Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW, Brunden KR, Wilson DA.
Response to comments on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models".
Science. 2013 May 24;340(6135):924-g.
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In our comments to Alzforum on 17 February 2012, we reported our failure to confirm the data of Cramer et al. in the APPSwFILon, PSEN1*M146L*L286V (5XFAD) mouse model of Alzheimer's disease. Mice were fed bexarotene 100 mg/kg/day for up to 50 days. We found no difference between test and control mice in a standard Morris water maze test, and no significant difference in the number of Aβ deposits. We did not publish these negative results, and only suggested that further in-depth investigation was indicated. That has now taken place with additional failures to confirm using other Tg mouse models. Given such data, it is difficult to be optimistic that bexarotene will be effective in treating AD.
Phase 2A Trial of Bexarotene in Patients with Alzheimer’s Disease
Cramer and colleagues (Cramer et al., 2012) reported the rapid reduction of soluble amyloid, as well as amyloid plaques, in two species of transgenic mice. The effect occurred over a period of only a few days and correlated with improved performance on murine cognitive tests. This report elicited substantial excitement in the scientific community, as the pathway by which bexarotene exerts its effects through the retinoid X receptors (RXR) has been subject to relatively little study and might represent a new avenue of therapy for Alzheimer’s disease (AD).
Attempts to reproduce this work (Fitz et al., 2013; Price et al., 2013; Tesseur et al., 2013; Veeraraghavalu et al., 2013) confirm some aspects of the original report and fail to replicate others. The two studies assessing memory (Fitz et al., 2013; Veeraraghavalu et al., 2013) both showed enhanced cognition following treatment with bexarotene. All studies showed target engagement with induction of ApoE isoforms and effects on ABCA1. Fitz and colleagues (Fitz et al., 2013) showed a remarkable effect on soluble Aβ, reducing the level of Aβ oligomers by 50 percent. None of the studies was able to reproduce the reported effect on fibrillar amyloid and plaque burden. Some studies cautioned against pursuing studies of bexarotene in AD patients (Tesseur et al., 2013; Veeraraghavalu et al., 2013).
The Cleveland Clinic Lou Ruvo Center for Brain Health has initiated a Phase 2A study of bexarotene in patients with AD. Patients with mild to moderate cognitive impairment or AD who have been verified by the presence of an amyloid burden on amyloid imaging are entered into a double-blind, randomized, placebo-controlled trial. One dose of bexarotene will be studied. The double-blind portion of the trial is one month in duration. The primary outcome is the reduction of plaque burden on amyloid imaging, and secondary outcomes include a variety of other biomarkers and clinical outcomes, including novel computerized assessments.
The implementation of a human clinical trial of bexarotene might be viewed as premature. Given the uniformly fatal nature of AD, the current absence of disease-modifying therapies, the preliminary evidence from animal models to AD, and the large available safety database indicate that a clinical trial of bexarotene in patients with AD is warranted. Preclinical studies provide preliminary information regarding construction of human clinical trials. The high rate of non-reproducibility of preclinical outcomes (Gunawardena) and the inconsistency exhibited by the available studies of bexarotene, even when conducted by expert experimentalists, are daunting. The variability of outcomes in these preclinical studies might function as a case study in the challenges of translating preclinical observations to clinical research. The utility of bexarotene for human AD can be resolved only by studying human AD. Studies of pharmacodynamics of the effects of bexarotene on ApoE in healthy controls will provide important biological information, but these effects might differ markedly from pharmacodynamics in AD where amyloid clearance, aggregation, and deposition are dramatically different from those in healthy volunteers.
A notable advantage of repurposing drugs approved for other indications that exhibit pharmacodynamic features relative to the treatment of AD is the safety data available on these agents. Bexarotene has been used in the treatment of many elderly patients with cutaneous T cell lymphoma since its approval. Moreover, AD patients and their caregivers have shown a high tolerance for side effects if treatments have promise of ameliorating their disease (Bearer et al., 2007). Thorough monitoring of both known and unknown side effects is required for responsible human clinical trials, and many safety measures are built into the clinical trial being performed at the Cleveland Clinic Lou Ruvo Center for Brain Health.
The clinical trial we are conducting will not solve the issue of whether bexarotene is a potential therapy for AD. It will not confirm or disprove any aspect of the amyloid hypothesis or the RXR pathway. It will resolve the issue of whether bexarotene given at a specific dose for a specific amount of time and measured with specific outcomes has measurable effects in patients with AD. This is the most information that any clinical trial can be expected to provide. A beneficial effect of bexarotene will be followed by further exploration of dose responses, the potential value of intermittent therapy to minimize toxicity, the testing of other agents with effects on RXR-related pathways, and optimization of a related molecule with a better adverse event profile. A negative outcome will be followed by a comprehensive review of dose and duration of therapy, optimal outcomes, and integration of emerging preclinical data.
The clinical trial being implemented at the Cleveland Clinic Lou Ruvo Center for Brain Health is a logical next step for exploring this potential pathway of therapy for AD. The trial is given increased urgency by the failure to produce disease-modifying effects through other approaches.
Like many others, our group was excited about the findings published by Gary Landreth's group (see Cramer et al., 2013) and we repeated the main experiments with short-term dosing of bexarotene in the mutant APPSWE/PS1ΔE9 mouse model. While the ABCA1 target was upregulated in APP/PS1 mice treated with bexarotene, this drug failed to attenuate Aβ plaques or fear-conditioning deficits. In addition, we are unable to replicate a robust and persistent fear-conditioning deficit in APPSWE/PS1ΔE9 mice even with an alternate, highly sensitive testing paradigm. Instead, we found significant gender differences present in plaque load and the fear-conditioning task, both primary measures used by Cramer et al.
Bexarotene has now been tested in several animal models of Aβ amyloidosis besides APPSWE/PS1ΔE9, including APP/PS1-21 and 5XFAD (Veeraraghavalu et al., 2013) and APPSWE/PS1ΔE9 with APOE3/4 allele knock-ins (Fitz et al., 2013). All have failed to replicate a change in soluble or plaque forms of Aβ in brain tissue, with the exception of a single positive finding from Verraraghavalu et al. that the non-pathogenic, soluble Aβ40 decreased after acute treatment with bexarotene in the 5XFAD mouse model, but not in the APPSWE/PS1ΔE9 or the APP/PS1-21 models. Fitz et al. reported a significant decrease in interstitial fluid Aβ levels, though this was not replicated in their ELISA analysis of brain tissue for soluble or insoluble Aβ.
Together, the array of published work on the effect of bexarotene on pathology and cognitive impairment in mouse models of Aβ amyloidosis produces no rigorous evidence that bexarotene is a suitable candidate for the treatment of Alzheimer’s disease.