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

基本信息

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
项目类别：
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&apos 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

项目摘要

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) 是一种毁灭性的疾病，因其标志性疼痛危象或血管闭塞事件 (VOE) 而被广泛认可。目前，VOE 发生后缺乏有效的疾病缓解疗法，并且缺乏有效的疼痛管理方法。阿片类药物仍然是治疗标准，试图掩盖令人衰弱的疼痛，再加上持续的阿片类药物危机，这导致 SCD 患者在寻求医疗护理时被视为“吸毒者”，从而削弱了对医疗保健系统的信心。此外，大量 VOE 和长期使用阿片类药物导致超过 50% 的 SCD 成人每天出现慢性疼痛，由此产生的急性和慢性疼痛对 SCD 患者产生了深远的影响。并反映在疾病负担统计中，其中 SCD 负担超过阿尔茨海默氏病、乳腺癌和结直肠癌、艾滋病毒/艾滋病、白血病和中风。针对 VOE 的有效疾病缓解治疗可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，这是一种用于 VOE 家庭自我管理的疾病缓解疗法，从而增强患者的能力并显着摆脱疾病的困扰。 IHP-102 是一种具有多效活性的新型聚糖疗法。针对 VOE 的多种途径机制，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 旨在用于 VOE 最早发作时的家庭自我给药。这种治疗方案结合了 SCD 社区的直接反馈，将彻底改变 SCD 护理并带来重大疾病负担。 VOE 的 Townes SCD 小鼠模型中的 -选择素介导的细胞结合，抑制补体介导的细胞裂解，并减少 75% 的血管闭塞，与其他模型高度不同。已批准或正在开发的 SCD 药物，具有多效性生物活性和家庭治疗模式。在拟议的工作中，我们将利用 SCD 疼痛模型来增强 IHP-102 的治疗潜力和临床转化。还扩大到 GMP 生产并进行 IND 支持研究，成功完成此处提出的目标将显着推进 IHP-102 的临床开发，并有助于全面实现其潜力。地址VOE 作为一种非阿片类药物方法，可减轻疼痛、缩短持续时间和相关并发症。