A drug that inhibits the formation of neurotoxic amyloid-β42 peptides slowed functional decline in patients with mild Alzheimer's disease by 46%, Dr. Gordon K. Wilcock and his colleagues have reported.
Patients who took the drug for 24 months fared significantly better than did those who switched to it after a year on placebo, prompting the investigators to conclude that tarenflurbil is truly a disease-modifying agent. “The randomized-start analysis suggests that, in patients with mild [Alzheimer's disease], treatment for 24 months resulted in greater benefit than did delayed treatment for 12 months,” they wrote. “This smaller benefit in a delayed-start group is consistent with modification of the underlying disease process rather than a purely symptomatic effect” (Lancet Neurol. 2008;7:483–93).
Although tarenflurbil showed no significant functional or cognitive benefit for those with moderate disease, its benefit for early Alzheimer's disease (AD) patients raises hopes that an effective disease-modifying agent might be in the offing. A phase III trial of the drug was set to wrap up this spring, and the results are eagerly awaited, Dr. Paul Aisen of the University of California, San Diego wrote in an accompanying commentary (Lancet Neurol. 2008;7:468–9). “In a few months, we will learn whether tarenflurbil will be the first anti-amyloid strategy to be efficacious in a pivotal trial,” wrote Dr. Aisen.
The study took place in 31 sites in Canada and the United Kingdom from November 2003 to April 2006. Dr. Wilcock of the University of Oxford, England, and his colleagues randomized 210 patients with mild to moderate Alzheimer's disease to one of three treatment regimens: tarenflurbil 400 mg twice daily, tarenflurbil 800 mg twice daily, or placebo.
After 12 months, 86 patients were included in a 12-month extension trial. In this study, patients taking the study drug continued on their respective regimens, while those taking placebo were randomized into the two active treatment arms.
Both trials included patients who had been stable on anticholinesterase drugs for at least 3 months prior to the study. All participants were assessed using the Alzheimer's Disease Assessment Scale, cognitive section (ADAS-cog), the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating (CDR) sum of box score. The patients' mean age was 74 years; the mean Mini-Mental State Examination score was 21. About 95% were taking anticholinesterase drugs. Mild Alzheimer's was present in 130 patients at baseline, while the rest had moderate-stage disease.
Neither dosage of the study drug had any beneficial effect on patients with moderate AD, Dr. Wilcock and his coinvestigators said. In fact, after 12 months, those taking placebo actually fared better than those taking the higher dosage of tarenflurbil did. “In this group, treatment with placebo was associated with a significantly lower rate of decline in global function than was 800 mg tarenflurbil,” the authors wrote.
Patients with mild disease responded much better to the drug. Compared with patients on placebo, those taking the 1,600- mg/day dosage experienced a 46% lower rate of decline on the ADCS-ADL and a 36% lower rate of decline on the CDR–both significant differences. While there was a trend toward a slower rate of cognitive decline (34% lower, compared with placebo), the difference did not reach statistical significance.
Global function was also assessed as an exploratory outcome measure with the clinician interview-based impression of change plus caregiver input. In this analysis, 31% of the patients taking the 1,600-mg/day dosage showed improved or unchanged function at 12 months, compared with only 19% of patients taking placebo.
After the initial 12-month study, 86 Canadian patients were enrolled in the 12-month extension study. Again, there were no significant beneficial effects in patients with moderate disease. However, compared with those on placebo, those taking 1,600 mg/day had significant slowing of decline in all three outcome measures: 44% less decline on the ADCS-ADL, 38% less decline on the CDR, and 61% less decline on the ADAS-cog.
There were five deaths in the first study; none was associated with the study drug.
Tarenflurbil is a selective amyloid-lowering agent (SALA). It works by changing the point at which the enzyme γ-secretase cleaves the amyloid-β protein. This prevents the formation of the toxic longer-chain amyloid-β42. SALAs such as tarenflurbil are designed to reduce soluble amyloid-β levels, with the aim of preventing plaque formation.
The drug was previously named R-flurbiprofen. Results of the phase II trial were initially reported at the July 2006 International Conference on Alzheimer's Disease. Dr. Wilcock is a paid investigator for Myriad Pharmaceuticals, the Salt Lake City company that funded the study.