2004 - Flurizan P1 Results
Tuesday, July 20 2004 - 6:30 AM
Myriad Genetics Presents Phase I Results at International Conference on Alzheimer's Disease
- Flurizan Safe and Well Tolerated in Healthy Older Volunteer Study -
SALT LAKE CITY, July 20 /PRNewswire-FirstCall/ -- Myriad Genetics, Inc. (Nasdaq: MYGN), presented new clinical trial data on its investigational Alzheimer's disease drug candidate, Flurizan(R) (R-flurbiprofen, MPC-7869), at the Ninth International Conference on Alzheimer's Disease and Related Disorders in Philadelphia, PA [Poster session P2, July 19, 2004, 12:30 - 2:45pm].
Dr. Edward H. Koo, M.D., Professor of Neurosciences at the University of California, San Diego presented results from a study of the safety and tolerability following 21-day administration of Flurizan in healthy elderly volunteers. The results were drawn from Myriad's Phase I randomized, double-blinded, placebo-controlled trial of Flurizan. The trial enrolled 48 people between the ages of 55 and 80 years, in four cohorts, which were studied over a three-week course of daily dosing with Flurizan. The first cohort was given 400mg daily, the second cohort 800mg, the third 1600mg and the fourth, a placebo. Dr. Koo reported that no serious adverse events were observed in any of the cohorts. These data complement the safety record established with Flurizan to date in three other completed trials among healthy individuals and patients.
In this trial designed to evaluate the safety of Flurizan, there were not only no serious adverse events, there were no dropouts from the trial due to any adverse event. The number and nature of adverse events collected was not significantly different between the treated groups or those on placebo. Specifically, no difference was observed between any of the groups in reports of adverse gastrointestinal events.
"We are very pleased that the results of this trial in older volunteers mirrors our experience with Flurizan in other human clinical trial settings, providing further evidence that Flurizan is safe and well-tolerated," said Adrian Hobden, Ph.D., President of Myriad Pharmaceuticals, Inc. "The safety profile appears well-suited to use with an Alzheimer's disease population."
Summary of Trial Results
Flurizan (R-flurbiprofen, MPC-7869) was safe and well tolerated in healthy older volunteers when administered in doses of up to 1600 mg/day for 21 days.
Current Development Status of Flurizan
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What is Flurizan?
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Flurizan™ for the Treatment and Prevention of Alzheimer's Disease
Flurizan™ holds promise as a safe and effective drug for the treatment and prevention of Alzheimer's disease. Flurizan™ is the pure R-enantiomer form of flurbiprofen - an NSAID (non-steroidal anti-inflammatory drug) with 25 years of clinical experience behind it. Unlike NSAIDs, however, Flurizan™ is not an inhibitor of cyclooxygenase enzymes (COX-1 and COX-2). The compound modulates the signal transduction and transcription activation pathways associated with nuclear factor kappa B (NFkB), a principle transcription factor in the expression of many molecules involved in cell growth, cell death and inflammation. In addition, Flurizan™ has recently been shown to reduce Abeta42 peptide levels in vitro and in vivo, and reduce amyloid pathology in the brain.1 Flurizan™ has an excellent safety profile and is very potent in animal models of cancer and Alzheimer's disease
Preclinical Studies
Flurizan™ has the potential to be the first drug to have a significant impact on the precise molecular causative agent of Alzheimer's disease and, thereby, slow or halt disease progression.
A large number of epidemiological studies have indicated that chronic use of NSAIDs reduces the risk of developing Alzheimer's disease.2 Most recently, the 'Rotterdam study', a long-term prospective study, which followed almost 7,000 patients for nearly seven years, found that the use of traditional NSAIDs for two years or more provided 80 percent protection against the development of Alzheimer's Disease.3 Moreover, the NSAID indomethacin appeared to slow the cognitive decline in patients with moderate Alzheimer's Disease in a placebo-controlled pilot study, although GI toxicity (accounting for over 20% dropout of the indomethacin treatment group) limited the scale of the study.4 Significantly, as described below, indomethacin has anti-amyloid activities in addition to its activity as an NSAID.
Recent preclinical data suggests that a certain subset of marketed NSAIDs selectively lowers the levels of the Abeta42 peptide, the molecule widely accepted to initiate the pathological cascade of events that leads to neurodegeneration in the Alzheimer's brain.5 In this study, indomethacin, ibuprofen and sulindac sulphide selectively decreased the Abeta42 peptide produced from a variety of cultured cells by up to 80%. The Abeta42-lowering activity of these NSAIDs was independent of cyclooxygenase (COX) inhibition and was not exhibited by most marketed NSAIDs; aspirin, naproxen, meloxicam, sulindac sulfone, SC-560 and celecoxib showed no ability to lower Abeta42 production.
Significantly, short-term administration of ibuprofen to a transgenic mouse model of Alzheimer’s disease lowered brain levels of Abeta42 in these mice.5 Independent studies of chronic high-dose ibuprofen administered to transgenic mice resulted in a significant reduction in amyloid plaque pathology in the brain and prevented the decline in behavioral measures of cognitive function.6, 7 In addition, it was recently reported that this regimen is capable of reversing memory loss and restoring normal memory in transgenic mice.8
Flurizan™ shows promise as a safe, effective drug for the treatment and prevention of Alzheimer's disease.
In support of these preclinical findings, a re-analysis of the Rotterdam results demonstrated that the protection against Alzheimer’s disease progression conferred by NSAID use was entirely attributable to that subset of NSAIDs (indomethacin, ibuprofen, and sulindac sulfide) that specifically lowers Abeta42.9 Recent clinical trials with rofecoxib and naproxen have yielded results consistent with the above observations. Neither naproxen (nonselective COX inhibitor) nor rofecoxib (COX-2 selective) exhibit Abeta42-lowering activity and neither drug demonstrated a slowing of the progression of Alzheimer's disease.10
Unfortunately, the high doses of ibuprofen and the other NSAIDs used in the preclinical studies entail an unacceptably high risk of GI toxicity. A number of companies have been evaluating gamma-secretase inhibitors as potential therapeutics for Alzheimer's Disease. However, these have recently been shown to be toxic, probably due to the inhibition of other essential gamma-secretase functions.11
Myriad, in collaboration with external researchers, has completed preclinical studies indicating that Flurizan™ is a potent and selective Abeta42-lowering agent in vitro and in vivo.1 The concentrations of Flurizan™ required to see a significant Abeta42-lowering effect are readily achievable in humans at doses that have been well-tolerated.
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