Flurizan (R-flurbiprofen) Trials. (if you would like to inquire about enrollment please see this link.)
Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) has been repeatedly associated with reduced risk for Alzheimer’s and in some of the biggest community based studies, patients taking ibuprofen were the largest group of apparently protected people (with reduced risk for Alzheimer’s). Based on this epidemiology data, our group tested chronic ibuprofen in a transgenic mouse model and found that it reduced inflammation (with IL-1ß as the index) but also amyloid accumulation. 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. PMID: 12421374 [PubMed - indexed for MEDLINE] How it did this was unclear because we could not show any evidence that ibuprofen changed the amount of amyloid precursor or its processing.
While these results were very encouraging, one problem with using ibuprofen is that NSAIDs of this type are “COX” inhibitors and this is associated with significant side-effect risks from chronic use. Then a combined effort from laboratories led by Drs Koo (UCSD) and Golde ( Mayo, Jacksonville) found that ibuprofen and related compounds in the same “profen” family could lower the formation of the longer and more toxic form of amyloid peptide (“abeta 42”) without changing overall abeta production. (This effect is caused by modulating favored “gamma secretase” cleavage site within amyloid precursor toward shorter, non-toxic “abeta 38”.) The same researchers showed that the profen effects on reducing abeta 42 did not require COX inhibition and therefore might be achieved without the same side-effect issues that traditional NSAIDs have.
At the time our study was published, a scientist who had worked on ibuprofen and related compounds at a major drug company came to us with the suggestion that we test the impact of a non-COX inhibiting profen drug called R-flurbiprofen, because if it had anti-amyloid effects it could be used at high doses without the side-effects caused by COX-inhibition. So we began testing R-flurbiprofen and when we learned of the work from Koo and Golde showing an ibuprofen effect on abeta 42, we focused our studies on abeta 42 inhibition. From these studies we published the first report (Morihara et al ) that like ibuprofen, R-flurbiprofen could selectively reduce abeta 42 production suggesting that it might be worth testing in the clinic. Further evidence for the same abeta 42 lowering activity in vitro and in transgenic mice came from the Koo and Golde labs.
Since then, R-flurbiprofen (called Flurizan or MPC-7869) has been tested in clinical trials with Alzheimer patients sponsored by Myriad Genetics (Salt Lake City, Utah) and led by Dr Gordon Wilcock of Bristol Univ, UK. The initial Phase I/ Phase II trials tested 400 and 800mg per day dosing and found no evidence of toxicity. They also found evidence strongly suggesting a dose-related slowing of disease progression, especially in milder patients. On the basis of these encouraging results, R-flurbiprofen is now in larger Phase III trials in AD patients powered with sufficient numbers of patients to establish whether this selective abeta 42 lowering drug can really slow development of Alzheimer’s, beginning at early stages.