Tarenflurbil: mechanisms and myths.

Alzheimer disease (AD), a serious neurodegenerative illness characterized by cognitive impairment and functional in-capacity, is thought to affect more than 26 million people worldwide, a number projected to expand to 106 million over the next several decades. The costs associated with this disease are estimated to be $25 billion, costs largely associated with the loss of independence and the need for care of these patients. It is no wonder that search for treatments is vigorous, with more than 700 trials registered on clinicaltrials.gov since 1997. One of the most common targets for treatment for AD is the manipulation of amyloid, which accumulates in the brain of those with the disease. One mechanism for this manipulation is the modulation of the enzyme γ-secretase, which may favor the production of a less toxic form of β-amyloid (Aβ). Tarenflurbil has demonstrated such activity in vitro and in in vivo animal studies, and it has shown relative safety in human trials. Hence, it was considered a viable candidate for phase 3 clinical trials in AD. The randomized placebo-controlled trial of tarenflurbil in patients with mild AD reported by Green et al1 is a well-conducted study of more than 1600 subjects with AD recruited from 133 sites across the United States. These investigators used a rigorous design and a long exposure period of 18 months. During the trial protocol, modifications were made (based on reanalysis of phase 2 data) consisting of shifting from 2 doses to a single high dose and modifying entry criteria to include only very mildly impaired subjects (with Mini-Mental State Examination [MMSE] scores of 20-26 inclusive). In the face of these modifications and the relatively long exposure period, most subjects (97%) were available for the primary analysis and the mean medication compliance rate was higher than 90%. It is therefore quite disappointing to see the dramatic lack of effect in the primary and secondary outcomes, with the exception of the Clinical Dementia Rating sum of boxes scores, which favored placebo. While so many things could go wrong in one of the few long trials that have been published to date, it appears that this cohort was typical of all that we know about patients with AD, with standard use of prescriptive cognitive enhancers, predictable decline in the placebo group in cognition, function, and behavior, no unusual adverse events, and no unreasonable loss to follow-up. We can therefore conclude with conviction that there was no benefit of tarenflurbil in this very typical group of patients with very mild AD. So why did this fail? Were there any data that should have limited enthusiasm to move to a phase 3 study? Was there false enthusiasm that moved this trial beyond the apparent data? There are several things to consider. The intent-to-treat analysis of the phase 2 study in mild to moderate AD demonstrated no significant benefit on the primary outcomes.2 Additional analyses that examined subgroups defined by MMSE scores identified a benefit in the group with the highest MMSE scores and a significant negative effect in several outcomes in those with lower MMSE scores. The decision to focus on this subgroup (mild) of a subgroup (mild to moderate) was solidified based on an analysis that demonstrated a differential treatment effect for the subgroup defined by a specific cut point on the MMSE. This approach to defining disease severity ex post facto identified a mild subgroup that demonstrated a benefit and a moderate subgroup that actually worsened. Dramatic differences in the direction of effect in subgroups seem biologically implausible. Should one suspect that at the shift of 1 point in an MMSE score, a patient was at risk for significant adverse effects with the agent that was otherwise beneficial? Could the results of the current trial suggest mathematical regression to the mean? The literature in clinical trials for the treatment of AD has many similar cases of failures in large trials that have based subject selection on a result in a subgroup of previous trials including acetylcarnitine, propentofylline, and most recently bapineuzumab. It would seem that the preliminary studies provided important information that forewarned of questionable effect, and further phase 2 testing might have been advisable before embarking on the “largest phase 3 trial to date.”1