[I7-2.001] IRX4204: A Clinical Stage, Potent, and Highly Selective RXR Agonist Compound Is Brain Penetrant, and Promotes Differentiation of Oligodendrocyte Precursor Cells (OPCs) In Vitro
Martin E. Sanders,1Satish Medicetty,2Rosh Chandraratna3
1HIllsborough, CA, USA, 2Cleveland, OH, USA, 3Santa Ana, CA, USA
Background: IRX4204 is a potent and highly selective small compound agonist of the RXR nuclear receptors. IRX4204 transactivates RXR α, β, and γ homodimers with EC50s less than 1 nM. IRX4204 also activates RXR/Nurr1 heterodimers with EC50 less than 1 nM, but does not activate RXR heterodimers with RAR, PPARγ, LXR, or FXR. IRX4204 is a clinical stage experimental therapeutic for various cancers. To date it has been administered to 61 patients with prostate, lung, and other cancers. The drug has been safe and well tolerated for up to 20 months of treatment, and has demonstrated evidences of targeted anti-cancer effects. IRX4204 is well absorbed, and has pharmacokinetics consistent with once per day oral dosing to humans. Methods: To assess IRX4204 as a potential treatment for MS, we evaluated its brain penetrance in healthy rats administered the compound orally once daily for 28 days. To assess IRX4204's potential for promoting myelin repair, we studied its effects on differentiation of OPCs into oligodendrocytes in vitro. Results: IRX4204 was highly brain penetrant, resulting in an approximately 1:1 ratio of concentrations of the compound in plasma versus brain tissue over the entire treatment course. IRX4204 promoted differentiation of OPCs into oligodendrocytes as demonstrated by increase in proteolipid protein, a major myelin protein. There was a dose-dependent increase in differentiation of OPCs into oligodendrocytes, including at concentrations as low as 0.1 nM. It had no adverse effect on viability of OPCs. Conclusions: IRX4204 penetrates the blood brain barrier following oral administration, and promotes differentiation of OPCs into oligodendrocytes in vitro. IRX4204 is a promising clinical stage experimental treatment for MS, having brain penetrance and a potentially myelin reparative mechanism of action.
Category - MS and CNS Inflammatory Disease: Clinical Science
Wednesday, April 30, 2014 5:30 PM
I7: INS Data Blitz: Emerging Therapeutic Advances in Multiple Sclerosis (2:00 PM-6:00 PM)