prlog.org/12758787-fda-approves-neurolixis-ind-application-for-clinical-trial-with-nlx-112-in-parkinsons-disease.html|title=FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease |publisher=Neurolixis, Inc |work=PRLog |date=12 March 2019 }}</ref> 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&nbsp;mg/kg.<ref>{{cite journal |last1=Depoortere |first1=R. |last2=Johnston |first2=T.H. |last3=Fox |first3=S.H. |last4=Brotchie |first4=J.M. |last5=Newman-Tancredi |first5=A. |title=The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques |journal=Parkinsonism & Related Disorders |date=September 2020 |volume=78 |pages=151–157 |doi=10.1016/j.parkreldis.2020.08.009 |pmid=32846366 }}</ref><ref>{{cite journal |last1=Fisher |first1=Ria |last2=Hikima |first2=Atsuko |last3=Morris |first3=Rebecca |last4=Jackson |first4=Michael J. |last5=Rose |first5=Sarah |last6=Varney |first6=Mark A. |last7=Depoortere |first7=Ronan |last8=Newman-Tancredi |first8=Adrian |title=The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets |journal=Neuropharmacology |date=May 2020 |volume=167 |pages=107997 |doi=10.1016/j.neuropharm.2020.107997 |pmid=32057799 |pmc=7103782 }}</ref>
⚫
[[F-15599]] (also known as NLX-101) was awarded Orphan Drug Status by the United States [[Food and Drug Administration]] (FDA) in October 2013<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=410613 |title=Search Orphan Drug Designations and Approvals |publisher=Accessdata.fda.gov |date=2013-10-25 |accessdate=2014-05-17}}</ref> and Orphan Medicinal Product designation by the [[European Medicines Agency]] in March 2014.<ref>{{cite web|url=http://ec.europa.eu/health/documents/community-register/html/o1242.htm |title=Community register of orphan medicinal products |publisher=Ec.europa.eu |date= |accessdate=2014-05-17}}</ref>

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]].<ref>{{cite web|url=http://www.bristol.ac.uk/news/2014/april/rett-syndrome-research.html|title=April: Rett syndrome research - News - University of Bristol|first=University of|last=Bristol|website=www.bristol.ac.uk}}</ref> In June 2015, Neurolixis was awarded a grant by the Rett Syndrome Research Trust to advance [[F-15599]] to clinical development.<ref>{{cite web|url=https://rettsyndrome.wordpress.com/2015/06/24/rsrt-awards-530000-to-neurolixis-for-clinical-development-of-nlx-101/|title=RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101|date=24 June 2015|publisher=}}</ref>
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.<ref>{{Cite news|url=https://www.thetimes.co.uk/article/life-changing-drug-to-calm-parkinsons-twitches-set-for-human-trials-pj6xqxfg7|title = 'Life-changing' drug to calm Parkinson's twitches set for human trials}}</ref> On 23 November 2020, [[Parkinson's UK]] and [[Michael J. Fox Foundation]], confirmed their funding in an official announcement.<ref>{{Cite press release|url=https://www.prnewswire.com/news-releases/global-charities-join-forces-to-drive-forward-new-drug-for-parkinsons-301178988.html|title = Global charities join forces to drive forward new drug for Parkinson's}}</ref>
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.<ref>{{ClinicalTrialsGov|NCT05148884|Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia}}</ref> 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]].<ref>{{Cite web|url=https://www.einnews.com/pr_news/622375270/neurolixis-announces-positive-ph2a-proof-of-concept-on-nlx-112-in-levodopa-induced-dyskinesia-in-parkinson-s-disease|title = Neurolixis Announces Positive Ph2A Proof-of-Concept on NLX-112 in Levodopa-Induced Dyskinesia in Parkinson's Disease |date = 20 March 2023 | via = Newsmatics Inc }}</ref>

