A novel glycan-based selectin and complement inhibitor for at-home disease-modifying rescue of pain crisis in sickle cell disease

镰状细胞病（SCD）是一种毁灭性的疾病，被广泛认为是其标志性的疼痛危象或血管闭塞事件（VOE）。目前缺乏有效的疾病改善治疗方法，一旦VOE开始，阿片类药物的疼痛管理仍然是标准的护理，试图掩盖使人衰弱的疼痛。再加上持续的阿片类药物危机，这导致SCD患者在寻求医疗服务时被视为“药物寻求者”，从而削弱了对医疗保健系统的信心，并使SCD患者试图自己管理VOE。此外，大量的VOEs和长时间的阿片类药物使用导致超过50%的SCD成年患者每天都有慢性疼痛。急性和慢性疼痛对SCD患者的影响是深远的，并反映在疾病负担统计中，SCD负担超过了阿尔茨海默病、乳腺癌和结直肠癌、艾滋病毒/艾滋病、白血病和中风。迫切需要一种有效的改善VOE疾病的治疗方法，解决其导致疼痛的复杂潜在通路机制。因此，我们正在开发IHP-102，这是一种用于在家自我管理VOE的疾病改善治疗方法，从而增强患者的能力，并使其远离疾病。IHP-102是一种新型的糖基治疗药物，具有多效性，针对多种通路机制，包括p -选择素和补体。解决结构性障碍对于真正影响患者至关重要；因此，IHP-102的目的是在VOE症状最早发作时进行家庭自我给药，从而绕过设备落后的医疗保健系统。这一治疗方案纳入了来自SCD社区的直接反馈，代表了一种重大的范式转变，将彻底改变SCD护理，并减轻疾病负担。我们已经证明IHP-102抑制p -选择素介导的细胞结合，抑制补体介导的细胞裂解，并在Townes SCD小鼠VOE模型中减少75%的血管闭塞。IHP-102与其他已批准或正在开发的SCD药物高度不同，具有多效性生物活性和基于家庭的治疗模式。在拟议的工作中，我们将利用SCD疼痛模型来建立IHP-102的治疗潜力和临床翻译的稳健性。我们还将扩大GMP生产并开展IND研究，从而进行首次人体i期临床试验。本文提出的目标的成功完成将显著推进IHP-102的临床发展，并有助于实现其作为非阿片类药物缓解疼痛、持续时间和相关并发症的整体解决VOE的潜力。

Sickle cell disease (SCD) is a devastating condition that is widely recognized for its hallmark pain crisis or vaso- occlusive events (VOE). There is currently a lack of effective disease-modifying therapies for VOE once it has begun, and pain management with opioids remains the standard of care in attempt to mask the debilitating pain. Combined with the ongoing opioid crisis, this has led to SCD patients being treated as ‘drug-seekers’ when seeking medical care, thus eroding confidence in the healthcare system, and leaving individuals with SCD to attempt to manage VOE on their own. Furthermore, numerous VOEs and prolonged opioid use lead to daily chronic pain in over 50% of adults with SCD. The resulting impact of acute and chronic pain on individuals with SCD is profound and is reflected in burden of disease statistics where SCD burden exceeds Alzheimer’s disease, breast and colorectal cancer, HIV/AIDS, leukemia, and stroke. An effective disease-modifying treatment for VOE that addresses its complex underlying path mechanisms that lead to pain is urgently needed. We are therefore developing IHP-102, a disease-modifying treatment for at-home self-management of VOE, thus empowering patients and providing significant freedom from disease. IHP-102 is a novel glycan-based therapeutic with pleiotropic activity that targets multiple path mechanisms of VOE, including P-selectin and complement. Addressing structural barriers is critical for true patient impact; therefore, IHP-102 is intended for home-based self-administration at the earliest onset of VOE symptoms, thus circumventing the largely ill-equipped healthcare system. This treatment profile incorporates direct feedback from the SCD community and would represent a major paradigm shift that would revolutionize SCD care and provide significant burden from disease. We have shown that IHP-102 inhibits P-selectin mediated cell binding, inhibits complement-mediated cell lysis, and reduces vaso-occlusions by 75% in the Townes SCD mouse model of VOE. IHP-102 is highly differentiated from other SCD drugs approved or in development, both with its pleiotropic biological activity and in its home- based treatment paradigm. In the proposed work, we will utilize SCD pain models to build robustness to the therapeutic potential and clinical translation of IHP-102. We will also scale up to GMP manufacturing and perform IND enabling studies, resulting in a first-in-human Phase 1 clinical trial. Successful completion of the aims proposed here will significantly advance the clinical development of IHP-102 and help to realize its potential to holistically address VOE as a non-opioid approach to alleviate pain, duration, and associated complications.