Neurolixis, Inc. Lead PI: Adrian Newman-Tancredi

Organization and Team Overview Neurolixis Inc. is a private biopharmaceutical company co-founded by Drs. Mark Varney & Adrian Newman- Tancredi and focused on the discovery and development of medicines to treat disorders of the brain.

Mark Varney, PhD. Chief Executive Officer, has over 20 years of pharma/biotech industry experience in CNS drug discovery, clinical development & commercialization. He has established expertise in research strategy, project leadership, portfolio management, business development (in- and out-licensing), patent strategy and raising equity from public and private investors. Previously Dr. Varney was CEO of Cortex, VP Drug Discovery at Sepracor and Bionomics, and Director at Merck and SIBIA Neurosciences. Dr. Varney received his Ph.D. and post-doctoral training at Oxford University, U.K. and has published over 50 manuscripts in peer-reviewed journals and is an inventor on more that 20 patents.

Dr. Newman-Tancredi, PhD, DSc Chief Scientific Officer, has over 20 years' experience of neuroscience research and drug discovery. Prior to joining Neurolixis, he was Director of Neurobiology and Project Manager at Pierre Fabre Laboratories and Servier, where he led multi-disciplinary programs that identified and characterized novel antipsychotics, antidepressants and analgesics. He has published over 140 articles in peer-reviewed journals, serves on the Editorial Board of the International Journal of Neuropsychopharmacology and as European Councilor of the International Society for Serotonin Research. He received his BSc, PhD and DSc from the University of Kent at Canterbury, U.K.

Opportunity Overview Neurolixis is developing NLX-112 (befiradol, Phase II), a highly selective serotonergic 5-HT1A receptor agonist, for the treatment of L-DOPA-induced dyskinesia (LID). LID represents a major source of disability, and there is no approved pharmacotherapy for its treatment.

NLX-112 has a unique pharmacologic profile: it is a fully efficacious and a highly selective agonist at 5-HT1A receptors and, unlike older generation 5-HT1A ‘partial agonists’ such as buspirone, tandospirone or sarizotan, NLX-112 fully activates 5-HT1A receptors and does not cross-react with other receptors that might interfere with its beneficial actions.

NLX-112 has previously been developed through to mid-Phase II clinical trials for diabetic neuropathy, and over 500 subjects have received NLX-112 at doses similar (or higher) to those expected to be effective in Parkinson’s disease (PD). Full GLP safety pharmacology and toxicology packages in three species supports exposure in humans of up to 13 weeks.

In previous studies in humans, NLX-112 was shown to be safe and generally well tolerated in healthy

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volunteers following acute and repeated dosing. Phase II clinical studies in patients with chronic pain demonstrated that NLX-112 was safe and well tolerated over 12 weeks.

In work funded by MJFF, Neurolixis has shown that NLX-112 fully inhibits LID in rodent models of PD (see below). The magnitude of these effects is more robust than that of other compounds tested to date. Furthermore, NLX-112 does not impair the beneficial effects of L-DOPA on the parkinsonian behaviors in rodents.

Details of MJFF Grants Neurolixis has been awarded four grants by the MJFF between 2011 and 2014. These grants have financed the investigation of NLX-112’s activity (in comparison with reference 5-HT1A receptor agonists) in rat models of PD and LID, as well as studies to better understand the underlying biology. The most recent grant supports pharmacokinetic and pharmacodynamic studies to enable modeling of the active doses of NLX-112 in preparation for clinical trials in PD patients.

Results and Potential Next Steps The novel pharmacology of NLX-112 is reflected in its superior activity in rodent models of PD, in which it potently and completely abolishes LID, whereas previously-tested serotonergic agonists only achieve a partial reduction. The anti-dyskinetic effect of NLX-112 is maintained in rats with repeated (daily) administration for two weeks. Notably, NLX-112 does not affect activity in the cylinder test, a model sensitive to agents that impair the antiparkinsonian effects of L-DOPA. The behavioral effects of NLX-112 were accompanied by neurochemical changes in brain: NLX-112 silences serotonergic neurons responsible for “false neurotransmitter” dopamine release and blunts the rapid L-DOPA-induced increases in dopamine levels that are thought to underlie induction of LID. Furthermore, NLX-112 also reduces behavioral signs of anxiety and depression in rodent models, indicating that it might have beneficial effects on mood in PD patients. Depression and anxiety can affect up to half of PD patients.

Taken together, these results suggest that NLX-112 is a promising candidate to treat LID in PD patients. The next step is to evaluate NLX-112 in PD patients with moderate to severe LID in a Phase 2 clinical study.

Intellectual Property Status Two issued US patents (with foreign equivalents) protect NLX-112: US 6,020,345 (expires in 2017) and US 7,208,603 (expires in 2022). A recent patent application (filed August, 2014) would provide protection through to August 2035. These patents are licensed exclusively to Neurolixis on a worldwide basis.

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