Background

This retinoid drug is approved by the FDA and EMA to treat T cell lymphoma of the skin. It is an agonist of a nuclear transcription factor called retinoid X receptor, which forms heterodimers with peroxisome proliferator-activated receptor γ (PPARγ) or liver X receptors (LXRs) to aid in the formation of ApoE lipoprotein particles. In 2012, bexarotene was reported to rapidly increase brain ApoE concentration, reduce interstitial fluid Aβ levels and amyloid deposition, and reverse cognitive deficits in APP/PS1 mouse models (Feb 2012 news). Subsequent studies, using the same or different rodent models and outcome measures, replicated only portions of the original findings (May 2013 news; Laclair et al., 2013; O'Hare et al., 2016). Other preclinical studies have implicated bexarotene in ApoE lipidation, reported ApoE isoform-specific effects, or postulated that bexarotene dampens network hyperexcitability (May 2014 news; Sep 2014 news; Bomben et al., 2014).

Findings

In 2014, a Phase 2 biomarker proof-of-concept study at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas evaluated the effect of a one-month blinded course of 300 mg bexarotene per day, followed by another month of open-label treatment. The primary outcome was brain amyloid load in 20 patients with probable Alzheimer's disease. Results published in January 2016 indicated no reduction in overall or regional amyloid burden in the group as a whole. A prespecified subgroup analysis by ApoE genotype found no amyloid reduction in ApoE4 carriers, but in ApoE4 noncarriers it did find regional amyloid reductions. These correlated with elevated serum Aβ42. Bexarotene-treated patients had significantly elevated blood lipid levels, a risk factor for stroke and heart attack (Cummings et al., 2016).

Also in 2014, a Phase 1 proof-of-mechanism pilot study conducted by ReXceptor Inc. and C2N in Orlando, Florida, began. It measures generation and clearance of newly generated CSF Aβ and ApoE in response to a five-day course of 450 mg bexarotene per day. This study enrolled 12 young healthy adults who are homozygote ApoE3 carriers. It found that bexarotene poorly entered the central nervous system. The plasma to CSF ratio was 85:1, with bexarotene below the limit of quantitation in most CSF samples. CSF ApoE increased by one-quarter, but Aβ peptides did not change (Ghosal et al., 2016).

For all bexarotene Alzheimer trials, see clinicaltrials.gov.