Name:	Flurizan™
Other Names:	MPC-7869, r-flurbiprofen, tarenflurbil
Therapeutic Applications:	Mild Alzheimer’s disease
Therapy Types:	Small molecule
Mechanisms:	Selective amyloid-lowering agent (SALA). Flurizan lowers levels of Aβ42, a major constituent of plaques and a key pathogenic agent of Alzheimer disease.
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Lowers toxic Aβ42 production by selectively modulating, but not inhibiting, γ-secretase activity to shift cleavage of amyloid precursor protein (APP) away from Aβ42 production toward shorter, less toxic peptide fragments. Selective modulation allows for γ- secretase activity on other biologically essential substrates.
Role in Alzheimer's Disease:	Selectively lowers production of toxic amyloid (Aβ42) and thus inhibits the cascade of amyloid accumulation, plaque formation, and neurodegeneration that are the hallmarks of dementia. Early intervention, and targeting the initial stage of the disease process, offers the potential for a therapy with disease modification properties. In mouse models, Flurizan™ reduced insoluble amyloid in the brain and improved spatial reference learning and memory.
Evidence pro its efficacy:	Phase 2 studies of Flurizan, in which patients took 800 mg. Flurizan twice daily, were recently completed. The results demonstrated significant positive effects as measured by ADAS-cog and global function assessment CDR-sb test. In addition to the whole treatment population response reaching statistical significance, a meaningful portion of the patients experienced zero decline after 2 years, or more notably, a reversal of decline to actual improvement in cognition and global function.
Companies:	Myriad Pharmaceuticals, Inc.
Notes:	See Myriad Press Release date 20 March 2007. See Alzforum News.

References

Wilcock GK, Black S, Haworth J, Laughlin M, Hendrix S, Binger M, Zavitz K, Swabb E, Hobden A. A Placebo- controlled, Double-blind Trial of the Selective Aâ-42 Lowering Agent, Flurizan (MPC-7869, (R)-flurbiprofen) in Patients with Mild to Moderate Alzheimer’s Disease. Alzheimer's Association International Conference on Prevention of Dementia, June 18-21, 2005 , Washington DC. Abstract

Lleó A, Berezovska O, Herl L, Raju S, Deng A, Bacskai BJ, Frosch MP, Irizarry M, Hyman BT. Nonsteroidal anti- inflammatory drugs lower Abeta(42) and change presenilin 1 conformation. Nat Med. 2004 Oct ;10(10):1065-6. Abstract

Nye JS, Ellerbrock BR, Pauley AM, et al. Modulators of the Gamma Secretase Reciprocally Regulate Short and Long Aβ Peptides and Spare ε-Site Cleavages. Proceedings of the 9th International Alzheimer's Disease and Related Disorders, July 17-22, 2004, Philadelphia.

Eriksen JL, Nicolle MM, Prescott S, Ozols VV, Zhuo JM, Smith TE, Beard JL, Weggen S, Sagi SA, Koo EH, Golde TE. Chronic treatment of transgenic APP mice with R- flurbiprofen. 2003 Abstract Viewer/Itinerary Planner, Program No. 295.22. Society for Neuroscience, Washington, DC.

Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Ozols V, Fauq A, Golde TE, Koo EH. Evidence that nonsteroidal anti- inflammatory drugs decrease amyloid beta 42 production by direct modulation of gamma-secretase activity. J Biol Chem. 2003 Aug 22;278(34):31831-7. Abstract

Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Golde TE, Koo EH. Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem. 2003 Aug 15;278 (33):30748-54. Abstract

Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE. NSAIDs and enantiomers of flurbiprofen target gamma- secretase and lower Abeta 42 in vivo. J Clin Invest. 2003 Aug 1;112(3):440-9. Abstract

Morihara T, Chu T, Ubeda O, Beech W, Cole GM. Selective inhibition of Abeta42 production by NSAID R-enantiomers. J Neurochem. 2002 Nov ;83(4):1009-12. Abstract