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.”