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 = 14.3 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 = 10 nM and 36 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.

Although few publications have inferred S1R agonists/antagonists modulate blood glucose, Di et.al (2017) reported S1R deficiency in knockout mice impacted regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis. The hypothesis that S1R deficiency causes down-regulation of the glucocorticoid receptor (GR) and attenuates GR-mediated feedback inhibition of HPA axis, as well as stress response of HPA axis, suggest that the inverse, the activation of S1R under normal conditions, may modulate glucocorticoid insulin suppression (as a direct S1R-GR effect) as well as cortisol levels (producing HPA axis feedback inhibition) and the neutrophil to lymphocyte ratio (NLR) as a biomarker for systemic inflammation. Exposure of INS-1 832/13 Rat Insulinoma Cell Line cultures to PRX-3140 and coadministration of 10 nM to 10 µM PRX-3140 with 100 nM cortisol (“low cortisol” condition) significantly increased insulin release compared to controls. Glucose and cortisol levels at 10, 30, 100 and 200 mg dose levels in the 14-day clinical study (NCT00384423) of PRX-3140 once-daily demonstrated a reduction compared to placebo. In both single-dose and 14-day studies, once-daily PRX-3140 from 5 to 15 mg demonstrated a downward trend in NRL. As an agonist of S1R that acts as a chaperone of GR, PRX-3140 has demonstrated GR modulating effects in INS-1 cells and in 14-day clinical studies in healthy adults with low incidence of side effects. The results of the present study suggest that S1R activation modulates glucocorticoid insulin suppression, cortisol levels, and inflammation

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

PRX-3140, a 5-HT4 Partial Agonist and Sigma-1 Agonist/Antagonist, Modulates Glucocorticoid Insulin Suppression and Cortisol Levels. Hood BL, McLaughlin JP, Alleyne AR, Thinschmidt JS, Harden SW, Frazier CJ, Talton JD. December 5, 2024. MedRxiv. doi: https://doi.org/10.1101/2024.12.04.24318244.

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