In other studies, [[befiradol]] showed pro-motility activity in a transgenic nematode worm model of spinocerebellar ataxia type 3<ref>{{cite journal |last1=Pereira-Sousa |first1=Joana |last2=Ferreira-Lomba |first2=Bruna |last3=Bellver-Sanchis |first3=Aina |last4=Vilasboas-Campos |first4=Daniela |last5=Fernandes |first5=Jorge H. |last6=Costa |first6=Marta D. |last7=Varney |first7=Mark A. |last8=Newman-Tancredi |first8=Adrian |last9=Maciel |first9=Patrícia |last10=Teixeira-Castro |first10=Andreia |title=Identification of the 5-HT1A serotonin receptor as a novel therapeutic target in a C. elegans model of Machado-Joseph disease |journal=Neurobiology of Disease |date=May 2021 |volume=152 |pages=105278 |doi=10.1016/j.nbd.2021.105278 |pmid=33516872 |doi-access=free }}</ref> (also known as SCA3 or [[Machado-Joseph disease]]), an orphan disorder. In July 2024, the [[European Commission]] granted Neurolixis [[Orphan Drug]] Designation for [[befiradol]] as a treatment of [[Spinocerebellar Ataxia]] based on these data and on results from a trasngenic mouse model of [[Spinocerebellar Ataxia]].<ref>{{cite web | url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-24-2951 | title=EU/3/24/2951 - orphan designation for treatment of spinocerebellar ataxia &#124; European Medicines Agency (EMA) | date=25 July 2024 }}</ref><ref>{{cite web | url=https://www.neurologylive.com/view/european-commission-grants-nlx-112-orphan-medicinal-product-designation-spinocerebellar-ataxia | title=European Commission Grants NLX-112 Orphan Medicinal Product Designation for Spinocerebellar Ataxia | date=6 October 2024 }}</ref>

[[Befiradol]] also reversed depression-like behavior and catalepsy induced by [[tetrabenazine]], a drug used for the treatment of [[Huntington's disease]].<ref>{{cite journal |last1=Jastrzębska-Więsek |first1=Magdalena |last2=Wesołowska |first2=Anna |last3=Kołaczkowski |first3=Marcin |last4=Varney |first4=Mark A. |last5=Newman-Tancredi |first5=Adrian |last6=Depoortere |first6=RonanY. |title=The selective 5-HT1A receptor agonist, NLX-112, overcomes tetrabenazine-induced catalepsy and depression-like behavior in the rat |journal=Behavioural Pharmacology |date=August 2022 |volume=33 |issue=5 |pages=333–341 |doi=10.1097/FBP.0000000000000681 |pmid=35695543 }}</ref>

