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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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Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial

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800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD.


Source, Findings

A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20–26) and moderate AD (baseline MMSE 15–19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p≥0·10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3·98 [95% CI 0·33 to 7·62] points per year, effect size [reduction from placebo decline rate] 46·4%, Cohen’s d 0·45; p=0·033) and global function (CDR-sb difference −0·80 [−1·57 to −0·03] points per year, effect size 35·7%, Cohen’s d 0·42; p=0·042); slowing of cognitive decline did not differ significantly (ADAS-cog difference −1·36 [−4·07 to 1·36] points per year, effect size 33·7%, Cohen’s d 0·20; p=0·327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (−52%, Cohen’s d −1·08; p=0·003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0–12 and a tarenflurbil group for months 12–24

Interpretation

800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD.

Funding
Myriad Pharmaceuticals.

 

Myriad Genetics Presents Mathematical Comparison of Disease Modification Trial Designs at Alzheimer’s Conference (MYGN)

Current Flurizan™ Phase 3 Study Design May Demonstrate Disease Modification (Alzheimer’s)

“We are excited about this persuasive mathematical comparison of clinical trial designs,” said Adrian Hobden, PhD, President of Myriad Pharmaceuticals, Inc. “We believe that this mathematical proof, coupled with the Flurizan trial design may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan.”


Salt Lake City, UT, Jun 11, 2007—Myriad Genetics, Inc. (NASDAQ: MYGN) (www.myriad.com) announced today that it presented a mathematical comparison of a “Staggered Start” and a “Randomized Withdrawal” clinical trial design with a “Natural History Staggered Start” clinical trial design at the Alzheimer’s Association Prevention Conference held June 9 – 12, 2007, in Washington, D.C. The analysis demonstrates that the “Natural History Staggered Start” trial design currently being used in the Flurizan Phase 3 study can provide the same level of disease modification support as the cross-over trial designs, which are challenged by ethical concerns, dropout bias and complications.

A disease modifying therapy for Alzheimer’s disease (AD) is one that has an impact on the underlying pathology of the disease and thus slows the rate of a patient’s decline over the course of long-term treatment. In contrast, the currently available AD medicines are believed to treat the symptoms of AD without impacting the underlying disease process or providing long lasting benefit. The development of robust methods to demonstrate disease modification in AD clinical trials has been a controversial issue in the field, and to date, there have been no studies that provide convincing evidence of disease modification in AD. Two clinical trial designs that could provide evidence for disease modification were originally proposed for AD studies over 10 years ago by Paul Leber, then the head of the Division of Neuropharmacological Drug Products of the FDA. These designs have come to be known as the “Randomized Withdrawal” and “Staggered Start” designs and are based on measuring clinical outcomes in a cross-over type study.

In the randomized withdrawal design, patients are withdrawn from therapy after a defined period to determine whether the long-lasting benefit to the patient is maintained, demonstrating disease modification, or if the patient drops back to the level of patients on placebo for the duration of the study. In a staggered start design, one group of patients receives the active study drug for the entire study period, while a second group initially receives placebo and then later is given the active drug. If the second group fails to “catch up” in the level of performance of the first group, this is taken to be evidence for a disease modifying effect of the drug. Unfortunately, these designs are difficult to implement and have rarely been used in clinical trials as they are complicated by very long study durations, leading to high dropout rates that introduce biased results, as well as presenting ethical concerns unacceptable to patients and their families.

A team of biostatisticians and mathematicians at Myriad, led by Suzanne Hendrix, Ph.D., Sasha Gutin, Ph.D., and Scott Horton, has proposed an alternative strategy designated the “Natural History Staggered Start” analysis, that compares the slopes of decline of drug treated patients with those of patients receiving placebo and corrects for the severity of disease at baseline. The mathematical analysis presented at the Alzheimer’s Association AD Prevention Conference demonstrates that this trial analysis methodology is mathematically equivalent to the “Staggered Start” and “Randomized Withdrawal” designs and provides the same level of evidence of a disease-modifying drug effect in a clinical trial that is not subject to the above-mentioned complications, bias and ethical challenges of the previous designs.

“We are excited about this persuasive mathematical comparison of clinical trial designs,” said Adrian Hobden, PhD, President of Myriad Pharmaceuticals, Inc. “We believe that this mathematical proof, coupled with the Flurizan trial design may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan.”

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 participants 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 whether the Flurizan Phase 3 study design may demonstrate disease modification; the Company’s use of the Natural History Staggered Start trial design and trial analysis methodology in its Flurizan Phase 3 clinical trials; the ability of the Natural History Staggered Start trial design and trial analysis methodology to provide the same level of disease modification support as the cross-over trial designs; the ability of the Natural History Staggered Start trial design and trial analysis methodology to demonstrate that this trial analysis methodology is mathematically equivalent to the “Staggered Start” and “Randomized Withdrawal” designs and provides the same level of evidence of a disease modifying drug effect in a clinical trial that is not subject to the complications, bias and ethical challenges of previous designs; the excitement of the Company about this persuasive mathematical comparison of clinical trial designs and the Company’s belief that this mathematical proof, coupled with the Flurizan trial design, may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan; the successful completion of the ongoing Flurizan Phase 3 trials; and whether the Flurizan Phase 3 trials results will demonstrate or support a claim of disease modification. 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.

Contact:
William A. Hockett
EVP, Corporate Communications
(801) 584-3600





 
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Posted by on June 12, 2007 in alzheimer's, genetics, myriad

 
 
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