A phase I clinical trial of Anakinra for Steroid-Resistant AIED

自身免疫性内耳疾病（AIED）是一种进展性感音神经性听力损失的病因学，目前对其了解甚少，约60%的病例可接受皮质类固醇治疗。由于未知的机制，这种反应随着时间的推移而消失。对于那些抗皮质类固醇的AIED患者，很少有治疗方案能有效地恢复或维持听力。大多数关于AIED患者的研究都集中在皮质类固醇反应的受试者上，因为他们更容易被识别为一个队列，并且被认为更有可能有炎症病因介导他们的感音神经性听力损失。迄今为止，对皮质类固醇抵抗的AIED患者尚无有效的治疗干预措施。IL-1是介导先天免疫反应的典型细胞因子。IL-1的表达决定了许多其他自身免疫性疾病和炎症性疾病的后期适应性t细胞反应。我们有初步证据表明，一些IL-1¿家族成员在AIED的皮质类固醇无反应患者中被异常调节，并可能导致类固醇抵抗。迄今为止，关于这种疾病中类固醇抵抗的相关机制的研究有限。我们的研究结果为Anakinra阻断IL-1治疗皮质类固醇耐药（无反应）AIED患者提供了基本原理，作为I期开放标签临床试验，以确定使用Anakinra是否可以改善这些患者的听力学阈值。R21将允许在小范围内测试这一假设。如果在这些患者（主要里程碑）中可以显示阿那白拉听力恢复疗效的证据，我们建议在更大的皮质类固醇耐药AIED患者（R33期）中验证阿那白拉的使用。

DESCRIPTION (provided by applicant): Autoimmune Inner Ear Disease (AIED) is a poorly understood etiology of progressive sensorineural hearing loss that is amenable to corticosteroid therapy in approximately 60% of cases. This response is lost over time due to unknown mechanisms. For those corticosteroid resistant AIED patients, few therapeutic alternatives are effective to restore or maintain hearing. The majority of studies on AIED patients have focused on corticosteroid responsive subjects as they have been easier to identify as a cohort, and are believed to be more likely to have an inflammatory etiology mediating their sensorineural hearing loss. To date, no effective therapeutic intervention exists for corticosteroid-resistant patients with AIED. IL-1¿ is the quintessential cytokine that mediates the innate immune response. Expression of IL-1¿ dictates many of the later adaptive T-cell responses in other autoimmune and inflammatory disorders. We have preliminary evidence that several IL-1¿ family members are aberrantly regulated in corticosteroid non- responders with AIED, and may contribute to steroid resistance. To date, there have been limited studies on the mechanisms related to steroid resistance in this disorder. Our findings provide the rationale for IL-1 blockade with Anakinra in corticosteroid resistant (non-responders) patients with AIED as a phase I open label clinical trial to determine if use of Anakinra can improve audiometric thresholds in these patients. The R21 will permit testing the hypothesis on a small scale. If evidence of efficacy for hearing restoration with anakinra can be shown in these patients (primary milestone), we propose to validate the use of anakinra in a larger cohort of corticosteroid resistant AIED patients (R33 phase). PUBLIC HEALTH RELEVANCE: Patients with immune mediated hearing loss are typically treated with corticosteroids. Of those treated, approximately 60% respond, however, that response may be lost over time. Other therapies use to date have proven largely ineffectual in improving hearing. This application proposes a phase I open label clinical trial of Anakinra for corticosteroid- resistant patients to determine if this therapy is efficacious in hearing restoration.