== Development of [[F-15599]] for autism spectrum disorders ==

⚫
[[F-15599]] (also known as [[NLX-101]]) was awarded [[Orphan Drug]] Status by the United States [[Food and Drug Administration]] (FDA) in October 2013<ref>{{cite web|url=http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfm?Index_Number=410613 |title=Search Orphan Drug Designations and Approvals |publisher=Accessdata.fda.gov |date=2013-10-25 |accessdate=2014-05-17}}</ref> and Orphan Medicinal Product designation by the [[European Medicines Agency]] in March 2014.<ref>{{cite web|url=http://ec.europa.eu/health/documents/community-register/html/o1242.htm |title=Community register of orphan medicinal products |publisher=Ec.europa.eu |date= |accessdate=2014-05-17}}</ref>
In collaboration with researchers at the [[University of Bristol]], Neurolixis was awarded a grant by the International Rett Syndrome Foundation to study [[F-15599]] in animal models of [[Rett syndrome]].<ref>{{cite web|url=http://www.bristol.ac.uk/news/2014/april/rett-syndrome-research.html|title=April: Rett syndrome research - News - University of Bristol|first=University of|last=Bristol|website=www.bristol.ac.uk}}</ref> In June 2015, Neurolixis was awarded a grant by the Rett Syndrome Research Trust to advance [[F-15599]] to clinical development.<ref>{{cite web|url=https://rettsyndrome.wordpress.com/2015/06/24/rsrt-awards-530000-to-neurolixis-for-clinical-development-of-nlx-101/|title=RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101|date=24 June 2015|publisher=}}</ref> 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]]<ref>{{cite journal |last1=Vidal |first1=Benjamin |last2=Fieux |first2=Sylvain |last3=Redouté |first3=Jérôme |last4=Villien |first4=Marjorie |last5=Bonnefoi |first5=Frédéric |last6=Le Bars |first6=Didier |last7=Newman-Tancredi |first7=Adrian |last8=Costes |first8=Nicolas |last9=Zimmer |first9=Luc |title=In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging |journal=Neuropsychopharmacology |date=October 2018 |volume=43 |issue=11 |pages=2310–2319 |doi=10.1038/s41386-018-0145-2 |pmid=30030540 |pmc=6135772 }}</ref> and [[positron emission tomography]].<ref>{{cite journal |last1=Levigoureux |first1=Elise |last2=Vidal |first2=Benjamin |last3=Fieux |first3=Sylvain |last4=Bouillot |first4=Caroline |last5=Emery |first5=Stéphane |last6=Newman-Tancredi |first6=Adrian |last7=Zimmer |first7=Luc |title=Serotonin 5-HT 1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [ 18 F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats |journal=ACS Chemical Neuroscience |date=17 July 2019 |volume=10 |issue=7 |pages=3108–3119 |doi=10.1021/acschemneuro.8b00584 |pmid=30576601 }}</ref> 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.<ref>{{cite journal |last1=Depoortère |first1=Ronan |last2=Papp |first2=Mariusz |last3=Gruca |first3=Piotr |last4=Lason-Tyburkiewicz |first4=Magdalena |last5=Niemczyk |first5=Monika |last6=Varney |first6=Mark A |last7=Newman-Tancredi |first7=Adrian |title=Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model |journal=Journal of Psychopharmacology |date=November 2019 |volume=33 |issue=11 |pages=1456–1466 |doi=10.1177/0269881119860666 |pmid=31290370 }}</ref> 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. These observations constituted the basis for a patent (US11974992B2] that was granted to Neurolixis by the [[United States Patent and Trademark Office]].<ref>https://patentimages.storage.googleapis.com/7d/3b/0e/f76b99fa1036bf/US11974992.pdf{{full|date=November 2024}}</ref><ref>{{Cite journal |last1=Tao |first1=X. |last2=Newman-Tancredi |first2=A. |last3=Varney |first3=M. A. |last4=Razak |first4=K. A. |date=2023-01-15 |title=Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice |journal=Neuroscience |volume=509 |pages=113–124 |doi=10.1016/j.neuroscience.2022.11.014 |pmid=36410632 |doi-access=free }}</ref> The potential therapeutic utility of [[F-15599]] for treatment of [[Central nervous system]] disorders involving serotonin systems was recently supported by a study at the Brain and Mind Research Institute at the [[University of Ottawa]] showing that the compound exerts rapid reorganization of serotonin projections in a transgenic mouse model.<ref>{{cite journal |last1=Vahid-Ansari |first1=Faranak |last2=Newman-Tancredi |first2=Adrian |last3=Fuentes-Alvarenga |first3=Alberto Francisco |last4=Daigle |first4=Mireille |last5=Albert |first5=Paul R. |title=Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice |journal=Neuropharmacology |date=December 2024 |volume=261 |pages=110132 |doi=10.1016/j.neuropharm.2024.110132 |doi-access=free |pmid=39208980 }}</ref>

