N-Methanocarbathymidine (N-MCT) for the treatment of herpes and pox virus infecti

N-甲基碳胸苷（N-MCT）用于治疗疱疹和痘病毒感染

• 批准号: 8451985
• 负责人: AQUILUR RAHMAN
• 金额: $ 100万
• 依托单位: N&N SCIENTIFIC, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451985
• 关键词: 14 year old; Accounting; Acute Toxicity Tests; Acyclovir; Address; Adult; Advanced Development; Adverse effects; Affect; Age; Animals; Antiviral Agents; Binding Proteins; Bioavailable; Biological Availability; Blood - brain barrier anatomy; Canis familiaris; Cardiovascular system; Cavia; Cells; Characteristics; Child; Chronic Disease; Clinical Trials; Congenital herpes simplex; Cowpox virus; Data; Development; Disease; Dose; Double Stranded DNA Virus; Drug Formulations; Drug Kinetics; Drug Stability; Drug resistance; Encephalitis; Exhibits; Face; Genital system; Grant; Herpes Labialis; Herpesviridae; Herpesvirus 1; Herpetic Stomatitis; Human Herpesvirus 2; Human Herpesvirus 4; Immunocompromised Host; Infection; Kaposi Sarcoma; Lead; Marketing; Maximum Tolerated Dose; Modeling; Mus; N-methanocarbathymidine; Neonatal; Oral; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma Proteins; Population; Poxviridae; Prophylactic treatment; Protein Binding; Public Health; Rattus; Recovery; Recurrence; Resistance; Schedule; Serological; Sexually Transmitted Diseases; Simplexvirus; Small Business Innovation Research Grant; Smallpox Viruses; Symptoms; Temperature; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Vaccinia virus; Variant; Virus; Virus Diseases; cytotoxicity; drug metabolism; genital herpes; genotoxicity; human disease; in vivo; pre-clinical; preclinical efficacy; preclinical study; preclinical toxicity; protein metabolism; research clinical testing

DESCRIPTION (provided by applicant): Diseases associated with the Poxviridae (smallpox, vaccinia and cowpox viruses), and Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV) dsDNA viruses represent major worldwide public health problems. N&N Scientific, Inc. (N&N) is developing a first of its class broad-spectrum orally bioavailable antiviral drug, N- methanocarbathymidine (N-MCT), which has exhibited potent activity against herpes and pox viruses and drug-resistant variants in vivo at doses that are non-cytotoxic in mice, rats, guinea pigs and dogs, even at doses 1000-fold higher than the therapeutic dose. These unique pharmacological characteristics suggest that N-MCT will be an ideal candidate for commercial development upon completing pre-IND studies and clinical trials. This Phase II SBIR proposal will help significantly to advance the development of N-MCT towards clinical testing. Herpes Simplex Virus (HSV) infection is a chronic disease that affects over 1 billion people worldwide, with distinct disease symptoms for each variant. Infections are commonly manifested as oral HSV-1 and HSV-2 infections, genital HSV-2 infection and HSV-8 infection in Kaposi's sarcoma, which are prevalent in sexually transmitted diseases and immunosuppressed patients. There are 500,000 new HSV-2 cases annually in the USA, and account for 75% of neonatal infections. HSV-1 infects between 20-40% of the adult population age 12 and over, and is manifested by recurrent facial cold sores that are treated predominantly with OTC remedies with limited efficacy. In children <14 years of age, as many as 35% have serologic evidence of HSV- 1 infection. To address the public health issues associated with HSV and a major commercial market, N&N proposes to develop N-MCT for the treatment and prophylaxis of genital HSV-2 infection, including neonatal infections, for which the current worldwide market is in excess of $2 billion. Current pre-IND studies of N-MCT conducted during the Phase I SBIR grant have demonstrated that N-MCT has several unique characteristics that make it particularly valuable for commercial development. These include: 1) Cytotoxicity only in HSV-infected cells 2) HSV-tk dependant antiviral activity 3) Activity against acyclovir (ACV)-resistant HSV 4) Activity against HSV-1, HSV-2, HSV-8, vaccinia and cowpox viruses 5) Greater potency than ACV across all doses 6) Activity against genital, neonatal and encephalitic HSV-2 infection, and activity against neonatal infection, even when administered 3 days post-infection, in contrast to the lack of activity of ACV 7) No cytotoxicity in mice, rats, guinea pigs and dogs at doses 1000-fold greater than the therapeutic dose 8) High oral bioavailability (80-90%) in mice, rats and dogs 9) Crosses the blood-brain barrier to eliminate HSV-2 encephalitis in mice, in contrast to a lack of efficacy f ACV 10) No toxicity in dogs administered N-MCT orally on a daily 14-day repeat dose schedule with a 14- day recovery period. 11) High drug stability at room temperature over one year with no decomposition SPECIFIC AIMS N&N proposes to develop the first of its class antiviral drug, N-MCT, for the treatment of HSV-2, including ACV- resistant variants. In the Phase I SBIR grant, N&N completed dose-range finding, 7-day acute toxicity testing in rats and dogs, PK studies in rats and dogs, as well as a 14-day repeat-dose toxicity and toxicokinetic study in dogs, including a cardiovascular assessment. N&N also completed efficacy studies in mice and guinea pigs to evaluate N-MCT against genital HSV-2 and neonatal and encephalitic infections, respectively. In this Phase II application, N&N proposes to complete an additional efficacy study in a genital HSV-2 guinea pig model resembling the human disease. In addition, we plan to complete the remaining preclinical toxicity studies, drug formulation and stability studies, plasma protein binding and metabolism and the synthesis of additional quantities of non- GMP and GMP N-MCT to advance N-MCT to clinical testing as a drug for the treatment of genital, neonatal and encephalitic HSV-2 infections. Specific Aim #1: To obtain additional preclinical efficacy data for N-MCT in a genital HSV-2 guinea pig model. Specific Aim #2: To synthesize sufficient non-GMP and GMP N-MCT for completion of preclinical studies, and formulation and stability studies, respectively. Specific Aim #3: To complete preclinical toxicology and toxicokinetic studies of N-MCT sufficient for filing an IND with the FDA. Formulation studies will define the optimal formulation for a confirmatory PK study in dogs. These studies will allow filing an IND application for the eventual initiation of Phase I clinical trials to determine the maximum tolerated dose, side effects, bioavailability, pharmacokinetics and the starting doses for Phase IIA clinical trials in patients with genital HSV-2 infections.

