17 December 2009. Tarenflurbil, aka flurizan, a γ-secretase modulator that showed promise in early preclinical and clinical trials, failed in Phase 3, as reported in the December 16 JAMA. The results will come as no surprise to those following the flurizan saga. Alzforum previously covered the Phase 3 data when they were presented at ICAD last year (see ARF related news story). Writing in JAMA for the Tarenflurbil Phase 3 Study Group, Robert Green, Boston University School of Medicine, and colleagues confirm that the drug had no statistically significant effect in co-primary outcome measures of cognition and activities of daily living.
The 18-month, randomized, placebo-controlled, double-blind trial was carried out at 133 centers in the U.S. Patients were administered placebo, 400 mg, or 800 mg of the drug twice daily. After analysis of earlier Phase 2 trial data, the Phase 3 trial was modified, with the approval of the FDA, such that only the highest dose was administered and only to patients with mild AD; patients with moderate AD were dropped from the trial. In the final analysis there was no difference between treatment and placebo arms in either the co-primary outcomes (the ADAS-Cog 80-point version and the ADCS activities of daily living scale) or a range of secondary outcomes that included measures of function (the CDR sum-of-boxes), cognition (the MMSE), psychopathology (Neuropsychiatric Inventory), quality of life (QQL-AD), and caregiver burden.
This was the first Phase 3 trial of a γ-secretase modulator, a class of drugs designed to shift the proteolytic profile of the enzyme away from the longer Aβ42 and toward shorter, less-amyloidogenic species, such as Aβ37 or Aβ38, rather than blocking the enzyme completely. Blocking γ-secretase cleavage of other transmembrane proteins, including Notch, can lead to intolerable side effects.
It is not clear why the trial failed, but Thomas Montine, University of Washington, Seattle, and Eric Larson, Group Health Research Institute, also in Seattle, list some potential reasons in an accompanying JAMA editorial. They suggest that the drug may not have achieved the concentration in the brain necessary to modulate the secretase, a possibility that may never be proven one way or the other, since the trial did not measure CSF Aβ levels. An earlier, 21-day study lends credence to this idea, however, finding that up to 800 mg of the drug twice daily failed to reduce Aβ42 in plasma or CSF (see Galasko et al., 2007). Montine and Larson also expressed a slightly more disheartening explanation for the trial’s failure. “Commonly used experimental models of Alzheimer disease may inadequately reflect the complexity of cognitive impairment and dementia in older patients and thereby provide falsely promising leads.” If true, then that could spell trouble ahead for other AD trials.—Tom Fagan.
Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH for the tarenflurbil Phase 3 Study Group. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease. A randomized controlled trial. JAMA 2009 December 16;302:2557-2564. Abstract
Montine TJ, Larson EB. Late-life dementias. Does this unyielding global challenge require a broader view? JAMA 2009 December 16;302:2593-2594. Abstract