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18-Month Phase III Trial Results for Tarenflurbil (Flurizan)

Unsuccessful phase III study does not mean the end of anti-amyloid therapies

Alzheimer’s Association International Conference on Alzheimer’s Disease 2008

Myriad Genetics (MYGN) announced on June 30, 2008, that its Phase III trial of tarenflurbil (Flurizan) had failed to achieve statistical significance on either of its two primary endpoints, and that the company was abandoning development of the compound for Alzheimer’s disease.

“While the results of the trial were certainly disappointing, just because the Flurizan Phase III clinical trial failed, doesn’t mean that other amyloid-targeted therapies in the clinical trial pipeline aren’t valid. We learn a great deal from every clinical study,” Gandy said. “There are many ways to impact amyloid and its role in Alzheimer’s. There are other drugs in development that target amyloid with mechanisms of action that are different from this one. One or more of these drugs may ultimately prove successful.”

At ICAD 2008, detailed data and results from the trial were presented for the first time by Robert C. Green, MD, MPH, of Boston University School of Medicine. Tarenflurbil is classified as a selective amyloid lowering agent, which was shown in nonclinical studies to modulate gamma secretase activity. The drug was in trials in people with mild Alzheimer’s to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

In the randomized, double-blind, placebo-controlled trial, 1,649 individuals with mild Alzheimer’s (mean MMSE in both groups = 23.3) were randomized 1:1 to receive tarenflurbil 800 mg twice-a-day or placebo for 18 months. The co-primary outcome measures of efficacy were two standard measures of cognition and the ability to accomplish activities of daily living, respectively the ADAS-cog and the ADCS-ADL, with assessments conducted every three months. The secondary outcome measure was the Clinical Dementia Rating scale. Exploratory outcomes included the Neuropsychiatric Inventory (NPI), Quality of Life-Alzheimer’s test, and Caregiver Burden Inventory.

The researchers found that the drug did not achieve statistical significance in either of its primary endpoints of cognition and activities of daily living. Also, it did not achieve statistical significance on the secondary endpoint. By the end of the 18-month trial, patients in both the tarenflurbil and placebo groups had declined approximately seven points on the ADAS-cog scale and 10 points on the ADCS-ADL scale.

According to the researchers, the reported adverse effects reflect the expected profile of the elderly population with Alzheimer’s and, in most participants, symptoms were well balanced between the tarenflurbil and placebo groups. However, in the tarenflurbil treatment group, there was increased frequency of anemia (9.7 percent vs. 4.5 percent), infections (pneumonia, H. zoster, sepsis) (6.9 percent vs. 2.9 percent), and gastrointestinal ulcers (1.7 percent vs. 0.4 percent).

“This was the largest and longest placebo-controlled AD treatment trial ever completed,” Green said. “While the trial did not meet its endpoints, it was well-designed and executed, and it provided clear answers regarding Flurizan’s lack of efficacy and its safety.”

“The fact that both the drug-treated and placebo groups declined over the course of the trial – and that the placebo-treated patients declined at the expected rate – shows that we can do this type of trial in people with mild Alzheimer’s. As the first trial to ever study a large population of mild Alzheimer’s patients, we’ve collected very valuable data on the progression of the disease in its earliest stages. We are confident that the results of this study will help researchers in their quest to develop new and better treatments for Alzheimer’s,” Green added.

“This drug candidate, in this dose, in this group did not work. But, like much good science, the study raises as many questions as it does provide answers. Was the dose right? Was the study long enough? Did they start the intervention early enough in the course of the disease? Designing and executing clinical studies that answer these questions will help us defeat Alzheimer’s disease,” Gandy said. “The only way we are going to solve the problem of Alzheimer’s is for scientists and companies to have the courage to make significant investments in these large scale trials – which may or may not work. This was a very well done study and the company and scientists are to be commended for that.”

Myriad Genetics Reports Results of U.S. Phase 3 Trial of Flurizan™ in Alzheimer’s Disease

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Flurizan’s Failure Leaves Key Alzheimer’s Theory Unresolved

clipped from blogs.wsj.com

Though Myriad Genetics was hoping its experimental Alzheimer’s drug Flurizan would surprise naysayers in the scientific and investment communities, the company instead announced that its Phase III clinical trial did indeed fail.

The company said Monday that the 18-month, 1,684-patient study – the largest Alzheimer’s-treatment study to date – showed Flurizan failed to improve cognitive functioning or activities of daily living, and added that Myriad is abandoning further efforts to develop the drug. This leaves Elan and Wyeth’s bapineuzumab and Eli Lilly’s gamma secretase inhibitor as the two leading candidates among disease-modifying Alzheimer’s drugs in development.

