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

描述(申请人提供)：镰状细胞病(SCD)是一种遗传性血液疾病，影响美国超过75,000人和全球数百万人。在美国，SCD患者的平均死亡率为40多岁，生活质量差，医疗费用高。在SCD中，2-珠蛋白的突变会导致脱氧镰状血红蛋白(Deoxy-HBs)在红细胞(RBC)内形成不溶于水的聚合物，使RBC变形成僵硬的形状或镰刀状细胞，阻塞毛细血管和小血管。尽管几十年来研究人员对SCD进行了广泛的研究，但除了羟基脲之外，其他疾病改良剂的开发进展甚微。因此，需要新的更安全和更有效的治疗抗恶心药物来治疗SCD患者，特别是儿童，这可以改善这种疾病患者的生活质量，延长患者的预期寿命，并减少估计的5亿美元的直接医院费用。尼日利亚的四种植物的干燥提取物多年来一直用于治疗SCD患者(NIPRISAN)。它已经在尼日利亚通过了多项临床试验，自2006年以来已被正式批准在该国用于治疗SCD。美国FDA已经确定NIPRISAN有足够的安全性和有效性数据来启动第三阶段临床试验。美国FDA植物审查小组(BRT)建议使用更简单的NIPRISAN配方，使用LC/MS为该配方开发化学指纹图谱，并澄清配方中的一些抗镰刀菌化合物，这将提高标准化并增加获得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。第二阶段提案的目标是为SCD患者的第一/第二阶段临床试验提供资金。这项研究的第一阶段假设是这种植物学的标准化配方是可能的。具体目标：生产一种更简单的植物学配方NIPRISAN，并定义该植物的LC/MS化学指纹图谱。鉴定植物药物混合物中的抗呕吐化合物，有助于植物制剂的标准化，并为未来作为临床候选药物的新的合成抗呕吐化合物的开发提供线索。提交植物学配方的IND。商业机会：迫切需要一种更安全、更有效的药物来治疗SCD，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，全球有数百万人。除了羟基脲，没有其他药物可以治疗这种疾病。因此，存在着对另一种疾病修饰药物的大量未得到满足的医疗需求。 公共卫生相关性：大约75,000名美国人患有镰状细胞病。受影响的人往往医疗费用高，生活质量差，过早死亡。可供选择的治疗方法很少。有大量未得到满足的医疗需求，需要新的安全有效的疾病修改药物，如这笔赠款中的药物，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.