描述（由申请人提供）：与Poxviridae（天花，离子和牛pox病毒）和Herpesviridae（HSV-1，HSV-2，HSV-8，HSV-8，VZV，EBV，EBV，EBV）相关的疾病。 N&N Scientific, Inc. (N&N) is developing a first of its class broad-spectrum orally bioavailable antiviral drug, N- methanocarbathymidine (N-MCT), which has exhibited potent activity against herpes and pox viruses and drug-resistant variants in vivo at doses that are non-cytotoxic in mice, rats, guinea pigs and dogs, even at doses比治疗剂量高1000倍。这些独特的药理学特征表明，N-MCT将是完成预先研究和临床试验后商业发展的理想候选者。这一II期SBIR提案将有助于大大提高N-MCT发展临床测试。单纯疱疹病毒（HSV）感染是一种慢性疾病，影响了全球超过10亿人，每种变体都有明显的疾病症状。在卡波西肉瘤中，感染通常表现为口服HSV-1和HSV-2感染，生殖器HSV-2感染和HSV-8感染，它们在性传播疾病和免疫抑制患者中普遍存在。美国每年有500,000例新的HSV-2病例，占新生儿感染的75％。 HSV-1感染了12岁及以上成年人人群的20-40％，并且由反复出现的面部唇疱疹表现出来，这些疮主要用有限疗效的OTC疗法治疗。在<14岁的儿童中，多达35％的患者具有HSV-1感染的血清学证据。为了解决与HSV相关的公共卫生问题和主要的商业市场，N＆N建议开发N-MCT，以治疗和预防生殖器HSV-2感染（包括新生儿感染），当前全球市场超过2美元 十亿。当前对I阶段SBIR赠款进行的N-MCT进行的预先研究表明，N-MCT具有多种独特的特征，使其对于商业开发特别有价值。其中包括：1）仅在HSV感染的细胞中细胞毒性2）HSV-TK依赖性抗病毒活性3）针对Acyclovir（ACV）抗性HSV的活性4）针对HSV-1，HSV-1，HSV-1，HSV-8，HSV-8，vaccinia和Cowpox病毒的活性比ACV更大的ACV和ENAT INIC 6）活性6） infection, and activity against neonatal infection, even when administered 3 days post-infection, in contrast to the lack of activity of ACV 7) No cytotoxicity in mice, rats, guinea pigs and dogs at doses 1000-fold greater than the therapeutic dose 8) High oral bioavailability (80-90%) in mice, rats and dogs 9) Crosses the blood-brain barrier to eliminate HSV-2小鼠的脑炎，与缺乏功效FACV 10）在每天14天重复剂量时间表中施用N-MCT的狗的毒性不存在14天。 11）在室温下，高药物稳定性在一年内，没有分解特定的目的N＆N提议开发其类抗病毒药药N-MCT的第一种，用于治疗HSV-2，包括抗ACV的变体。在I期SBIR赠款中，N＆N完成了剂量范围发现，大鼠和狗的7天急性毒性测试，对大鼠和狗的PK研究，以及14天的重复剂量毒性和狗的毒理学研究，包括心血管评估。 N＆N还完成了小鼠和豚鼠的疗效研究，以评估N-MCT针对生殖器HSV-2，新生儿和脑感染的N-MCT。在此II期应用中，N＆N建议在类似于人类疾病的生殖器HSV-2豚鼠模型中完成一项额外的功效研究。此外，我们计划完成剩余的临床前毒性研究，药物制剂和稳定性研究，血浆 蛋白质结合和代谢以及额外量的非GMP和GMP N-MCT的合成，以将N-MCT推向临床测试，以作为治疗生殖器，新生儿和脑力HSV-2感染的药物。特定目的＃1：在生殖器HSV-2豚鼠模型中获得N-MCT的其他临床前疗效数据。具体目的＃2：分别综合足够的非GMP和GMP N-MCT来完成临床前研究，配方和稳定性研究。特定目的＃3：完成N-MCT的临床前毒理学和毒理学研究，足以向IND提交FDA。配方研究将定义狗中验证性PK研究的最佳制定。这些研究将允许提交 最终启动I期临床试验的IND应用，以确定生殖器HSV-2感染患者的最大耐受剂量，副作用，生物利用度，药代动力学和IIA期临床试验的起始剂量。