In Vivo Efficacy Studies of Clofazimine against CDAD in Hamster Model

 描述(由申请人疾控中心提供，在2013年的一份报告中指出，艰难梭菌(CD)相关疾病(CDAD)是每年造成至少14,000人死亡的“紧急公共卫生威胁”。CDAD的一个主要原因是暴露于广谱抗生素导致正常肠道细菌群的破坏，Cd及其毒素的无节制生长导致结肠壁严重的炎性损害。最近出现和传播的一种毒力更强的CD毒株(NAP1/027/B1)伴随着当前甲硝唑(MET)和万古霉素治疗方案的疗效下降，有时导致致命情况。最近来自NIAID的RFI(#HHS-NIH-NIAID-BAA-15-037)表明，迫切需要一种治疗剂，能够克服因出现CD耐药菌株和/或在医院环境中摄取和生长新孢子而产生的复发问题。对于主要制药公司来说，投资于低投资回报的新抗菌剂的发现和开发既是一种激励，也是一种成本限制，使仿制药的重新用途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进行了详细的测试，发现其在培养中对包括NAP1/027/B1在内的许多D菌株具有良好的活性，但对大多数肠道正常菌群则不是如此。这些数据使我们研究了CFM治疗CDAD的特性，发现值得探索。这些是：1)CFM已有超过40年的安全使用历史，用于麻风和耐多药结核病的治疗；2)它也被用于治疗克罗恩病，一种肠道炎症状况，以及其他自身免疫性疾病；3)它的杀菌活性似乎可以阻止目标细菌出现耐药突变；4)它已显示出令人满意的药理和毒理数据；5)即使一次服用也有8-10天的半衰期，一个疗程后长达70天的疗程可防止医院再次感染新孢子。这些特性使CFM成为在CDAD动物模型中探索其有效性的极佳候选者。为此，我们需要非稀释剂SBIR第一阶段资金来做：1)药代动力学研究，以确定可以优化CFM在肠道中的生物利用度的药物配方和最低给药剂量；2)建立我们手中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低CDNAP1/027/B1孢子数量；然后，3)在CDAD动物身上测试3)预选剂量的CFM预选制剂，以显示存活的改善。可接受的数据将导致SBIR II期研究，以优化剂量，在CD攻击之前或之后的治疗时间，以实现动物模型中超过27天的100%存活，目标是在此II期期间进行初步临床试验。

 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.