Collins, Thomas R.
ARTICLE IN BRIEF
IRX4204, a retinoid X receptor-agonist studied for prostate cancer, also promotes differentiation of oligodendrocytes and the formation of regulatory T cells and inhibits the formation of TH 17 cells in vitro, suggesting its potential for myelin repair in multiple sclerosis.
Figure. TRANSACTIVAT...Image Tools
PHILADELPHIA—A compound that has been under study for prostate cancer also promotes differentiation of oligodendrocytes and the formation of regulatory T cells and inhibits the formation of TH 17 cells in vitro, suggesting it is worth further exploration as a possible multiple sclerosis (MS) treatment, researchers said here at the AAN Annual Meeting in April.
IRX4204 is a retinoid X receptor (RXR)-agonist that is highly specific to RXR and does not transactivate the retinoic acid receptors (RARs), avoiding some of the potential side effects associated with RAR agonists, said Martin Sanders, MD, the chairman and chief executive officer of Io Therapeutics, a small company based in Santa Ana, CA, that owns the drug and is exploring its potential applications.
Dr. Sanders and colleagues had researched the compound's effects in prostate cancer patients, finding it produced sustained decreases in prostate specific antigens.
Over 70 patients have been treated with IRX4204 in prostate and other cancer trials, Dr. Sanders said, and few drug related adverse events have been observed, he said.
“It's already been used in humans — and that's huge,” Dr. Sanders said. “We have treated patients for up to 20 months and they've tolerated the drug well.
“Our intent is to move this into clinical trials,” he added. “We'd like to do both relapsing and remitting and progressive MS clinical trials. We've got to figure out how to finance those.”
HISTORY OF DEVELOPMENT
In 2011, at another lab, researchers in Cambridge examined the transcriptional profile at the separate stages of spontaneous remyelination that follows demyelination in rodents, and found that the receptor RXR-gamma was differentially expressed during remyelination. They then found that knockdown of RXR-gamma inhibited oligodendrocyte differentiation in culture, showing that RXR-gamma helps differentiation of oligodendrocyte precursor cells.
Some of the work of Io Therapeutics springs from these findings.
In vitro studies by the company show that mouse oligodendrocyte precursor cells treated with IRX4204 produce significantly more oligodendrocytes than control cells, suggesting that the compound might promote myelin repair.
Researchers have also found that the compound enhanced the differentiation of Foxp3+ regulatory T (T-reg) cells in vitro. Moreover, when an RAR antagonist was added, the effect on the T-reg differentiation was not affected, suggesting that IRX4204's effects act strictly through the RXR receptor.
Researchers have also found that, in vitro, the compound suppresses the formation of TH 17 cells, which growing evidence suggests have a pathogenic role in MS.
In mouse models of MS, mice given IRX4204 had better EAE scores 13 days after treatment than those that were not given the drug. EAE scores measure the severity of experimental autoimmune encephalomyelitis, the mouse form of MS.
Taken together, the findings offer at least the potential of a drug that could help treat MS in several ways, through its effects on the immune system and by actually promoting remyelination.
QUESTIONS ABOUT THE APPROACH
After his presentation, Dr. Sanders was asked about whether a more direct way to address myelin repair would be to target the RXR gamma receptor specifically. He said that might be true, but would be very difficult to pull off.
“We know from an extensive amount of chemistry that was done that trying to design a compound that would fit selectively in the pocket of RXR gamma — and that would not fit also in the ligand binding pockets of the alpha and beta isoforms — is at the very least difficult, if not impossible,” he said.
Figure. DR. MARTIN S...Image Tools
“We are sort of crawling forward with the neurology world trying to figure out how to determine in humans whether or not this drug will be an effective treatment for promoting remyelination,” he said. “Our perspective is that it has enough [of an] immunomodulatory profile that it warrants evaluation in MS patients on that basis alone, but given its potential for being a dual action drug with both immunomodulatory and myelin reparative activities, it is a uniquely attractive therapeutic candidate for MS.”
Bruce Trapp, PhD, chair of the department of neurosciences at the Lerner Research Institute of the Cleveland Clinic, who heard the presentation, said the observations of the drug's effects so far merit more evaluation.
“The drug looks promising based upon in vitro studies,” he said. “It does have some advantages over other RXR/RAR inhibitors and appears to be well-tolerated by humans and it gets into the brain.”
“The next step is to test [this compound] in an in vivo model of remyelination,” Dr. Trapp said. “If that is positive, a phase 2 trial may be appropriate.”
Dr. Sanders said an animal model assessment of remyelination is in the plans.
“We do need, I believe, to do an animal model on myelin repair on one of the models that is not immune-system driven.”
LINK UP FOR MORE INFORMATION:
•. Huang JK1, Jarjour AA, Nait Oumesmar B, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci
•. AAN Annual Meeting Abstract: A Clinical Stage, Potent, and Highly Selective RXR Agonist Compound Is Brain Penetrant, and Promotes Differentiation of Oligodendrocyte Precursor Cells (OPCs) In Vitro: http://bit.ly/1pp0vis