Name:	PRX-03140
Other Names:	7-isopropyl-6-oxo-5(3-piperidin-1-yl-propylcarbamoyl)-6,7-dihydro-thieno[2,3-b]pyridine-4-olate, potassium salt
Therapeutic Applications:	Alzheimer disease
Therapy Types:	Small molecule
Mechanisms:	Partial 5-HT4 receptor agonist
Development Status:	investigational in U.S.
FDA Phase:	Inactive
Primary Medical Role:	Cognition enhancement
Role in Alzheimer's Disease:	Increases acetylcholine (ACh) production and/or release (Mohler, 2005). Neuroprotective, with potential for disease modification. Stimulates sAPPα production (Lezoualc'h, 2005); increases NGF (Shachem, 2006) and BDNF (Shachem, 2006; Granholm, 2005) brain levels; reduces Aβ1- 40/42 levels (Shachem, 2006).
Pharmacological Role:	5-HT4 receptor stimulation leads to increases in production/release of ACh in the brain; activation of 5- HT4 also promotes the α-secretase pathway, leading to secretion of the soluble form of amyloid precursor protein (sAPPα), and decreases Aβ levels; sAPPα is neuroprotective, increases NGF, enhances memory, and competes with amyloidogenic (insoluble) APP peptides.
Contraindications:	Dementia other than Alzheimer type, Parkinson disease, use of certain restricted medications, history of stroke, seizure, or epilepsy.
Side Effects:	A phase Ib randomized, placebo-controlled, double-blind, repeat-dose pilot study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRX-03140 in subjects with mild to early moderate Alzheimer disease was conducted between July 2005 and August 2005 and was the first clinical evaluation of PRX- 03140. In this study, 12 otherwise healthy PRX-03140-naïve male (N = 6) and female adults (>45 years old) with a diagnosis of mild to moderate Alzheimer disease were randomized in a 2:1 ratio (50 mg PRX-03140:placebo) to a 14-day once daily dosing regimen. In this study, four of the 12 subjects experienced a total of 13 AEs during the study. There were no adverse effects resulting in discontinuation, and no AEs rated severe in intensity. In the PRX 03140 50 mg group, three of eight subjects experienced a total of 11 AEs, and one of the four subjects in the placebo group experienced two AEs. Only diarrhea occurred in more than one subject: two subjects in the PRX 03140 50 mg group (one possibly related and one unlikely related) and one subject in the placebo group (unlikely related). Overall, four AEs (all in the PRX 03140 50 mg group) were considered possibly related to the study medication: lethargy, dyspepsia, diarrhea, and irritability. Twelve AEs were considered mild in severity and one (shoulder pain, in the PRX 03140 50 mg group) was considered moderate. Eleven of the 13 AEs resolved during the study, and two (one in each treatment group) were ongoing at the subjects’ last evaluation.
Evidence pro its efficacy:	A phase 1b randomized, placebo-controlled, double-blind, repeat-dose pilot study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRX-03140 in subjects with mild to early moderate Alzheimer disease was conducted between July 2005 and August 2005 and was the first clinical evaluation of PRX- 03140 in the target population. The results of the psychometric tests were similar for the two treatment groups. For the RTI (reaction time) portion of the CANTAB test (speed of response), the PRX 03140 50 mg group showed more improvement from baseline in choice reaction time at both assessment times (study days 13 and 15) compared to the placebo group, although the differences between the treatment groups were not statistically significant for this test or any other portion of the CANTAB test.
Companies:	EPIX Pharmaceuticals, Inc.
Notes:	Phase II study of PRX-03140 in subjects receiving a stable dose of Donepezil (ClinicalTrials.gov NCT00672945) was terminated in July 2009 when EPIX Pharmaceuticals liquidated business as an alternative to formal bankruptcy. The PRX-03140 program will be sold at auction. Contact Joseph F. Finn, Jr. at 781-237-8840 if you are interested in participating in the auction. This record updated Jan 23, 2010.

References

Shachem S. PRX-03140: A Novel 5-HT4 Partial Agonist with a Dual Cholinergic/Disease-Modifying Mechanism for the Treatment of Alzheimer Disease 10th International Conference on Alzheimer’s Disease (ICAD) July 14-20, 2006; Madrid, Spain.

Granholm AE, Umphlet C, Moore AB, Bimonte-Nelson HA, Nelson ME, Shacham S. Effects of PRX-03140, a serotonin 5- ht4 receptor partial agonist, on cognition and growth factor levels in the aged rat Program No. 656.6. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005.

Lezoualc'h F, Gastineau M, Robert SJ, Araujo JA, Studzinski CM, Poma R, Head E, Milgram NW, Shacham S. PRX- 03140, a novel selective partial 5-ht4 receptor agonist, increases secretion of the nonamyloidogenic form of the amyloid precursor protein Program No. 324.12. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005.

Mohler EG, Shacham S, Noiman S, Gold PE, Ragozzino ME. PRX- 03140, A novel 5-HT4 agonist, enhances memory and increases hippocampal acetylcholine efflux. Program No. 653.10. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2005.

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