Formulation and Standardization of a Sickle Cell Disease Drug for Clinical Trial

描述（由申请人提供）：镰状细胞病（SCD）是一种遗传性血液疾病，影响美国75，000多人和全球数百万人。在美国，SCD患者的平均死亡率在40多岁，生活质量差，医疗费用高。在SCD中，2-珠蛋白的突变导致脱氧镰状血红蛋白（脱氧-HbS）在红细胞（RBC）内形成不溶性聚合物，使RBC变形为刚性形状或阻塞毛细血管和小血管的镰状细胞。尽管数十年来研究人员对SCD进行了广泛的研究，但在开发除羟基脲之外的其他疾病修饰剂方面进展甚微。因此，需要新的更安全和更有效的治疗性抗镰状剂来治疗SCD患者，特别是儿童，这可以改善生活质量，增加这种疾病患者的预期寿命，并减少估计5亿美元的直接住院费用。在尼日利亚，四种植物的干燥提取物已用于治疗SCD患者多年（NIPRISAN）。它已经在尼日利亚进行了多项临床试验，自2006年以来已正式批准在该国用于治疗SCD。美国FDA已确定NIPRISAN有足够的安全性和有效性数据，可以开始III期临床试验。美国FDA植物审查小组（BRT）建议采用更简单的NIPRISAN配方，使用LC/MS开发配方的化学指纹图谱，并阐明配方中的一些抗镰状化化合物，这将提高标准化程度，并增加获得FDA上市批准的可能性。我们的长期目标是生产一种治疗SCD的新药。II期提案的目标是为SCD患者的I/II期临床试验提供资金。这项研究的第一阶段假设是，这种植物的标准化配方是可能的。具体目标：生产一种更简单的NIPRISAN植物制剂，并定义该植物的LC/MS化学指纹。确定植物药混合物中的抗镰状化化合物，这有助于植物制剂的标准化，并为未来开发新的合成抗镰状化化合物作为临床候选物提供线索。申请植物制剂的IND。商业机会：迫切需要一种更安全，更有效的治疗SCD的药物，特别是在儿童中。美国有75，000至100，000名SCD患者，欧洲有50，000名SCD患者，全球有数百万名。除了羟基脲，没有其他药物可以改变这种疾病。因此，对于另一种疾病修饰药物存在大量未满足的医疗需求。 公共卫生相关性：大约75，000美国人患有镰状细胞病。那些受影响的人往往有高昂的医疗费用，生活质量差，早死。治疗选择很少。有大量的未满足的医疗需求，新的安全和有效的疾病修饰药物，如在这个赠款，以治疗这种疾病。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a hereditary blood disorder, affecting over 75,000 people in the United States and millions of people worldwide. In the US, those with SCD have an average mortality in their 40s, a poor quality of life and high medical costs. In SCD, a mutation in 2-globin causes deoxygenated sickle hemoglobin (deoxy-HbS) to form insoluble polymers inside red blood cells (RBCs), which deforms the RBCs into rigid shapes or sickle cells that occlude capillaries and small blood vessels. Despite the extensive studies of SCD by researchers over several decades, there has been little progress in the development of additional disease modifying agents beyond hydroxyurea. Therefore, new safer and more effective therapeutic antisickling agents are needed to treat patients with SCD, particularly children, which could improve the quality of life and increase the life expectancies of sufferers of this disease and reduce the estimated $500 million in direct hospital costs. A dried extract of four plants has been used to treat patients with SCD in Nigeria for many years (NIPRISAN). It has been through multiple clinical trials in Nigeria and has been formally approved for use in that country since 2006 for the treatment of SCD. The US FDA has determined there is sufficient safety and efficacy data for NIPRISAN to start a Phase III clinical trial. The US FDA Botanical Review Team (BRT) suggested a simpler formulation of NIPRISAN, development of a chemical fingerprint for the formulation using LC/MS and elucidation of some of the anti-sickling compounds in the formulation would improve standardization and increase the probability of obtaining FDA marketing approval. Our long-term goal is to produce a new drug to treat SCD. The goal of the Phase II proposal is to fund Phase I/II clinical trials in patients with SCD. The Phase I hypothesis of this research is that a standardized formulation of this botanical is possible. Specific Aims: Produce a simpler botanical formulation of NIPRISAN and define a LC/MS chemical fingerprint for the botanical. Identify anti-sickling compounds in the mixture of botanicals that can help in standardization of the botanical formulation and provide leads for new synthetic antisickling compounds for future development as clinical candidates. File an IND for the botanical formulation. Commercial Opportunity: A safer and more effective drug to treat SCD is desperately needed, particularly in children. There are 75,000 to 100,000 SCD patients in the US, 50,000 SCD patients in Europe and many million world-wide. There are no other drugs that modify this disease besides hydroxyurea. Therefore, there is a large unmet medical need for another disease modifying drug. PUBLIC HEALTH RELEVANCE: About 75,000 Americans have Sickle Cell Disease. Those affected often have high medical costs, a poor quality of life, and early death. Treatment options are few. There is a substantial unmet medical need for new safe and effective disease modifying drugs, like the one in this grant, to treat this disease.