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Posted by on July 1, 2008 in alzheimer's, bob demarco, flurizan

 

Immune Antibodies Penetrate Neurons to Clear Alzheimer’s-Linked Amyloid

Discovery Could Advance Treatment for Alzheimer’s, Immune Diseases, Weill Cornell Team Says

Researchers at Weill Cornell Medical College have gotten much closer to understanding how immune-based therapies can treat Alzheimer’s disease — by studying how antibodies go inside brain cells to reduce levels of Alzheimer’s-linked amyloid peptides that form plaques between neurons.

“This internalization and activity of the antibody within the cell was a big surprise and something we really haven’t appreciated in neurological medicine. It gives us new hope for the use of immunotherapy against Alzheimer’s, while casting intriguing new light on other disease processes,” says senior author Dr. Gunnar Gouras, associate professor of neurology and neuroscience at Weill Cornell Medical College and associate attending neurologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

His team’s study will appear as a prestigious “paper of the week” in an upcoming issue of the Journal of Biological Chemistry, and was published in the May 1 online edition of the journal.

Read the original source material and the article in its entirity at the Weill Cornell Medical W

 

Drinking juice may delay onset of Alzheimer’s disease


Drinking fruit or vegetable juice may be better for you than you think. A new research study shows that drinking fruit or vegetable juice may delay the onset of Alzheimer’s disease.

Researchers at the Group Health Center for Health Studies in Seattle, Washington
following nearly 2,000 adults for 10 years found drinking fruit or vegetable juice more than three times a week cuts the risk of developing Alzheimer’s by 76 percent compared to drinking it less than once a week. They found having juice once or twice a week reduced risk by 16 percent.

Highlights from the Study include:

“The theory is that the brain accumulates damage due to oxidation as we age, and if you can protect the brain from that damage you can protect the person from Alzheimer’s disease and other causes of dementia,” said Eric Larson, MD.

Researchers saw the protective benefits from any type of juice. The study also found there are more antioxidants in juice than in vitamin C and E supplements.

According to Dr. Larson, juice is made using parts of the fruit with the highest concentration of natural antioxidants. “The theory is the brain accumulates damage due to oxidation as we age and if you can protect the brain from that damage, you can protect the person from Alzheimer’s disease and other causes of dementia,” he said.

In most cases, juice is produced using the core, the seeds and the skin — parts of the fruit or vegetable people do not normally consume. The food is mashed together to create a concentrate. Juice is made in cold process, so nutrients aren’t damaged by heat. Juice will usually have a defined level of purity based on percentage of fruit juice. Juice should not be confused with squash, which is usually an artificial juice that can be diluted with water.

In theory, grape, apple and orange juices are very potent in antioxidants and could be the most effective at preventing Alzheimer’s disease, according to Dr. Larson. In the study, those who did not drink fruit juice, but ate several servings of fruit per week, saw some benefit. However, those who drank juice saw the most benefit.

Study participants who drank juice once or twice a week reduced their Alzheimer’s risk by 16 percent. Those who drank juice three times per week reduced their risk by 76 percent. Before you drink 10 glasses of orange juice each day, be aware there may be threshold for antioxidant consumption. Going above that amount may not necessarily bring benefits.

More on this study as it becomes available

 

Alzheimer’s Disease Rate Rises to More Than Five Million in the United States

Someone Develops Alzheimer’s Every 72 Seconds, According To New Alzheimer’s Association Report.

The Alzheimer’s Association today reports that in 2007 there are now more than 5 million people in the United States living with Alzheimer’s disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer’s disease and other dementias.

Alzheimer’s Disease Prevalence Rates Rise to More Than Five Million in the United States

The Alzheimer’s Association today reports that in 2007 there are now more than 5 million people in the United States living with Alzheimer’s disease. This number includes 4.9 million people over the age of 65 and between 200,000 and 500,000 people under age 65 with early onset Alzheimer’s disease and other dementias. This is a 10 percent increase from the previous prevalence nationwide estimate of 4.5 million.

The greatest risk factor for Alzheimer’s is increasing age, and with 78 million baby boomers beginning to turn 60 last year, it is estimated that someone in America develops Alzheimer’s every 72 seconds; by mid-century someone will develop Alzheimer’s every 33 seconds.