== Preclinical drug discovery ==

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,<ref>{{cite web | url=https://patents.google.com/patent/WO2017220799A1/en?oq=WO2017220799A1 | title=Compounds for treating disorders sensitive to serotoninergic regulation controlled by the 5-ht1a receptors | date=23 June 2017 }}</ref> and it issued in the USA under patent number US10562853B2.<ref>{{cite web | url=https://patents.google.com/patent/US10562853B2/en?oq=US10562853B2+ | title=Compounds for treating disorders sensitive to serotoninergic regulation controlled by the 5-HT1A receptors }}</ref> The NCEs are selective serotonin [[5-HT1A receptor]] agonists that show [[functional selectivity]] for either [[extracellular signal-regulated kinases]] activation<ref name="Sniecikowska et al Novel Aryloxyethyl Derivatives">{{cite journal |last1=Sniecikowska |first1=Joanna |last2=Gluch-Lutwin |first2=Monika |last3=Bucki |first3=Adam |last4=Więckowska |first4=Anna |last5=Siwek |first5=Agata |last6=Jastrzebska-Wiesek |first6=Magdalena |last7=Partyka |first7=Anna |last8=Wilczyńska |first8=Daria |last9=Pytka |first9=Karolina |last10=Pociecha |first10=Krzysztof |last11=Cios |first11=Agnieszka |last12=Wyska |first12=Elżbieta |last13=Wesołowska |first13=Anna |last14=Pawłowski |first14=Maciej |last15=Varney |first15=Mark A. |last16=Newman-Tancredi |first16=Adrian |last17=Kolaczkowski |first17=Marcin |title=Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT<sub>1A</sub> Receptor-Biased Agonists with Robust Antidepressant-like Activity |journal=Journal of Medicinal Chemistry |date=14 March 2019 |volume=62 |issue=5 |pages=2750–2771 |doi=10.1021/acs.jmedchem.9b00062 |pmid=30721053 |doi-access=free }}</ref> or for [[beta arrestin]] activation.<ref>{{cite journal |last1=Sniecikowska |first1=Joanna |last2=Gluch-Lutwin |first2=Monika |last3=Bucki |first3=Adam |last4=Więckowska |first4=Anna |last5=Siwek |first5=Agata |last6=Jastrzebska-Wiesek |first6=Magdalena |last7=Partyka |first7=Anna |last8=Wilczyńska |first8=Daria |last9=Pytka |first9=Karolina |last10=Latacz |first10=Gniewomir |last11=Przejczowska-Pomierny |first11=Katarzyna |last12=Wyska |first12=Elżbieta |last13=Wesołowska |first13=Anna |last14=Pawłowski |first14=Maciej |last15=Newman-Tancredi |first15=Adrian |last16=Kolaczkowski |first16=Marcin |title=Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT 1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile |journal=Journal of Medicinal Chemistry |date=8 October 2020 |volume=63 |issue=19 |pages=10946–10971 |doi=10.1021/acs.jmedchem.0c00814 |pmid=32883072 |pmc=7586344 }}</ref> It has been suggested that such compounds may have utility for treatment of distinct CNS disorders.<ref>{{cite journal |last1=Sniecikowska |first1=Joanna |last2=Newman-Tancredi |first2=Adrian |last3=Kolaczkowski |first3=Marcin |title=From Receptor Selectivity to Functional Selectivity: The Rise of Biased Agonism in 5-HT1A Receptor Drug Discovery |journal=Current Topics in Medicinal Chemistry |date=10 December 2019 |volume=19 |issue=26 |pages=2393–2420 |doi=10.2174/1568026619666190911122040 |pmid=31544717 }}</ref> In particular, [[NLX-204]] shows preferential activation of [[extracellular signal-regulated kinases]]<ref name="Sniecikowska et al Novel Aryloxyethyl Derivatives"/> and exhibits rapid-acting antidepressant-like activity in rodent models.<ref>{{cite journal |last1=Głuch-Lutwin |first1=Monika |last2=Sałaciak |first2=Kinga |last3=Pytka |first3=Karolina |last4=Gawalska |first4=Alicja |last5=Jamrozik |first5=Marek |last6=Śniecikowska |first6=Joanna |last7=Kołaczkowski |first7=Marcin |last8=Depoortère |first8=Ronan Y. |last9=Newman-Tancredi |first9=Adrian |title=The 5-HT1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression |journal=Behavioural Brain Research |date=February 2023 |volume=438 |pages=114207 |doi=10.1016/j.bbr.2022.114207 |pmid=36368443 }}</ref>

== External links ==

* [https://www.neurolixis.com/en/ Neurolixis website]


== References ==
== References ==

Latest revision as of 06:14, 4 December 2024

Neurolixis
IndustryBiopharmaceuticals
Founded2011
Headquarters
United States Edit this on Wikidata
Key people
Mark A. Varney, Adrian Newman-Tancredi
Websitehttps://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).

