Development of the RXR agonist IRX4204 to treat Multiple Sclerosis and other Immune related Diseases

开发 RXR 激动剂 IRX4204 用于治疗多发性硬化症和其他免疫相关疾病

基本信息

批准号：
9201916
负责人：
Rosh Chandraratna
金额：
$ 85.44万
依托单位：
IO THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-11 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201916
关键词：
Acute Adrenal Cortex Hormones Advanced Development Adverse effects Affect Agonist American Animal Model Autopsy Bexarotene Blinded Budgets CNS autoimmune disease Cancer Patient Canis familiaris Cardiovascular system Cells Chronic Chronic Disease Clinical Clinical Chemistry Clinical Data Clinical Research Clinical Trials Clinical Trials Design Controlled Clinical Trials Data Development Disease Disease Progression Disease remission Doctor of Philosophy Dose Drug Evaluation Drug Kinetics Evaluation Experimental Autoimmune Encephalomyelitis Flare Funding Future Gel Genes Goals Guidelines Health Hematology Human Immune Immune system Industry Inflammatory Interleukin-17 Japanese Population Laboratories Licensure Longitudinal Studies Malignant Neoplasms Medical Microscopic Modeling Multiple Sclerosis Mus Myelin Myelin Sheath Neurodegenerative Disorders Neurology Neurons Notification Nuclear Receptors Oligodendroglia Oral Oral Administration Organ Paralysed Parkinson Disease Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Preclinical Testing Process Production Progress Reports Protein Isoforms RXR Randomized Randomized Controlled Clinical Trials Rattus Receptor Activation Regulation Regulatory Affairs Regulatory T-Lymphocyte Relapse Research Risk Rodent SJL Mouse Safety Severity of illness Small Business Innovation Research Grant Social Welfare Specific qualifier value Staging Testing Therapeutic Time Tissues Toxic effect Toxicology United States National Institutes of Health Urinalysis base cancer type capsule clinical efficacy drug testing effective therapy efficacy trial experience immunoregulation in vivo meetings mouse model multiple sclerosis patient multiple sclerosis treatment nanomolar neuroprotection novel oligodendrocyte precursor patient population pre-clinical preclinical efficacy preclinical safety precursor cell protective effect receptor repaired research clinical testing respiratory safety study safety testing sex small molecule treatment duration

项目摘要

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.

多发性硬化症（MS）是一种慢性进行性衰弱的中枢神经系统的自身免疫性疾病美国〜40万名患者。 MS的急性耀斑用皮质类固醇治疗，但皮质类固醇不是疾病改良。尽管在美国批准了几种生物制剂和药物用于慢性疾病改良 MS的治疗，没有一个完全抑制疾病进展，并且都具有明显的毒性或安全性问题。这是MS仍然是一种严重的使人衰弱的疾病，对更安全和更有效的治疗方法，特别是对于具有其他作用机制的治疗，除了免疫调节机制；例如直接影响神经保护和/或促进的机制髓鞘保护或修复。 IO Therapeutics正在开发IRX4204来治疗MS，因为它具有很大的临床前数据表明它有可能通过多个有效地治疗MS患者作用机制，包括免疫调节，神经保护和髓磷脂受保护/修复作用。 IRX4204是一种合成的口服化合物，它是RXR的潜在和高度选择性的激动剂核受体。该化合物与当前唯一批准的RXR激动剂（Bexarotene），在与Bexarotene相比，它作为RXR激动剂的潜力大约高100倍，RXR激活发生在亚纳摩尔（NM）浓度下，最大RXR激活发生在大约1 nm处对于所有三个RXR同工型。药物浓度下的IRX4204没有RAR，PPAR的活性 FXR和LXR核接收器，它们被贝克索烯激活。 IRX4204反式激活RXR/NURR1和 RXR/NUR77异二聚体以亚NM浓度为单位。这些RXR异二聚体在其活动中实施在免疫系统和中枢神经系统上。我们已经在癌症或帕金森氏病的人类中测试了IRX4204 在美国两个IND下，它已被证明对人类的管理很容易且安全慢性神经退行性疾病。 IRX4204的独特药物活动，结合其人类临床数据证明了长期给药后安全性，口服药代动力学与一旦每天口服剂量，就大大降低了IRX4204作为晚期临床阶段的风险 MS的治疗候选人。该申请正在寻求资金，以将IRX4204的开发发展为 MS患者的2阶段随机，失明和受控的有效试验。在进行慢性临床之前在MS患者的试验中，该公司必须在大鼠和狗中进行六个月的GLP毒理学研究。这些都是需要符合ICH和FDA指南，以给人类实验化合物六几个月或更长时间。根据公司与FDA的讨论，持续六个月的慢性毒理学研究大鼠和狗是将IRX4204推进慢性控制阶段2的唯一未满足的要求临床试验提供了MS患者临床效率的初步证据，并且患有其他类型的患者神经退行性疾病。