These new estimates, as well as other data concerning the disease and its effects, are issued today as hundreds of advocates from across the country gather in the nation’s capitol for the Alzheimer’s Association’s annual Public Policy Forum. The report titled, 2007 Alzheimer’s Disease Facts and Figures, is being released at a hearing today chaired by Senator Barbara Mikulski. Senators Barbara Mikulski and Christopher Bond and Representatives Edward Markey and Christopher Smith have introduced bipartisan legislation to address problems identified in the Association’s report. The Association’s report details the escalation of Alzheimer’s disease which now is the seventh leading cause of death in the country and the fifth leading cause of death for those over age 65. It also offers numerous statistics that convey the burden that Alzheimer’s imposes on individuals, families, state and federal governments, businesses, and the nation’s health care system. For example:

Without a cure or effective treatments to delay the onset or progression of the Alzheimer’s, the prevalence could soar to 7.7 million people with the disease by 2030, which is more than the population of 140 of the 236 United Nations countries.

By mid-century, the number of people with Alzheimer’s is expected to grow to as many as 16 million, more than the current total population of New York City, Los Angeles, Chicago and Houston combined.

As the prevalence impact of Alzheimer’s grows, so does the cost to the nation. The direct and indirect costs of Alzheimer’s and other dementias amount to more than $148 billion annually, which is more than the annual sales of any retailer in the world excluding Wal-Mart.

“Alzheimer’s Disease Facts and Figures clearly shows the tremendous impact this disease is having on the nation; and with the projected growth of the disease, the collective impact on individuals, families, Medicare, Medicaid, and businesses will be even greater,” says Harry Johns, President and CEO of the Alzheimer’s Association. “However there is hope. There are currently nine drugs in Phase III clinical trials for Alzheimer’s several of which show great promise to slow or stop the progression of the disease. This, combined with advancements in diagnostic tools, has the potential to change the landscape of Alzheimer’s.”

According to the latest statistics from the Centers for Disease Control and Prevention, from 2000-2004 death rates have declined for most major diseases — heart disease (-8 percent), breast cancer (-2.6 percent), prostate cancer (-6.3 percent) and stroke (-10.4 percent), while Alzheimer’s disease deaths continue to trend upward, increasing 33 percent during that period.

“We must make the fight against Alzheimer’s a national priority before it’s too late. The absence of effective disease modifying drugs, coupled with an aging population, makes Alzheimer’s the health care crisis of the 21st century,” Johns said.

Medicare currently spends nearly three times as much for people with Alzheimer’s and other dementias than for the average Medicare beneficiary. Medicare costs are projected to double from $91 billion in 2005 to more than $189 billion by 2015, more than the current gross national product of 86 percent of the world’s countries. In 2005, state and federal Medicaid spending for nursing home and home care for people with Alzheimer’s and other dementias was estimated at $21 billion; that number is projected to increase to $27 billion by 2015.

The new report also highlights the impact that Alzheimer’s has on states with more than 6 in 10 (62%) having double digit growth in prevalence by the end of the decade. In addition, Alaska (+47%), Colorado (+47%), Utah (+45%), Wyoming (+43%), Nevada (+38%), Idaho (+37%), Oregon (+33%), and Washington (+33%) will experience increases ranging from one-third to one-half. The states with the largest numbers of deaths due to Alzheimer’s disease in 2003 were (1) California, (2) Florida, (3) Texas, (4) Pennsylvania, and (5) Ohio.

The Alzheimer’s Association is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer’s. For more than 25 years, the Association has provided reliable information and care consultation; created services for families; increased funding for dementia research; and influenced public policy changes.

Source Alzheimer’s Association

 

Exercise slows decline in Alzheimer’s patients

I can attest, exercise makes a difference. My mother now has the tendency to sit around all day. On those days when I can get her to go to Gold’s Gym with me she is a completely different person. The look on her face, from dull to smiling, is more than enough to tell me that exercise works to her benefit.

The article on the next page talks about the effects of exercising on Alzheimer’s patients.

“Nursing home residents with Alzheimer’s disease who participate in a moderate exercise program have a significantly slower deterioration than those who receive routine medical care, researchers have shown.”

Exercise slows decline in Alzheimer’s patients

NEW YORK (Reuters Health) – Nursing home residents with Alzheimer’s disease who participate in a moderate exercise program have a significantly slower deterioration than those who receive routine medical care, researchers have shown.

Dr. Yves Rolland, of Hospital La Grave-Casselardit in Toulouse, France, and colleagues examined the effects of a program of exercise for one hour twice weekly on activities of daily living, physical performance, nutritional status, behavioral disturbance and depression among 134 Alzheimer’s disease patients in nursing homes.

