NT502 (N-desethyloxybutynin)

About N-desethyloxybutynin

N-desethyloxybutynin is a novel active metabolite of oxybutynin chloride, an FDA-approved anticholinergic indicated for the treatment of overactive bladder. NT502 is a new chemical entity and selective anticholinergic agent that we are developing as an oral, once- or twice-daily treatment to reduce chronic sialorrhea in patients with neurological conditions associated with excessive salivation and drooling. Based on preclinical data, NT502 has been shown to be preferential for blocking muscarinic receptors in the salivary glands and may offer the potential for an improved tolerability profile and an easier-to-dose oral formulation compared to currently approved chronic sialorrhea treatment options. The NT502 Phase 1 trial was a single-dose open-label, randomized, parallel study assessing the systemic exposure and safety of four ion-resin, modified-release ODT formulations of NT502 and oxybutynin in 30 healthy patients. The top-line results from this study confirmed a N-desethyloxybutynin formulation for further clinical development.

About Chronic Sialorrhea

Patients with neurological disease experience sialorrhea due to decreased intra-oral salivary clearance associated with neuromuscular dysfunction. Anatomic abnormalities and side effects from certain medications including anticonvulsants and antipsychotics can also cause chronic, excessive drooling. Chronic sialorrhea can lead to significant physical and psychosocial complications, including perioral chapping, dehydration, infection, foul odor, stigmatization, and increased dependency and level of care, all of which can create an additional burden for these medically complicated patients. Current anticholinergic agents are associated with treatment-limiting adverse events and require titration and dosing up to three times per day, presenting complexity and inconvenience to patients and caregivers. As such a significant unmet medical need remains for chronic sialorrhea patients.

References

1. Hockstein NG et. al. Sialorrhea: a management challenge. Am Fam Physician 2004; 69:2628-34. 2. Banfi P et al. A review of options for treating sialorrhea in amyotrophic lateral sclerosis. Respir Care 2015;60(3):446-454. 3. Boyce HW and Bakheet MR. Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease. J Clin Gastroenterol 2015; 39(2): 89-97. 4. Glader L, et al. Sialorrhea: Bottom line ‘evidence-informed’ recommendations for children/youth with Cerebral palsy who have sialorrhea. AACPDM Care Pathways 2016 5. Maher S et al. Clozapine-induced hypersalivation: an estimate of prevalence, severity and impact on quality of life. Ther Adv Psychopharmacol 2016; 6(3):178-184. 6. Stroup TS and Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry 2018;17:341-356. 7. Lakraj AA et al. Sialorrhea: Anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins 2013;5:1010-1031. 8. Kalf JG et al. Prevalence and definition of drooling in Parkinson’s disease: a systemic review. J Neurol 2009; 256:1391-1396. 9. Marras C et al. npj Parkinson’s Disease volume 4, Article number: 21 (2018). 10. Reid SM et al. Prevalence and predictors of drooling in 7- to 14-year-old children with cerebral palsy: a population study. Dev Med Child Neurol 2012;54(11):1032-6. 11. Maenner MJ et al. Prevalence of cerebral palsy and intellectual disability among children identified in two US national surveys, 2011-2013. Ann Epidemiol 2016;26(3):222-226. 12. Alhashemi HH. Dysphagia in severe traumatic brain injury. Neurosciences 2010;15(4):231-236. 13. Cohen DL et al. Post-stroke dysphagia: a review and design of consideration for future trials. Int J Stroke 2016;11(4)399-411. 14. Mozaffarian D et al. Heart disease and stroke statistics – 2016 update. Circulation. 2015;133:e38-e360. 15. Taylor CA et al. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths – US, 2007 and 2013. MMWR. March 17, 2017. Vol. 66, No. 9 16. McGrath J et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epi Rev 2008;30:67-76.