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

一种新型基于聚糖的选择素和补体抑制剂，用于家庭缓解镰状细胞病疼痛危机

• 批准号: 10785873
• 负责人: John Paderi
• 金额: $ 258.91万
• 依托单位: IHP THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785873
• 关键词: Acute; Acute Pain; Acute pain management; Address; Adult; Affect; Alzheimer' s Disease; American; Animal Model; Behavior; Binding; Biological; Biological Assay; Biological Availability; Blood; Blood Vessels; Blood capillaries; Canis familiaris; Caring; Cell Adhesion; Cells; Chronic; Clinical; Clinical Research; Colorectal Cancer; Communities; Complement; Complement Inactivators; Complex; Cytolysis; Development; Disease; Dose; Early Intervention; Endothelium; Erythrocytes; Event; Expectancy; Feedback; Freedom; Functional disorder; Guidelines; HIV/AIDS; Healthcare Systems; Home; Individual; Ischemia; Lead; Life; Marketing; Masks; Mediating; Medical; Methods; Opioid; Organ; P-Selectin; Pain; Pain management; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polysaccharides; Qualifying; Rattus; Safety; Selectins; Self Administration; Self Management; Sickle Cell Anemia; Specific qualifier value; Stroke; Symptoms; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Work; analytical method; burden of illness; cell type; chronic pain; clinical development; clinical translation; commercialization; debilitating pain; design; effective therapy; empowerment; first-in-human; hemoglobin polymer; hydroxyurea; leukemia; malignant breast neoplasm; manufacture; manufacturing scale-up; mouse model; new therapeutic target; non-opioid analgesic; novel; opioid epidemic; opioid use; pain behavior; pain model; pain reduction; pain self-management; patient-level barriers; scale up; sickling; side effect; standard of care; statistics; subcutaneous; symptom management; tissue injury

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.

镰状细胞病（SCD）是一种破坏性疾病，其标志性疼痛危象或血管闭塞事件（VOE）被广泛认可。目前，一旦VOE开始，就缺乏有效的疾病修饰疗法，并且使用阿片类药物进行疼痛管理仍然是试图掩盖衰弱疼痛的护理标准。再加上持续的阿片类药物危机，这导致SCD患者在寻求医疗保健时被视为“寻求药物者”，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，许多VOE和长期使用阿片类药物导致超过50%的SCD成人每日慢性疼痛。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数据中，其中SCD负担超过阿尔茨海默病，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VOE疾病修饰治疗方法，以解决其导致疼痛的复杂潜在路径机制。因此，我们正在开发IHP-102，这是一种针对VOE的家庭自我管理的疾病改善治疗方法，从而赋予患者权力并使其远离疾病。IHP-102是一种新型的基于聚糖的治疗剂，具有多效性活性，靶向VOE的多途径机制，包括P-选择素和补体。解决结构性障碍对于真正的患者影响至关重要;因此，IHP-102旨在在VOE症状最早出现时进行家庭自我管理，从而避开设备简陋的医疗保健系统。这种治疗方案结合了SCD社区的直接反馈，代表了一个重大的范式转变，将彻底改变SCD护理，并提供显著的疾病负担。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溶解，并在V0 E的Townes SCD小鼠模型中将血管闭塞减少75%。IHP-102与其他已批准或正在开发的SCD药物高度不同，无论是其多效性生物活性还是其家庭治疗模式。在拟议的工作中，我们将利用SCD疼痛模型建立IHP-102治疗潜力和临床转化的稳健性。我们还将扩大GMP生产规模，并进行IND使能研究，从而进行首次人体1期临床试验。成功完成本文提出的目标将大大推进IHP-102的临床开发，并有助于实现其作为非阿片类药物方法全面解决VOE的潜力，以减轻疼痛，持续时间和相关并发症。