Treatment of Complement-Mediated Myelitis

摘要 我们打算开发我们的主要候选药物，作为一种有效、有效和改善疾病的治疗方法。 孤儿病，神经脊髓炎视神经频谱障碍(NMOSD)，预计疗效远远优于 目前的单一疗法，Soliris(Eculizumab)。Soliris被批准用于治疗NMOSD，非典型 尿毒症综合征(AHUS)和重症肌无力(MG)。从机制上讲，Soliris既阻挡了经典(CP) 补体的替代途径(AP)。2019年，FDA批准了这一广谱 NMOSD的补体阻滞剂，尽管它对替代途径(AP)没有选择性，已被 被认为是该病中脑细胞死亡的唯一机制。索利斯机械论 阻断经典通路(CP)令人担忧，因为治疗可能会使患者容易患上 继发性细菌和病毒感染。Soliris的使用继续扩大，成为缓解疾病的唯一治疗手段。 与NMOSD相关的病理学。 我们的临床候选药物NM5072是AP的选择性抑制剂，因此不会损害CP 激活。通过选择性地阻断AP的上游，产生两种最关键的促炎因子 C3a和C5a分子被抑制。在这种药物的开发过程中取得的进展已经建立了许多 益处，包括：a)缺乏CP抑制，b)抑制AP的效力，c)成功的毒理学研究，d) 在健康志愿者身上完成了成功的I期临床试验。总的来说，这些都实现了 里程碑为作为治疗NMOSD的治疗药物的临床成功提供了信心。总而言之， 我们的药物在正常人血清中的初步非临床数据和健康人的I期试验结果 志愿者，复制我们的体外和体外研究结果：在最低剂量为1 mg/kg时，该药物可阻断AP在 一种剂量依赖的方式，所有这些都维持CP活性。选择性阻断AP，剂量为1 mg/kg 人类进一步证实了这种药物比Soliris更优越的治疗效力。另一个显著的优势是 我们的新药是，它不需要加载剂量就能达到治疗水平，证明了 这种药物的使用也是患者友好的。 水通道蛋白-4(AQP4)-Ig G阳性的患者被正式诊断为NMOSD。在这份提案中， 我们概述了我们使用流式细胞术方法对NMOSD样本进行评估性筛选的策略 由肖恩·皮托克博士的实验室开发，用于选择AQP4-IgG阳性的个体。这些 血清样本将用我们的AP/CP和转换酶试验进一步鉴定，以确定NM5072‘S AP/CP激活的选择性和体外补体抑制的程度。接下来，我们的目标是 使用NMOSD血清进行组织交叉反应研究，以评估组织结合。最后，我们将跟随 对恒河猴进行为期3个月、每周12次的重复剂量毒理学研究，以支持未来的多剂量 在人类身上的研究。鉴于我们的主要候选药物的独特作用机制和人体内对 阻断AP，我们相信我们的药物将为NMOSD的治疗提供特殊的治疗效果。

ABSTRACT We intend to develop our lead drug candidate as a potent, efficacious, and disease-modifying treatment for the orphan disease, Neuromyelitis Optica Spectrum Disorder (NMOSD), with efficacy anticipated to be far superior to the current monotherapy, Soliris (eculizumab). Soliris is approved for the treatment of NMOSD, atypical uremic syndrome (aHUS), and Myasthenia Gravis (MG). Mechanistically, Soliris blocks both the classical (CP) and the alternative pathways (AP) of complement. In 2019, the FDA approved this broad-spectrum complement blocker for NMOSD, despite its non-selectivity to the alternative pathway (AP), which has been implicated as the sole mechanism for cellular death of the brain cells in the disease. Soliris' mechanistic blockade of the classical pathway (CP) is concerning, given that treatment may render patients vulnerable to secondary bacterial and viral infections. Use of Soliris continues to expand as a sole means of therapy for relief of NMOSD-related pathology. Our clinical drug candidate, NM5072, is a selective inhibitor of the AP and therefore does not impair CP activation. By selectively blocking the AP upstream, the production of the two most critical pro-inflammatory molecules, C3a and C5a, is inhibited. Progress during development of this drug has established numerous benefits, including; a) lack of CP inhibition, b) potency in AP inhibition, c) successful toxicology studies, and d) completion of a successful phase I clinical trial in healthy volunteers. Collectively, these accomplished milestones offer confidence in clinical success as a therapeutic drug for treatment of NMOSD. Collectively, preliminary non-clinical data of our drug in normal human serum and results from the phase I trial in healthy volunteers, replicate our in vitro and ex vivo findings that at a 1mg/kg minimum dose, the drug blocks the AP in a dose-dependent manner, all while sustaining CP activity. Selective blockade of the AP at a 1 mg/kg dose in humans further confirms this drug's superior therapeutic potency over Soliris. Another significant advantage of our new drug is that it does not require a loading dose to reach therapeutic levels, demonstrating that administration of this drug is also patient-friendly. Patients who exhibit positivity to Aquaporin-4 (AQP4)-IgG are officially diagnosed as NMOSD. In this proposal, we outline our strategy in evaluative screenings of NMOSD samples using the flow cytometry methods developed by Dr. Sean Pittock's laboratory to select those individuals who are positive AQP4-IgG. These serum samples will be further characterized using our AP/CP and convertase assays to determine NM5072's selectivity of AP/CP activation and the extent of complement inhibition in vitro. Following this, we aim to conduct tissue cross-reactivity studies using the NMOSD serum to assess tissue binding. Finally, we will follow up with a 3-month 12-weekly repeat-dose toxicology study in rhesus monkeys to enable future multi-dose studies in human. Given the unique mechanism of action of our lead drug candidate and in-human potency for blocking the AP, we believe that our drug will provide exceptional therapeutic benefits for treatment of NMOSD.