Multiple Sclerosis (MS) is a chronic progressive debilitating autoimmune disease of the CNS affecting ~400,000 patients in the US. Acute flares of MS are treated with corticosteroids, but corticosteroids are not disease-modifying. Although several biologics and drugs are approved in the US for chronic disease-modifying treatment of MS, none completely inhibits disease progression, and all have significant toxicities or safety issues. Thus, MS remains a serious debilitating disease with significant unmet medical need for safer and more effective treatments, especially for treatments with mechanisms of action other than, or in addition to immunomodulatory mechanisms; such as mechanisms directly effecting neuroprotection, and/or promoting myelin protection or repair. Io Therapeutics is developing IRX4204 to treat MS because it has substantial preclinical data indicating it has potential to be effective in the treatment of MS patients by multiple mechanisms of action, including immunomodulation, neuroprotection, and myelin protective/reparative effects. IRX4204 is a synthetic orally available compound, which is a potent and highly selective agonist for the RXR nuclear receptors. The compound is distinctive from the only currently approved RXR agonist (bexarotene), in that it is approximately 100-fold more potent as an RXR agonist than bexarotene, with RXR activation occurring at sub-nanomolar (nM) concentrations, and maximal RXR activation occurring at approximately 1 nM for all three RXR isoforms. IRX4204 at pharmacologic concentrations is devoid of activity at RAR, PPAR, FXR, and LXR nuclear receptors, which are activated by bexarotene. IRX4204 transactivates RXR/Nurr1 and RXR/Nur77 heterodimers at sub-nM concentrations. These RXR heterodimers are implicated in its activities on immune system and CNS. We have already tested IRX4204 in humans with cancer or Parkinson?s disease under two US INDs, and it has been shown to be well tolerated and safe for administration to humans with chronic neurodegenerative disease. The unique pharmacologic activities of IRX4204, combined with its human clinical data demonstrating safety following chronic administration, and oral pharmacokinetics consistent with once daily oral dosing, has substantially diminished the risk of IRX4204 as an advanced clinical stage therapeutic candidate for MS. This application is seeking funds to advance the development of IRX4204 into Phase 2 randomized, blinded, and controlled efficacy trials in MS patients. Prior to conducting chronic clinical trials in MS patients, the company must perform six month GLP toxicology studies in rats and dogs. These are required to meet ICH and FDA guidelines for administration of an experimental compound to humans for six months or longer. Per company discussions with the FDA, chronic toxicology studies of six months duration in rats and dogs are the only unmet requirements for advancing IRX4204 into the chronic controlled phase 2 clinical trials to provide preliminary evidence of clinical efficacy in MS patients, and patients with other types of neurodegenerative diseases.

Public Health Relevance

Our studies focus on the development of a novel, orally available small molecule drug, IRX4204, to treat Multiple Sclerosis (MS). Extensive preclinical testing supports that IRX4204 may be effective for the treatment of MS by multiple mechanisms of action, including novel effects on the immune system, protective effects on neurons, and protective or reparative effects on the myelin sheaths surrounding neurons and IRX4204 has already been shown to be safe and well tolerated in long term studies in humans having cancer, and in a short term study in patients with early Parkinson?s disease. Upon completion of the proposed 6 month toxicology studies in rats and dogs, the company plans to conduct rigorous testing of the safety and efficacy of chronic administration of IRX4204 in controlled clinical trials in both relapsing-remitting, and progressive MS patient populations, treated with the drug for six months or longer, i.e., studies of sufficient duration to demonstrate clinical efficacy in these MS patient populations.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1)
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Minnicozzi, Michael
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Io Therapeutics, Inc.
Santa Ana
United States
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