PRX-3140 Oral Capsule - Phase 2a clinical program

PRX-3140 (CAS: 869493-26-5)

5-HT4 Selective Agonist and Sigma-1 agonist/antagonist

Oral Swallowed Capsule - Phase 1 & 2 clinical studies

The figure on the right shows the docked pose of PRX-3140

in the binding pocket of the Sigma-1 receptor (PDB ID: 6DK1)

PRX-3140 is an orally-bioavailable selective partial agonist to the 5-Hydroxytryptamine receptor 4 (5-HT4) and a ligand for the Sigma-1 and Sigma-2 receptors. PRX-3140 is a highly selective and potent (Ki = 22-37 nM) 5-HT4R agonist in radioligand binding assays with more than 100-fold difference in affinities compared with all other 5-HT receptors tested. PRX-3140 behaves as a partial agonist in cell lines expressing either the human 5-HT4aR, 5-HT4bR or 5-HT4eR isoforms, stimulating cAMP production to 30%-60% compared to 5-HT. PRX-3140 also demonstrates binding to both the Sigma-1 and Sigma-2 receptors (Ki = 79-100 nM and 99-160 nM, respectively) in radioligand binding assays, but demonstrates no significant affinity for more than 50 other receptors tested including GPCRs, ion channels and receptor tyrosine kinases. PRX-3140 demonstrates high CNS penetration without inducing significant distal gastrointestinal motility observed with gastrointestinally active 5-HT4 agonists (e.g. cisapride, tegaserod).

PRX-3140 stimulates cognition and memory by selectively activating the 5-HT4 G-protein coupled receptor (GPCR) in the brain to produce and release acetylcholine, a neurotransmitter that plays a role in learning and memory. As Alzheimer's disease progresses, acetylcholine production declines, and brain levels of this critical neurotransmitter decline, as well. PRX-3140 has the potential to slow the progression of the disease with fewer and less severe side effects than current Alzheimer’s drugs. Recently, PRX-3140 was also shown to be a ligand for the sigma-1 and sigma-2 receptor.

A randomized, double-blind, placebo-controlled Phase 2a clinical trial was completed to assess the effects of PRX-3140 following two weeks of treatment as monotherapy and, separately, in combination with donepezil (Aricept®) in patients with mild Alzheimer's disease. PRX-3140 appeared to be well tolerated alone and in combination with Aricept® with no serious drug-related adverse events. The FDA approved a Physician-Sponsored IND and continuation of the fourth, six-month open label extension of PRX-3140.

An oral capsule formulation of PRX-3140 has completed five Phase 1 and 2 clinical studies and is in Phase 2 clinical development.

Clinical Trials (Completed)

  • NCT00693004 Study of PRX-03140 Monotherapy in Subjects With Alzheimer's Disease

  • NCT00672945 A Study of PRX-03140 in Subjects With Alzheimer's Disease Receiving a Stable Dose of Donepezil

  • NCT00384423 Short Term Effects of PRX-03140 in Patients With Mild Alzheimer's Disease Being Treated With Aricept

  • NCT01492699 Pilot Study of PRX-03140 to Assess Safety for Use in Adult Subjects With Post Traumatic Stress Disorder

Intellectual Property

Nanopharmaceutics holds world-wide exclusive rights to U.S. patents 7,488,736, 7,407,966, 7,576,211, 7,598,265, 7,982,040, 8,114,894, 11,725,016, 11,993,609 and related foreign filings. A new composition-of-matter patent related to sustained-release formulations has been filed.

References

The 5-hydroxytryptamine4 receptor agonists prucalopride and PRX-03140 increase acetylcholine and histamine levels in the rat prefrontal cortex and the power of stimulated hippocampal θ oscillations. Johnson DE, Drummond E, Grimwood S, Sawant-Basak A, Miller E, Tseng E, McDowell LL, Vanase-Frawley MA, Fisher KE, Rubitski DM, Stutzman-Engwall KJ, Nelson RT, Horner WE, Gorczyca RR, Hajos M, Siok CJ. J Pharmacol Exp Ther. 2012 Jun;341(3):681-91. doi: 10.1124/jpet.112.192351. Epub 2012 Mar 9. PMID: 22408061

5-HT(4) receptor agonist mediated enhancement of cognitive function in vivo and amyloid precursor protein processing in vitro: A pharmacodynamic and pharmacokinetic assessment. Shen F, Smith JA, Chang R, Bourdet DL, Tsuruda PR, Obedencio GP, Beattie DT. Neuropharmacology. 2011 Jul-Aug;61(1-2):69-79. doi: 10.1016/j.neuropharm.2011.02.026. Epub 2011 Mar 12. PMID: 21392515