The patients were 83 years old on average. They were assigned to the exercise program, which focused on walking, strength, balance and flexibility training, or to routine medical care for 12 months.

As reported in the Journal of the American Geriatrics Society, 110 participants completed the study. Among the 56 subjects in the exercise group who completed the study, the rate of adherence to the program was about 33 percent on average.

At the end of the 12 months, the average activities-of-daily-living score was significantly more improved in the exercise group than in the routine medical care group, Rolland’s team reports.

In addition, average walking speed improved significantly more in the exercise group than in the routine medical care group at 6 months and 12 months.

However, the exercise program had no apparent effect on behavioral disturbance, depression or nutritional assessment scores.

ORIGINAL SOURCE: Journal of the American Geriatrics Society, February 2007.

 

Myriad Genetics Presents Additional Flurizan Phase 2 Study Data (Alzheimer’s)

Overall, 42% of patients on Flurizan showed improvement or no decline in one or more of the three primary endpoints of cognition, global function and activities of daily living, compared to 10% of patients on placebo.


42% of Patients on Flurizan™ Had Improved or Not Declined After 24 Months

SALT LAKE CITY, UT, March 05, 2007—Myriad Genetics, Inc. (NASDAQ: MYGN) (www.myriad.com) announced today that it presented additional results of its completed Phase 2 follow-on study of Flurizan™ in patients with mild Alzheimer’s disease at the annual meeting of the American Association for Geriatric Psychiatry (AAGP), held March 1-4, 2007 in New Orleans. The data indicate that Flurizan may be capable, not only of slowing the decline of Alzheimer’s disease, but of halting the disease in its tracks. In this study, many patients with Alzheimer’s disease got no worse over two full years, and in some cases, patients treated with Flurizan appear to have improved.

At 24 months, study participants in the Phase 2 trial with mild Alzheimer’s disease taking 800 mg twice daily Flurizan experienced a 67% improvement in their level of cognitive decline compared with placebo, as measured by the Mini Mental State Exam (MMSE) score. This difference was highly significant statistically (p=0.001). Additionally, based upon the MMSE score, three times the percentage of patients on Flurizan demonstrated improvement in cognition or zero decline, compared to patients on placebo: Forty-two percent of patients on 800 mg twice daily Flurizan experienced improvement or zero decline, compared with 14% of patients taking placebo. MMSE is the primary test used by most clinicians to help diagnose, assess and monitor progression of patients with Alzheimer’s disease. It was also the principal criterion for selecting patients to enroll in the Phase 2 study, and is a secondary endpoint in the two ongoing Phase 3 trials of Flurizan.

Overall, 42% of patients on Flurizan showed improvement or no decline in one or more of the three primary endpoints of cognition, global function and activities of daily living, compared to 10% of patients on placebo. On the test that measures cognition, ADAS-cog, 25% of study participants taking 800 mg BID of Flurizan showed cognitive improvement or experienced zero decline in cognition after 24 months, compared with none on placebo. With the CDR-sb test, a measure of overall function in Alzheimer’s patients, 29% of study participants on Flurizan experienced an improved or zero decline score, compared with none of those on placebo.

Robert C. Green, M.D., MPH, Co-Director, Alzheimer’s Disease Clinical & Research Program, Professor of Neurology, Genetics and Epidemiology at the Boston University School of Medicine, and a lead investigator on the Phase 3 trial of Flurizan, commented, “This analysis of patient response to Flurizan in the Phase 2 trial suggests that the drug may, in many patients, actually halt disease progression over a 24-month time frame. Since Flurizan appears to slow the biological progression of the disease, this is an exciting and novel finding, and if replicated in the ongoing Phase 3 trials will be extraordinarily important.”

To recap the efficacy results of the Phase 2 study at month 24 presented earlier, mild patients taking 800 mg of Flurizan twice daily had an effect size of 72%, with a statistically significant value of p=0.0005, as measured by their global function on the CDR-sb test. In activities of daily living, the patients showed a statistically significant 67% effect size (p=0.015). Cognition improvement showed an effect size of 52% at 24 months on the ADAS-cog scale. These data suggest that there is a substantial benefit from Flurizan.

The additional data presented at the AAGP meeting and announced today add detail to these effect sizes by demonstrating that, not only did the population as a whole respond to the treatment, but a meaningful portion of the patients who responded to the treatment did so by experiencing either zero decline after two years or a reversal of their decline to actual improvement, something that is very rare in Alzheimer’s disease. Comparisons to placebo at 24 months refer to the placebo group as originally randomized.

