Novel Therapy for Hyperphosphatemic Familial Tumoral Calcinosis (hfTC) and Generalized Hyperphosphatemia

高磷血症家族性肿瘤钙质沉着症 (hfTC) 和全身性高磷血症的新疗法

基本信息

批准号：
10818072
负责人：
KENNETH E WHITE
金额：
$ 30.19万
依托单位：
FGF 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：
2023-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10818072
关键词：
Adherence Affect Age Amputation Ankle Anti-Inflammatory Agents Antibodies Biochemical Biological Biology Biotechnology Blood Vessels Blood flow Bone Pain Businesses Calcinosis Cell Line Childhood Chimeric Proteins Clinical Data Clinical Trials Collaborations Data Development Diagnosis Disease Effectiveness Elbow Enzyme-Linked Immunosorbent Assay Erythema Exanthema Excision Exhibits FDA approved Familial hypophosphatemic bone disease Familial tumoral calcinosis Family Fibroblast Growth Factor Funding Future Gene Expression Profile Genes Goals Half-Life Hip region structure Hormone secretion Hormones Human Hyperostosis In Vitro Incidence Indiana Injections Intramuscular Kidney Knockout Mice Label Lead Lesion Life Mammalian Cell Measures Metabolism Modeling Molecular Mus Muscle Mutation Operative Surgical Procedures Orphan Drugs Osteocytes Pain Palliative Care Patients Persons Pharmaceutical Preparations Phase Physicians Production Program Development Property Proteins Rare Diseases Recombinant Fibroblast Growth Factor Recurrence Replacement Therapy Research Rodent Serum Signal Transduction Skeletal Muscle Skin Small Business Technology Transfer Research Symptoms Syndrome Testing Therapeutic Tumor Debulking Universities Vascular calcification Vitamin D Wild Type Mouse Work autosome bone calcification clinical investigation commercialization experience fibroblast growth factor 23 in vivo in vivo evaluation infection rate inorganic phosphate kidney cell lead candidate mineralization molecular marker mouse model nano novel novel therapeutics off-label use pediatric patients positional cloning pre-clinical primary outcome receptor scale up scapula voucher

项目摘要

Abstract Hyperphosphatemic familial tumoral calcinosis (hfTC) is a disease in which patients cannot produce the bioactive form of the hormone Fibroblast growth factor-23 (FGF23), which is secreted by osteocytes to rid the body of phosphate by acting on the kidney. hfTC is characterized by markedly elevated serum phosphate (Pi) which causes large intramuscular calcifications to develop. The calcification burden in hfTC can be substantial, with some mineralizations growing to weigh 2-4 pounds, becoming very painful and recur after resection. Pediatric patients can become debilitated, as the lesions can break the skin to increase infection rates, and some patients have had amputations due to loss of vascular blood flow. Currently there are no FDA-approved agents or clinical trials for hfTC. The only available treatments are off-label palliative care, which is minimally effective with poor adherence. Patients with hfTC have inactivating mutations in the FGF23 gene itself or in genes associated with the intracellular processing/secretion of bioactive FGF23. Dr. White carried out the original positional cloning of FGF23 to identify the molecular basis of autosomal dominant hypophosphatemic rickets (ADHR; Nat Gen, 2000), and his lab characterized FGF23 inactivating mutations from hfTC families. The circulating half-life of human FGF23 is 20-40 minutes, making endogenous FGF23 replacement therapy impractical. To fill this unmet therapeutic need, Dr. White and his partners with outstanding commercialization experience formed FGF Therapeutics to pursue novel therapies for diseases of aberrant phosphate handling. To extend the half-life of FGF23 into a therapeutic range, Dr. White developed a humanized FGF23-Fc region fusion protein harboring FGF23-stabilizing mutations (‘FGF23-Fc1’). Recombinant FGF23-Fc1 is secreted by mammalian cells in scale up cultures, and in the presence of the FGF23 co-receptor Klotho, retains bioactivity like native FGF23. Further, FGF23-Fc1 can be detected by human ELISAs in the nanogram range 24 h after injection in normal mice, whereas endogenous recombinant FGF23 was undetectable. The objective of this Phase I proposal is to develop a lead FGF23-Fc1 molecule for clinical investigation through the specific aims: 1) Verify and optimize the candidate pre-clinical FGF23-Fc1 protein in vitro; and 2) Test the in vivo bioactivity of FGF23-Fc1 for extended half-life and rescue of the Fgf23-KO hfTC mouse model. In sum, the primary outcome of this proposal is refinement and further development of a lead FGF23-Fc1 candidate for hfTC replacement therapy. Following successful accomplishment of these aims, the fully humanized FGF23-Fc1 will be used to perform IND-enabling studies in Phase II to establish PK and TK. Our worldwide connections with physicians and the team’s >20 year experience in the FGF23 field will support these future studies.

抽象的高磷血症家族性肿瘤钙质沉着症 (hfTC) 是一种患者无法产生生物活性物质的疾病成纤维细胞生长因子 23 (FGF23) 激素的形式，由骨细胞分泌，以清除体内的 hfTC 的特点是血清磷酸盐 (Pi) 显着升高。导致大的肌内钙化发展，hfTC 的钙化负担可能很大。有些矿化物会重达 2-4 磅，变得非常疼痛，并且在儿科切除后会复发。患者可能会变得虚弱，因为病变可能会破坏皮肤从而增加感染率，并且有些患者由于血管血流丧失而导致截肢，目前尚无 FDA 批准的药物或临床。 hfTC 的试验中，唯一可用的治疗方法是标签外姑息治疗，这种治疗效果较差。 hfTC 患者的 FGF23 基因本身或与 FGF23 相关的基因存在失活突变。 White 博士对生物活性 FGF23 的细胞内加工/分泌进行了原始定位克隆。 FGF23 鉴定常染色体显性低磷血症性佝偻病的分子基础（ADHR；Nat Gen，2000），和他的实验室表征了 hfTC 家族的 FGF23 失活突变的人类循环半衰期。 FGF23 为 20-40 分钟，使得内源性 FGF23 替代疗法无法填补这一空白。出于需要，White博士和他具有杰出商业化经验的治疗伙伴组建了FGF 寻求针对异常磷酸盐处理疾病的新疗法以延长半衰期。 FGF23进入治疗范围，White博士开发出人源化FGF23-Fc区融合蛋白 FGF23 稳定突变（“FGF23-Fc1”）由哺乳动物细胞大规模分泌。培养物，并且在 FGF23 辅助受体 Klotho 存在的情况下，保留了与天然 FGF23 一样的生物活性。正常小鼠注射后 24 小时，FGF23-Fc1 可通过人类 ELISA 检测到纳克范围，而内源性重组 FGF23 是无法检测到的。该 I 期提案的目标是开发。通过以下特定目标进行临床研究的先导 FGF23-Fc1 分子：1) 验证和优化体外候选临床前 FGF23-Fc1 蛋白；2) 测试 FGF23-Fc1 的体内生物活性以延长 Fgf23-KO hfTC 小鼠模型的半衰期和拯救总之，该提案的主要成果是。改进和进一步开发用于 hfTC 替代疗法的主要 FGF23-Fc1 候选药物。成功实现这些目标后，完全人源化的 FGF23-Fc1 将用于执行 IND 启用 II 期研究旨在建立 PK 和 TK 我们与医生和团队超过 20 年的全球联系。 FGF23 领域的经验将支持这些未来的研究。