Alzheimer's Club

"The media jumped all over the news from the Dementia Prevention Conference about a possible treatment for Alzheimer’s disease with the drug R-flurbiprofen (Flurizan) which is entering a Phase III clinical trial. The results so far, however, have been only mildly successful with the headlines on the Phase II study being “Flurizan Phase II Trial Shows No Overall Benefit.” Still, there is hope for this beta-amyloid altering drug being developed by Myriad Pharmaceuticals.

The Amyloid Hypothesis

[Dr.Koudinov: Make sure you did not miss coverage of the amyloid dogma by the Wall Steet Journal, and my letter to WSJ editor]

The "amyloid hypothesis" states that Alzheimer's disease is initiated by the production, aggregation and deposition of the toxic amyloid beta (Ab) peptide leading to disruption of cell-to-cell communication and eventually to the death of neurons in the brain.

The amyloid hypothesis remains the predominant scientific explanation for the cause of Alzheimer's disease and is the culmination of more than a decade of scientific research from around the world.

It has been discovered that the amyloid precursor protein, APP, is cleaved first by an enzyme called beta-secretase and is then cut into smaller fragments (amyloid peptides) by a second enzyme called gamma-secretase. These amyloid peptides are of several different lengths that have differing properties. Accumulation of the longer 42 amino acid form of this peptide (Ab42) causes cell death in the brain and initiates the formation of plaques, whereas shorter forms of the amyloid peptide are less toxic and do not initiate plaque deposits.

Some approaches to Ab42 reduction have been to block the activity of the gamma-secretase enzyme with drugs called "gamma-secretase inhibitors." This has led to safety concerns because many other essential proteins throughout the body are normally processed by gamma-secretase.

In contrast to the gamma-secretase inhibitor approach, Myriad scientists have pursued a different strategy to lowering Ab42 production and have selected the investigational compound Flurizan based on its ability to act as a modulator, rather than an inhibitor, of the gamma-secretase enzyme in cultured human cells and in animal models.

Insight as to how Ab42 may be implicated in Alzheimer's disease is the result of remarkable progress in Alzheimer's research that has occurred over the last two decades. Clinical trials are currently being conducted to develop drugs that will hopefully lead to disease-modifying therapies for this devastating disease.

Dementia is an umbrella term for many conditions, including Alzheimer's. Increasing age is currently considered the greatest risk factor for Alzheimer’s, with one in 10 of senior citizens over 65 and almost half of those over 85 affected. An estimated 4.5 million Americans have Alzheimer’s, which is twice as many as in 1980. By 2050, without gains in prevention, there could be as many as 16 million with the disease. Research has suggested it is the disease most feared by baby boomers and senior citizens.

Phase II trial shows that treatment with R-flurbiprofen (Flurizan) did not help individuals with mild or moderate Alzheimer’s disease when results for all 207 participants were considered as a whole, according to a report from Myriad, the drug’s developer.

However, the company says it saw some encouraging signs when data for just the 128 participants with mild Alzheimer’s were analyzed separately. Based on these preliminary results, Myriad plans to move forward with a Phase III trial and is recruiting participants throughout the United States.

In the Flurizan Phase III trial, about 100 U.S. sites will enroll approximately 750 individuals with mild to moderate Alzheimer’s disease. Participants will be randomly assigned to receive 400 or 800 milligrams of Flurizan twice daily or a placebo. The trial is designed to determine whether those assigned to either dose of Flurizan fare better in mental function or ability to carry out daily activities than those on the placebo. Trial details are posted in the federal online medical research database at ClinicalTrials.gov.

"We are pleased to hear that Myriad is sufficiently encouraged to go ahead with the Phase III trial," says William H. Thies, Ph.D., Alzheimer’s Association vice president, medical and scientific affairs. "R-flurbiprofen theoretically works by modifying beta-amyloid processing in a different way than most other drugs currently in clinical trials. It would be a worthwhile contribution to clinical knowledge to see how this drug performs in a larger trial designed to explore some of the early signs Myriad sees in their data.”

The company made a presentation of the details about their Phase II results at the Alzheimer’s Association International Conference on Prevention of Dementia in yesterday.

According to Myriad, the Phase II participants with mild Alzheimer’s who were taking the highest experimental dose of R-flurbiprofen showed a tendency to do better than those receiving the placebo on tests of memory and thinking skills, ability to carry out daily activities and overall function. However, those benefits did not meet statistical criteria for having a high likelihood of being due to the effects of the drug rather than to chance.

The company then further subdivided the data to focus on participants with mild Alzheimer’s taking the highest dose who also developed high levels of the drug in their bloodstream. That group experienced a statistically significant benefit in their ability to carry out daily activities and their overall function, but not on measures of memory and thinking skills.

Flurbiprofen is one of a handful of nonsteroidal anti-inflammatory drugs (NSAIDs) shown in laboratory and animal studies to reduce levels of beta-amyloid, a protein fragment considered a prime suspect in Alzheimer’s disease.

Generic flurbiprofen is a mixture of "R" and "S" molecules whose structures are mirror images of one another. Myriad’s Flurizan, also known by the investigational name MPC-7869, contains only R-flurbiprofen, the form that seems to have the greatest impact on beta-amyloid but has little or no anti-inflammatory effect. The anti-inflammatory effects of NSAIDs are associated with certain serious side effects, including bleeding in the stomach and intestines and increased risk of heart attack and stroke.

What the market thinks

In March, Decision Resources, Inc., one of the world's leading research and advisory firms focusing on pharmaceutical and health care issues, forecasts that the launches of Neurochem's Alzhemed and Myriad Genetics' Flurizan will be major factors in driving the market for the treatment of Alzheimer's disease to more than double to $4 billion by 2013.

According to the new Pharmacor study entitled Alzheimer's Disease, a dramatic change in market dynamics will begin half way through the study's 2003 to 2013 forecast period, as the first disease-modifying therapies—including Alzhemed (NC-531) and Flurizan (R-flurbiprofen)—enter the market. These two therapies will account for more than 56% of Alzheimer's disease treatment sales in the United States, Western Europe and Japan.

"Acetylcholinesterase inhibitors (AChEIs) will continue to dominate the Alzheimer's disease market until 2008, with the defining trend during this period being a shift in market share among competing AChEIs," said Michelle Grady, analyst at Decision Resources.

"Eisai/Pfizer's Aricept (donepezil) will retain its leadership position, as Shire/Janssen's Reminyl (galantamine) and, to a lesser extent, Novartis's Exelon (rivastigmine) gain market share. However, sales of these drugs will decline during the second half of the study period because of the expiry of their patents. All agents in this class will lose patent protection by 2013."

With the commercial launch of the biomarker Pittsburgh Compound B and the availability of disease-modifying drugs during the second half of the forecast period, the study also finds that physicians will begin diagnosing Alzheimer's disease earlier in the progression of the illness."

Source: Dementia Prevention Conference: Is Flurizan the Alzheimer's Treatment the World Awaits? Studies so far have shown modest results, new study underway. SeniorJournal.com (21 June 2005) [FullText]