Development of befiradol (NLX-112) for movement disorders

[edit]

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. In July 2024, the European Commission granted Neurolixis Orphan Drug Designation for befiradol as a treatment of Spinocerebellar Ataxia based on these data and on results from a trasngenic mouse model of Spinocerebellar Ataxia.[16][17]

Befiradol also reversed depression-like behavior and catalepsy induced by tetrabenazine, a drug used for the treatment of Huntington's disease.[18]

Development of F-15599 for autism spectrum disorders

[edit]

F-15599 (also known as NLX-101) was awarded Orphan Drug Status by the United States Food and Drug Administration (FDA) in October 2013[19] and Orphan Medicinal Product designation by the European Medicines Agency in March 2014.[20] In collaboration with researchers at the University of Bristol, Neurolixis was awarded a grant by the International Rett Syndrome Foundation to study F-15599 in animal models of Rett syndrome.[21] In June 2015, Neurolixis was awarded a grant by the Rett Syndrome Research Trust to advance F-15599 to clinical development.[22] 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[23] and positron emission tomography.[24] 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.[25] 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. These observations constituted the basis for a patent (US11974992B2] that was granted to Neurolixis by the United States Patent and Trademark Office.[26][27] The potential therapeutic utility of F-15599 for treatment of Central nervous system disorders involving serotonin systems was recently supported by a study at the Brain and Mind Research Institute at the University of Ottawa showing that the compound exerts rapid reorganization of serotonin projections in a transgenic mouse model.[28]

Preclinical drug discovery

[edit]

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,[29] and it issued in the USA under patent number US10562853B2.[30] The NCEs are selective serotonin 5-HT1A receptor agonists that show functional selectivity for either extracellular signal-regulated kinases activation[31] or for beta arrestin activation.[32] It has been suggested that such compounds may have utility for treatment of distinct CNS disorders.[33] In particular, NLX-204 shows preferential activation of extracellular signal-regulated kinases[31] and exhibits rapid-acting antidepressant-like activity in rodent models.[34]

[edit]

