In Vivo Efficacy Studies of Clofazimine against CDAD in Hamster Model

 描述（由2013年报告中确定的申请人CDC提供，C。艰难梭菌（CD）相关疾病（CDAD）是“紧急公共卫生威胁”，每年造成至少14，000人死亡。CDAD起源的主要因素是暴露于广谱抗生素，导致正常肠道细菌植物群的破坏，CD及其毒素的不受抑制的生长，导致结肠壁的严重炎症损伤。最近出现和传播的更具毒性的CD菌株（NAP 1/027/B1）伴随着甲硝唑（MET）和万古霉素的当前药物方案的疗效降低，有时导致致命性疾病。最近来自NIAID的RFI（# HHS-NIH-NIAID-BAA-15-037）显示迫切需要一种治疗剂，其可以克服由CD的抗性菌株的出现和/或由医院环境中新孢子的摄入和生长引起的复发问题。主要制药公司投资于发现和开发新的抗微生物剂，投资回报率低，这既有激励作用，又有成本限制，使仿制药的再利用成为最受欢迎的选择。基于20多年来使用氯法齐明（CFM）抗生素治疗结核病（TB）的工作，PI进行了详细测试，发现其对培养物中的许多D菌株（包括NAP 1/027/B1）具有优异的活性，而对大多数肠道正常植物群则不然。这些数据使我们研究CFM治疗CDAD的特性，并发现值得探索。这些是：1）CFM在麻风瘤型麻风和多重耐药TB治疗中具有超过四十年的安全使用历史; 2）它还被用于对抗克罗恩病（一种肠道炎症病症）以及其他自身免疫病症; 3）它的杀菌活性似乎排除了靶细菌的耐药突变体的出现; 4）它已显示出用于人类使用的有希望的药理学和毒理学数据; 5）即使在单次给药后8-10天的半衰期，以及在一个疗程后长达70天的半衰期，可以防止医院中新孢子的再感染。这些特性使得CFM成为探索其在CDAD动物模型中的功效的绝佳候选物。为此，我们需要非稀释性SBIR I期资金来做：1）药代动力学研究，以确定药物制剂和最低递送剂量，这将优化CFM在肠腔中的生物利用度; 2）在我们手中建立CDAD动物模型的条件，特别是确定杀死所有克林霉素治疗动物的最小量的CD NAP 1/027/B1孢子;接着3）在CDAD动物上测试3个预选剂量的预选CFM制剂以显示存活率的改善。可接受的数据将导致SBIR II期研究，以优化剂量，CD激发前后的治疗时间，以在动物模型中实现超过27天的100%存活率，这是在该II期期间进行初始临床试验的目标。

 DESCRIPTION (provided by applicant CDC identified in a 2013 report, C. difficile (CD) associated disease (CDAD) as "urgent public health threat" responsible for at least 14,000 deaths annually. A primary factor for origin of CDAD is exposure to broad spectrum antibiotics causing a disruption of normal intestinal bacterial flora, unchecked growth of CD and its toxins causing serious inflammatory damage to colon wall. Recent emergence and spread of a more virulent strain of CD (NAP1/027/B1) is accompanied by a decrease in efficacy of current drug regimens of metronidazole (MET) and vancomycin leading at times, to fatal conditions. Recent RFI from NIAID (# HHS-NIH-NIAID-BAA-15-037) shows an urgent need for a therapeutic agent that can overcome the re-occurrence problems arising from either emergence of resistant strains of CD and/or from ingestion and growth of new spores in a hospital setting. It is both, incentive and cost prohibitive for major pharmaceuticals to invest in discovery and development of new antimicrobial agents with low return on investment, leaving repurposing of generics as a favorite choice. Based on over 20 yrs of work on tuberculosis (TB) with clofazimine (CFM) antibiotic, the PI tested in detail and found its activity to be excellent against many strains of D including NAP1/027/B1 in culture and not so for a majority of normal flora of the gut. This data led us to examine the properties of CFM to treat CDAD and found to be worth exploring. These are: 1) CFM has over forty years' history of safe use in lepromatous leprosy and multidrug- resistant TB treatment; 2) It has also been used against Crohn's disease, an inflammatory condition of the intestine, as well as other autoimmune conditions; 3) Its bactericidal activity appears to preclude the emergence of resistant mutants of targeted bacteria; 4) It has exhibited promising pharmacological and toxicological data for human use; 5) Half-life of 8-10 days even after a single dose, and upto 70 days after a course of treatment could protect against reinfection with new spores in a hospital. These properties make CFM great candidate to explore its efficacy in a CDAD animal model. To this end, we need non-dilutive SBIR phase I funding to do: 1) Pharmacokinetic study to identify drug formulation and lowest delivery dose that would optimize bioavailability of CFM in the gut lumen; 2) establish conditions of animal model for CDAD in our hands especially to determine minimal amount of CD NAP1/027/B1 spores to kill all clindamycin treated animals; followed by 3) testing 3 pre-selected doses of preselected formulation of CFM on CDAD animals to show improvement in survival. Acceptable data would lead to SBIR phase II study to Optimize Dose, time to treat before or after CD challenge to achieve 100% survival for over 27 days in animal model, a goal to do initial clinical trials during this Phase II period.