Name:	Phenserine
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Oral, small molecule
Mechanisms:	Acetylcholinesterase inhibitor; Aβ modulator
Development Status:	investigational in U.S.
FDA Phase:	Inactive
Primary Medical Role:	None as yet.
Role in Alzheimer's Disease:	Phenserine was in clinical study for Alzheimer disease for several years, after preclinical demonstrations of cognitive improvement in both rodents and dogs. Three Phase 3 clinical trials were initiated in 2003 and 2004. Phenserine showed no statistically significant effect on cognition endpoint ADAS-Cog in each of these two Phase 3 trials. Post-hoc analysis of all three Phase 3 clinical trials identified that the group of subjects receiving the highest tested dose (15 mg per day) for more than 12 weeks demonstrated a statistically significant benefit of phenserine over placebo in ADAS-Cog, but only a trend toward improvement in the CIBIC+ measure.
Pharmacological Role:	Phenserine, a phenylcarbamate derivative of physostigmine, is a selective, non-competitive acetylcholinesterase inhibitor that has additional modulatory effects on Aβ levels. Phenserine interacts with the 5’- untranslated region of the APP gene and reduces translation of APP mRNA into protein. Both enantiomers (-)- and (+)-phenserine are equipotent in dose-dependent and time-dependent negative regulation of APP mRNA translation, but (+)-phenserine (posiphen) is inactive as an acetylcholinesterase inhibitor, and therefore may be dosed much higher. See related ARF news A Plus-side to Phenserine.
Side Effects:	Similar to other AChE inhibitors, the dose-limiting side effects of phenserine are gastrointestinal, including nausea and vomiting. Headache has also been reported as a common side effect. The completed Phase 3 study of phenserine in which patients were dosed for more than 12 weeks at doses of up to 15 mg twice daily demonstrated no unexpected safety or tolerability concerns.
Evidence pro its efficacy:	Unpublished results suggest a small benefit on cognition and biomarkers (see ARF related conference story). Results from preclinical animal studies indicate that phenserine is rapidly absorbed and cleared from the body, but produces a rapid, potent, and long-lasting AChE inhibition. Phenserine is also found to improve the performance of aged rats in a complex maze task without producing obvious side effects.
Evidence con its efficacy:	One Phase 3 clinical study comparing phenserine to placebo failed to demonstrate efficacy on ADAS-Cog and CIBIC+ primary outcome measures. Two additional concurrent clinical trials were halted and the data from these were merged and analyzed as a single trial, which also failed to demonstrate a statistically significant benefit for phenserine over placebo in the same outcome measures after 3 months of treatment (see ARF related news story).
Companies:	TorreyPines Therapeutics, Inc.
Notes:	TorreyPines Therapeutics has licensed the development of phenserine for ALzheimer Disease to QR Pharma (November 18, 2008). Last updated: 19 December 2008

References

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Morse LJ, Payton SM, Cuny GD, Rogers JT. FDA-Preapproved Drugs Targeted to the Translational Regulation and Processing of the Amyloid Precursor Protein. J Mol Neurosci. 2004 ;24(1):129-36. Abstract

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Shaw KT, Utsuki T, Rogers J, Yu QS, Sambamurti K, Brossi A, Ge YW, Lahiri DK, Greig NH. Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci U S A. 2001 Jun 19;98 (13):7605-10. Abstract

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Patel N, Spangler EL, Greig NH, Yu QS, Ingram DK, Meyer RC. Phenserine, a novel acetylcholinesterase inhibitor, attenuates impaired learning of rats in a 14-unit T-maze induced by blockade of the N-methyl-D-aspartate receptor. Neuroreport. 1998 Jan 5;9(1):171-6. Abstract

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Iijima S, Greig NH, Garofalo P, Spangler EL, Heller B, Brossi A, Ingram DK. Phenserine: a physostigmine derivative that is a long-acting inhibitor of cholinesterase and demonstrates a wide dose range for attenuating a scopolamine-induced learning impairment of rats in a 14-unit T-maze. Psychopharmacology (Berl). 1993;112(4):415-20. Abstract