References

[edit]
  1. ^ "neurolixis.com". neurolixis.com. Archived from the original on 2014-05-17. Retrieved 2014-05-17.
  2. ^ "Pôles Sud n°50 - le magazine de l'agglomération de Castres-Mazamet". Archived from the original on 2015-06-26. Retrieved 2015-06-25.
  3. ^ "NEUROLIXIS ANNOUNCES IN-LICENSING OF TWO CLINICAL COMPOUNDS FROM PIERRE FABRE MEDICAMENT" (PDF). neurolixis.com. September 23, 2013. Retrieved 2019-06-05.
  4. ^ "Parkinson's Disease Grants funded by the Michael J. Fox Foundation | The Michael J. Fox Foundation". Michaeljfox.org. 2012-10-26. Retrieved 2014-05-17.
  5. ^ "Predicting the Efficacious Dose of the Selective 5-HT1A Agonist NLX-112". The Michael J. Fox Foundation for Parkinson's Research - Parkinson's Disease.
  6. ^ "Partnering Program of the Michael J. Fox Foundation for Parkinson?s Research | Parkinson's Disease Information". Archived from the original on 2015-06-26. Retrieved 2015-06-25.
  7. ^ "Investing in a new treatment for dyskinesia - Parkinson's UK". www.parkinsons.org.uk. 24 January 2018.
  8. ^ "FDA Approves Neurolixis IND Application for a Clinical Trial with NLX-112 in Parkinson's Disease". PRLog (Press release). Neurolixis, Inc. 12 March 2019.
  9. ^ Depoortere, R.; Johnston, T.H.; Fox, S.H.; Brotchie, J.M.; Newman-Tancredi, A. (September 2020). "The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques". Parkinsonism & Related Disorders. 78: 151–157. doi:10.1016/j.parkreldis.2020.08.009. PMID 32846366.
  10. ^ Fisher, Ria; Hikima, Atsuko; Morris, Rebecca; Jackson, Michael J.; Rose, Sarah; Varney, Mark A.; Depoortere, Ronan; Newman-Tancredi, Adrian (May 2020). "The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic and anti-parkinsonian-like effects in MPTP-treated marmosets". Neuropharmacology. 167: 107997. doi:10.1016/j.neuropharm.2020.107997. PMC 7103782. PMID 32057799.
  11. ^ "'Life-changing' drug to calm Parkinson's twitches set for human trials".
  12. ^ "Global charities join forces to drive forward new drug for Parkinson's" (Press release).
  13. ^ Clinical trial number NCT05148884 for "Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia" at ClinicalTrials.gov
  14. ^ "Neurolixis Announces Positive Ph2A Proof-of-Concept on NLX-112 in Levodopa-Induced Dyskinesia in Parkinson's Disease". 20 March 2023 – via Newsmatics Inc.
  15. ^ Pereira-Sousa, Joana; Ferreira-Lomba, Bruna; Bellver-Sanchis, Aina; Vilasboas-Campos, Daniela; Fernandes, Jorge H.; Costa, Marta D.; Varney, Mark A.; Newman-Tancredi, Adrian; Maciel, Patrícia; Teixeira-Castro, Andreia (May 2021). "Identification of the 5-HT1A serotonin receptor as a novel therapeutic target in a C. elegans model of Machado-Joseph disease". Neurobiology of Disease. 152: 105278. doi:10.1016/j.nbd.2021.105278. PMID 33516872.
  16. ^ "EU/3/24/2951 - orphan designation for treatment of spinocerebellar ataxia | European Medicines Agency (EMA)". 25 July 2024.
  17. ^ "European Commission Grants NLX-112 Orphan Medicinal Product Designation for Spinocerebellar Ataxia". 6 October 2024.
  18. ^ Jastrzębska-Więsek, Magdalena; Wesołowska, Anna; Kołaczkowski, Marcin; Varney, Mark A.; Newman-Tancredi, Adrian; Depoortere, RonanY. (August 2022). "The selective 5-HT1A receptor agonist, NLX-112, overcomes tetrabenazine-induced catalepsy and depression-like behavior in the rat". Behavioural Pharmacology. 33 (5): 333–341. doi:10.1097/FBP.0000000000000681. PMID 35695543.
  19. ^ "Search Orphan Drug Designations and Approvals". Accessdata.fda.gov. 2013-10-25. Retrieved 2014-05-17.
  20. ^ "Community register of orphan medicinal products". Ec.europa.eu. Retrieved 2014-05-17.
  21. ^ Bristol, University of. "April: Rett syndrome research - News - University of Bristol". www.bristol.ac.uk.
  22. ^ "RSRT Awards $530,000 to Neurolixis for Clinical Development of NLX-101". 24 June 2015.
