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

描述(申请人提供)：自身免疫性内耳疾病(AIED)是一种鲜为人知的进行性感音神经性听力损失的病因，在大约60%的病例中可接受皮质类固醇治疗。由于未知的机制，这种反应会随着时间的推移而丢失。对于那些皮质类固醇抵抗的AIED患者，几乎没有其他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激素敏感的受试者上，因为他们更容易被识别为队列，并且被认为更有可能有炎症病因来调节他们的感音神经性听力损失。到目前为止，还没有对耐糖皮质激素的AYD患者进行有效的治疗干预。IL-1β是介导先天免疫反应的典型细胞因子。在其他自身免疫和炎症性疾病中，IL-1的表达决定了许多后来的适应性T细胞反应。我们有初步证据表明，在AED的皮质类固醇无反应者中，几个IL-1家族成员的调节异常，可能与类固醇抵抗有关。到目前为止，关于这种疾病中与类固醇耐药相关的机制的研究有限。我们的研究结果提供了在AEDI期开放临床试验中使用阿纳金拉阻断IL-1的理论基础，以确定阿纳金拉是否能改善这些患者的听力阈值。R21将允许在小规模上测试这一假设。如果在这些患者中能够证明阿纳金拉听力恢复的有效性(主要里程碑)，我们建议在更大的皮质类固醇抵抗型AED患者队列中验证阿纳金拉的使用(R33期)。 公共卫生相关性：免疫介导性听力损失的患者通常使用皮质类固醇治疗。然而，在接受治疗的患者中，大约60%的人有反应，但随着时间的推移，这种反应可能会消失。到目前为止，使用的其他疗法在改善听力方面基本上是无效的。本申请提出了一项阿纳金拉的I期开放式临床试验，用于皮质类固醇耐药患者，以确定该疗法在听力恢复方面是否有效。

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.