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Mild to moderate Alzheimer disease
Oral, small molecule
Acetylcholinesterase inhibitor; Aβ modulator
investigational in U.S.
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.
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.
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Unpublished results suggest a small benefit on cognition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).
TorreyPines Therapeutics, Inc.
TorreyPines Therapeutics has licensed the development of
phenserine for ALzheimer Disease to QR Pharma (November 18,
Last updated: 19 December 2008
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Cholinesterase inhibitors, beta-amyloid precursor protein
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