  23. ^ Vidal, Benjamin; Fieux, Sylvain; Redouté, Jérôme; Villien, Marjorie; Bonnefoi, Frédéric; Le Bars, Didier; Newman-Tancredi, Adrian; Costes, Nicolas; Zimmer, Luc (October 2018). "In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging". Neuropsychopharmacology. 43 (11): 2310–2319. doi:10.1038/s41386-018-0145-2. PMC 6135772. PMID 30030540.
  24. ^ Levigoureux, Elise; Vidal, Benjamin; Fieux, Sylvain; Bouillot, Caroline; Emery, Stéphane; Newman-Tancredi, Adrian; Zimmer, Luc (17 July 2019). "Serotonin 5-HT 1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [ 18 F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats". ACS Chemical Neuroscience. 10 (7): 3108–3119. doi:10.1021/acschemneuro.8b00584. PMID 30576601.
  25. ^ Depoortère, Ronan; Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Niemczyk, Monika; Varney, Mark A; Newman-Tancredi, Adrian (November 2019). "Cortical 5-hydroxytryptamine 1A receptor biased agonist, NLX-101, displays rapid-acting antidepressant-like properties in the rat chronic mild stress model". Journal of Psychopharmacology. 33 (11): 1456–1466. doi:10.1177/0269881119860666. PMID 31290370.
  26. ^ https://patentimages.storage.googleapis.com/7d/3b/0e/f76b99fa1036bf/US11974992.pdf[full citation needed]
  27. ^ Tao, X.; Newman-Tancredi, A.; Varney, M. A.; Razak, K. A. (2023-01-15). "Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice". Neuroscience. 509: 113–124. doi:10.1016/j.neuroscience.2022.11.014. PMID 36410632.
  28. ^ Vahid-Ansari, Faranak; Newman-Tancredi, Adrian; Fuentes-Alvarenga, Alberto Francisco; Daigle, Mireille; Albert, Paul R. (December 2024). "Rapid reorganization of serotonin projections and antidepressant response to 5-HT1A-biased agonist NLX-101 in fluoxetine-resistant cF1ko mice". Neuropharmacology. 261: 110132. doi:10.1016/j.neuropharm.2024.110132. PMID 39208980.
  29. ^ "Compounds for treating disorders sensitive to serotoninergic regulation controlled by the 5-ht1a receptors". 23 June 2017.
  30. ^ "Compounds for treating disorders sensitive to serotoninergic regulation controlled by the 5-HT1A receptors".
  31. ^ a b Sniecikowska, Joanna; Gluch-Lutwin, Monika; Bucki, Adam; Więckowska, Anna; Siwek, Agata; Jastrzebska-Wiesek, Magdalena; Partyka, Anna; Wilczyńska, Daria; Pytka, Karolina; Pociecha, Krzysztof; Cios, Agnieszka; Wyska, Elżbieta; Wesołowska, Anna; Pawłowski, Maciej; Varney, Mark A.; Newman-Tancredi, Adrian; Kolaczkowski, Marcin (14 March 2019). "Novel Aryloxyethyl Derivatives of 1-(1-Benzoylpiperidin-4-yl)methanamine as the Extracellular Regulated Kinases 1/2 (ERK1/2) Phosphorylation-Preferring Serotonin 5-HT1A Receptor-Biased Agonists with Robust Antidepressant-like Activity". Journal of Medicinal Chemistry. 62 (5): 2750–2771. doi:10.1021/acs.jmedchem.9b00062. PMID 30721053.
  32. ^ Sniecikowska, Joanna; Gluch-Lutwin, Monika; Bucki, Adam; Więckowska, Anna; Siwek, Agata; Jastrzebska-Wiesek, Magdalena; Partyka, Anna; Wilczyńska, Daria; Pytka, Karolina; Latacz, Gniewomir; Przejczowska-Pomierny, Katarzyna; Wyska, Elżbieta; Wesołowska, Anna; Pawłowski, Maciej; Newman-Tancredi, Adrian; Kolaczkowski, Marcin (8 October 2020). "Discovery of Novel pERK1/2- or β-Arrestin-Preferring 5-HT 1A Receptor-Biased Agonists: Diversified Therapeutic-like versus Side Effect Profile". Journal of Medicinal Chemistry. 63 (19): 10946–10971. doi:10.1021/acs.jmedchem.0c00814. PMC 7586344. PMID 32883072.
  33. ^ Sniecikowska, Joanna; Newman-Tancredi, Adrian; Kolaczkowski, Marcin (10 December 2019). "From Receptor Selectivity to Functional Selectivity: The Rise of Biased Agonism in 5-HT1A Receptor Drug Discovery". Current Topics in Medicinal Chemistry. 19 (26): 2393–2420. doi:10.2174/1568026619666190911122040. PMID 31544717.
  34. ^ Głuch-Lutwin, Monika; Sałaciak, Kinga; Pytka, Karolina; Gawalska, Alicja; Jamrozik, Marek; Śniecikowska, Joanna; Kołaczkowski, Marcin; Depoortère, Ronan Y.; Newman-Tancredi, Adrian (February 2023). "The 5-HT1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression". Behavioural Brain Research. 438: 114207. doi:10.1016/j.bbr.2022.114207. PMID 36368443.
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