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: 8250894
• 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/8250894
• 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; 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. PUBLIC HEALTH RELEVANCE: Diseases associated with Poxviridae (smallpox, vaccinia and cowpox viruses, and Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV) viruses represent major worldwide public health problems. N&N Scientific, Inc. is developing the 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 through further preclinical studies that lead to an IND application and clinical trials. This Phase II SBIR proposal will help to advance N-MCT towards Phase I clinical testing by completing pre-IND requirements and additional efficacy studies in animals for the eventual treatment of genital and neonatal HSV-2 infections.

描述（由申请人提供）：与痘病毒科（天花、牛痘病毒和牛痘病毒）和疱疹病毒科（HSV-1、HSV-2、HSV-8、VZV、EBV）双链DNA病毒相关的疾病代表了全球主要的公共卫生问题。 N&N Scientific, Inc. (N&N) 正在开发同类首个广谱口服生物可利用抗病毒药物 N-亚甲基碳胸苷 (N-MCT)，该药物在体内表现出针对疱疹和痘病毒以及耐药变种的有效活性。即使剂量比治疗剂量高 1000 倍，对小鼠、大鼠、豚鼠和狗也无细胞毒性。这些独特的药理学特征表明，在完成 IND 前研究和临床试验后，N-MCT 将成为商业开发的理想候选者。该 II 期 SBIR 提案将极大地促进 N-MCT 向临床测试的发展。单纯疱疹病毒 (HSV) 感染是一种慢性疾病，影响全球超过 10 亿人，每种变种都有不同的疾病症状。感染常见表现为口腔HSV-1和HSV-2感染、生殖器HSV-2感染和卡波西肉瘤HSV-8感染，多见于性传播疾病和免疫抑制患者。美国每年新增 50 万例 HSV-2 病例，占新生儿感染的 75%。 HSV-1 感染 20-40% 的 12 岁及以上成年人，表现为复发性面部唇疱疹，主要采用非处方药治疗，但疗效有限。在 14 岁以下的儿童中，多达 35% 的儿童有 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商业市场，N&N 提议开发 N-MCT 用于治疗和预防生殖器 HSV-2 感染，包括新生儿感染，目前全球市场价值超过 2 美元 十亿。目前在第一阶段 SBIR 资助期间进行的 N-MCT IND 前研究表明，N-MCT 具有几个独特的特性，使其对商业开发特别有价值。这些包括： 1) 仅在 HSV 感染的细胞中具有细胞毒性 2) HSV-tk 依赖性抗病毒活性 3) 针对阿昔洛韦 (ACV) 耐药 HSV 的活性 4) 针对 HSV-1、HSV-2、HSV-8、牛痘和牛痘的活性5) 在所有剂量下均比 ACV 具有更强的效力 6) 具有抗生殖器、新生儿和脑炎 HSV-2 感染的活性，以及​​抗病毒活性新生儿感染，即使在感染后 3 天施用，与缺乏活性的 ACV 相比 7) 在比治疗剂量大 1000 倍的剂量下，对小鼠、大鼠、豚鼠和狗没有细胞毒性 8) 高口服生物利用度（ 80-90%) 在小鼠、大鼠和狗中 9) 穿过血脑屏障消除小鼠的 HSV-2 脑炎，而在小鼠中则缺乏功效ACV 10) 按每日 14 天重复剂量计划口服 N-MCT 并有 14 天恢复期的狗没有毒性。 11) 室温下药物稳定性高，一年以上不会分解 具体目标 N&N 提议开发同类抗病毒药物中的第一种 N-MCT，用于治疗 HSV-2，包括 ACV 耐药变种。在 I 期 SBIR 资助中，N&N 完成了剂量范围发现、大鼠和狗的 7 天急性毒性测试、大鼠和狗的 PK 研究，以及狗的 14 天重复剂量毒性和毒代动力学研究，包括心血管评估。 N&N 还完成了小鼠和豚鼠的功效研究，以评估 N-MCT 分别针对生殖器 HSV-2 以及新生儿和脑炎感染的效果。在此 II 期申请中，N&N 提议在类似于人类疾病的生殖 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数量的非 GMP 和 GMP N-MCT 的合成，以将 N-MCT 作为治疗生殖器、新生儿和脑炎 HSV-2 感染的药物推进临床测试。具体目标#1：获得 N-MCT 在生殖 HSV-2 豚鼠模型中的额外临床前疗效数据。具体目标#2：合成足够的非 GMP 和 GMP N-MCT，分别用于完成临床前研究以及制剂和稳定性研究。具体目标#3：完成 N-MCT 的临床前毒理学和毒代动力学研究，足以向 FDA 提交 IND。制剂研究将为犬类验证性 PK 研究确定最佳制剂。这些研究将允许归档 最终启动 I 期临床试验的 IND 申请，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。 公共卫生相关性：与痘病毒科（天花、痘苗病毒和牛痘病毒以及疱疹病毒科（HSV-1、HSV-2、HSV-8、VZV、EBV）病毒相关的疾病代表了全球主要的公共卫生问题。N&N Scientific, Inc. 正在开发同类中第一个广谱口服生物可利用的抗病毒药物，N-亚甲基碳胸苷（N- MCT），在体内对小鼠、大鼠、豚鼠和狗无细胞毒性的剂量下，甚至在比治疗剂量高 1000 倍的剂量下，表现出对疱疹和痘病毒以及耐药变体的有效活性。独特的药理学特征表明，N-MCT 将成为通过进一步的临床前研究进行商业开发的理想候选者，这些研究将导致 IND 申请和临床试验，该 II 期 SBIR 提案将有助于推动 N-MCT 进入临床阶段。我通过完成 IND 前要求和额外的动物疗效研究来进行临床测试，以最终治疗生殖器和新生儿 HSV-2 感染。