The vast majority of patients in this Phase 2 study, approximately 94% at the time of enrollment, were receiving stable doses of acetylcholinesterase inhibitors, which are FDA-approved drugs for symptomatic treatment of Alzheimer’s disease. Thus, the benefits of Flurizan observed in these patients were over and above the current standard of care.

“The 24 month Phase 2 responder analysis provides further evidence of efficacy against mild Alzheimer’s disease that is consistent with our understanding of Flurizan’s mechanism of action as a SALA,” said Adrian Hobden, Ph.D., President of Myriad Pharmaceuticals, Inc. “The results support our belief that Flurizan is modifying the course of the underlying disease process.”

About Flurizan
Myriad has two Phase 3 trials of Flurizan ongoing in patients with mild Alzheimer’s disease. In each study, participants are taking 800 mg of Flurizan or placebo twice daily, and the last participant enrolled will have taken the study drug for 18 months. Flurizan is the first in a new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs). Flurizan lowered levels of Abeta42 in cellular assays and animal models. Abeta42 is the primary constituent of senile plaque that accumulates in the brain of patients with Alzheimer’s disease. It is thought to be the key initiator of Alzheimer’s disease, since Abeta42 has the greatest tendency to aggregate, cause neuronal damage and initiate amyloid deposits in the brain. Most genetic mutations that cause early-onset Alzheimer’s disease appear to do so by increasing production of Abeta42. Myriad believes that Flurizan is the most advanced drug candidate that modifies the production of Abeta42 to be evaluated in a clinical trial for the treatment of Alzheimer’s disease.

About Myriad
Myriad Genetics, Inc. is a biopharmaceutical company focused on the development and marketing of novel healthcare products. The Company develops and markets molecular diagnostic products, and is developing and intends to market therapeutic products. Myriad’s news and other information are available on the Company’s Web site at http://www.myriad.com. Flurizan is a trademark of Myriad Genetics, Inc. in the United States and other countries.

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include: the capacity of Flurizan to not only slow the decline of Alzheimer’s disease, but halt the disease in its tracks; the suggestion that patients on Flurizan with Alzheimer’s disease will get no worse, and in some cases reverse the course of the disease, resulting in patient improvement; the showing of improvement or no decline of patients on Flurizan on one or more of the three primary endpoints of cognition, global function and activities of daily living; the suggestion that Flurizan may, in many patients, actually halt disease progression over a 24-month time frame; the appearance that Flurizan slows the biological progression of the disease, and the extraordinary importance of this finding if replicated in the ongoing Phase 3 trials; the suggestion that there is a substantial benefit from Flurizan; the demonstration that not only did the population as a whole respond to the treatment, but a meaningful portion of the patients who responded to the drug did so by experiencing either zero decline after two years or a reversal of their decline to actual improvement; the efficacy of Flurizan against Alzheimer’s disease consistent with the understanding of Flurizan’s mechanism of action as a SALA; the Company’s belief that Flurizan is modifying the course of the underlying disease process; the appearance that Flurizan is modifying the underlying course of the disease process; the continued encouragement of the Company by the potential of Flurizan to treat mild Alzheimer’s disease; the anticipated completion of the Phase 3 trial, in order to confirm similar efficacy results for Flurizan in a larger population; the anticipated completion of enrollment of patients with mild Alzheimer’s disease in a global Phase 3 trial; and the belief that Flurizan is the most advanced drug candidate in a clinical trial that inhibits the production of Abeta42 to be evaluated in a clinical trial for the treatment of Alzheimer’s disease. These forward-looking statements are based on management’s current expectation and are subject to certain risks and uncertainties that could cause actual results to differ materially from those set forth or implied by forward-looking statements. These include, but are not limited to, uncertainties as to the extent of future government regulation of Myriad Genetics’ business; uncertainties as to whether Myriad Genetics and its collaborators will be successful in developing, and obtaining regulatory approval for, and commercial acceptance of, therapeutic compounds; the risk that markets will not exist for therapeutic compounds that Myriad Genetics develops or if such markets exist, that Myriad Genetics will not be able to sell compounds, which it develops, at acceptable prices; and the risk that the Company will not be able to sustain revenue growth for its predictive medicine business and products. These and other risks are discussed under the heading “Risk Factors” contained in Item 1A in our Annual Report on Form 10-K for the year ended June 30, 2006, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of this release, and Myriad undertakes no duty to update this information unless required by law.

 
 
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