Bexarotene in Alzheimer’s Disease: A case of lack of replication, lack of replication, lack of replication

In a previous blog (see here) we briefly discussed drug repositioning as an alternative approach to identifying novel therapies for Alzheimer’s disease. This strategy follows in the wake of the recent failures last year of the large Phase 3 trials with Bapineuzumab and Solineuzumab. At the forefront of drug repositioning has been Baxter International’s Gammagard which is one of a number of IVIG (intravenous immunoglobulin; obtained from the pooled plasma of healthy volunteers) treatments approved for boosting the immune system. Based on an initial small, 18-month, 24-patient study in which Alzheimer’s patients appeared to respond to the therapy (see here), Phase 3 studies were initiated. However, hopes were never especially high given that the proposed mechanism – infused antibodies would help clear amyloid peptide and/or tau protein – was vague at best and was not based upon preclinical mechanistic studies. Unfortunately these doubts proved warranted when in early May, a press release from Baxter (see here) disclosed that Gammagard had failed it’s primary endpoints and as a result it became yet another casualty in the Alzheimer drug development mine field.

In contrast to Gammagard, for which there is a marked absence of preclinical data to support its use in Alzheimer’s disease, a paper from Cramer and colleagues made quite a splash when it was published in Science in early 2012 (see here). They described how the Eisai skin cancer drug Bexarotene (marketed as Targretin) enhanced the clearance of amyloid and improved cognitive performance in preclinical animal models. Bexarotene was approved by the FDA in December of 1999 for the treatment of refractory cutaneous T-cell lymphoma and in the aftermath of the Science publication, doctors were inundated with requests for “off-label” prescriptions of Bexarotene for the treatment of Alzheimer’s patients (see here, for example). Although perfectly legal, the off-label prescribing of Bexarotene raises separate issues of patient safety and ethics (as discussed in the New England Journal of Medicine), especially since the clamour for Bexarotene was based on preliminary evidence from a single study. Indeed, recent studies have failed to replicate important aspects of the initial report (see here, here, here and here, with the authors response here). Most notably, although some inconsistent effects on amyloid peptide concentrations and cognitive improvements were observed, there was a failure to replicate the reduction in amyloid plaques reported in the initial study. These studies highlight the difficulty in reproducing preclinical data, a topic illustrated very well by the Bayer group (see here). Obviously, the publication of a single article, albeit in an august journal such as Science, should be treated with caution until it is replicated. Nevertheless, clinical studies have commenced and the effects of Bexarotene are being studied in the clinic in a Phase Ib biomarker study in healthy young adults as well as in Alzheimer’s disease patients in a Phase 2 [18F]AV-45 amyloid imaging trial. It is a sobering reflection on the large unmet need in Alzheimer’s disease that despite all the caveats and with the limitations highlighted even within the popular press (e.g. “A huge caveat here is that many promising drugs seem to work in mice but fail when used in humans”, Forbes magazine, 10th of February, 2012), a single publication can create a demand for the off-label use of a drug that is has significant side-effects but for which there is, as yet, no evidence of clinical efficacy in Alzheimer’s disease.

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