SBIR-STTR Award

The antiviral market is experiencing considerable growth with a predicted market value that is expected to double in size to more than $44B by 2010. Among the drugs that are experiencing considerable growth are those targeted to HSV-1 and -2. Anti-herpes product sales in 2007 in the United States for all indications were in excess of $2 and are projected to reach $2.5 billion in the next decade. While HSV infections are usually not life-threatening, they increase susceptibility to HIV infection and pose a major risk to immunocompromised patients. This is particularly true in India and Southeast Asia where HIV and HSV infection rates are climbing, and thus on a global scale, there will be a large demand for new antiviral drugs. There are currently no antiviral drugs licensed for use by the FDA for prophylaxis against virus infection. N&N Scientific, Inc. (N&N) is an early stage pharmaceutical company whose first product candidate is N- methanocarbathymidine (N-MCT), a promising antiviral drug that has shown potent and selective activity against the Herpes and Orthopoxvirus families. N&N proposes to develop N-MCT as a therapeutic against the Herpesviridae, Papillomaviridae and Poxviridae genera of Class I dsDNA viruses, which include HSV-1, HSV-2, HSV-8, VZV, EBV, smallpox, Vaccinia, cowpox, and HPV. N-MCT is active against all dsDNA viruses, except CMV, including acyclovir (ACV)-resistant HSV-1 and cidofovir (CDV)-resistant cowpox viruses, and has not been tested as yet against HPV. N- MCT has no apparent cytotoxicity in uninfected tissues, in contrast to cidofovir, which requires hospitalization to treat its associated renal toxicity. An additional market niche for N-MCT is its use in the area of biodefense as a prophylactic and therapeutic treatment against the biological threat agent, smallpox. N-MCT has potent antiviral activity against both cowpox and vaccinia, which should translate to other Orthopoxviruses, such as smallpox. Based on the initial findings of Edward Jenner that people exposed to cowpox did not get sick from smallpox, a modified vaccinia virus was used to vaccinate against both cowpox and smallpox. Thus, the use of N-MCT as an anti-biothreat agent is potentially applicable to the emerging market of biodefense. In mid-2004, shortly after the US anthrax incidents, President Bush signed into effect Project BioShield, whose mission is to: "ensure that resources are available to pay for "next-generation" medical countermeasures." It is expected that Project BioShield will be salvaged under the pending legislation forming the Biomedical Advanced Research and Development Authority, HHS, with appropriations expected to reach $6B that would allow the government to serve as the investment partner for emerging companies focusing on new vaccines or drugs as the next generation countermeasures against anthrax, smallpox and other agents. Given the safety and efficacy profile for N-MCT against poxviruses in animal studies, it will be an ideal candidate for government support in a wide variety of viral-based biodefense initiatives. N-MCT is activated only in virus-infected cells by the HSV thymidine kinase (TK). N-MCT is converted into the active triphosphate metabolite by a three step phosphorylation process, of which only the second step is selectively accomplished by HSV-TK. The triphosphate metabolite appears to have little if any cytotoxicity to uninfected cells in vitro and in vivo in contrast to acyclic antiviral drugs, such as ganciclovir. Preclinical studies with this compound have shown the following promising characteristics: 1) It inhibits HSV-1, HSV-2, HSV-8 (Kaposi's Sarcoma Virus), as well as Vaccinia and Cowpox viruses 2) It is cytotoxic only in virus-infected cells 3) It is active against acyclovir-resistant HSV and cidofovir-resistant cowpox virus 4) It is equally or more potent than the leading antiviral drugs acyclovir, ganciclovir and cidofovir 5) It is nontoxic at dose producing potent anti-pox virus activity in infected mice, in contrast to the high renal toxicity associated with cidofovir 6) It is active and bioavailable by the oral route of administration In this application, N&N proposes to complete all preclinical studies required to advance N-MCT to Phase I clinical development as an anti-HSV and anti-pox virus drug. Specific Aim #1: To synthesize sufficient N-MCT for completion of preclinical studies. Specific Aim #2: To complete evaluation of N-MCT in vitro against smallpox, and in vivo against HSV-2-infected mice. This proposal does not include studies in monkypox-infected cynomolgus monkeys, which if successful, will require further testing in smallpox-infected primates, and will be done in collaboration with Dr. John Huggins, USAMRIID. Specific Aim #3: To complete preclinical toxicology and pharmacokinetic studies of N-MCT for filing an IND with the FDA. These studies will allow initiation of Phase I clinical trial to determine the maximum tolerated dose, toxicity, bioavailability and pharmacokinetic parameters.

Public Health Relevance:
Diseases associated with the Poxviridae genus of dsDNA viruses (smallpox, vaccinia and cowpox viruses, as well as the Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV, CMV) and Papillomaviridae (HPV) genera, represent major worldwide public health problems. The broad-spectrum orally bioavailable antiviral drug being developed by N&N Scientific, Inc. is N-methanocarbathymidine (N-MCT) that has exhibited substantial activity against herpes and pox viruses and drug-resistant variants in vivo at doses that have not produced any general cytotoxicity in mice. These unique pharmacological characteristics suggest that N-MCT would be an ideal candidate for further preclinical studies that lead to an IND and clinical trials, and the funds sought will help significantly in furthering its development.

Public Health Relevance Statement:
Diseases associated with the Poxviridae genus of dsDNA viruses (smallpox, vaccinia and cowpox viruses, as well as the Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV, CMV) and Papillomaviridae (HPV) genera, represent major worldwide public health problems. The broad-spectrum orally bioavailable antiviral drug being developed by N&N Scientific, Inc. is N-methanocarbathymidine (N-MCT) that has exhibited substantial activity against herpes and pox viruses and drug-resistant variants in vivo at doses that have not produced any general cytotoxicity in mice. These unique pharmacological characteristics suggest that N-MCT would be an ideal candidate for further preclinical studies that lead to an IND and clinical trials, and the funds sought will help significantly in furthering its development.

NIH Spending Category:
Biodefense; Emerging Infectious Diseases; Infectious Diseases; Orphan Drug; Sexually Transmitted Diseases/Herpes; Small Pox

Project Terms:
(N)-MCT; 1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine; 1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; 2'-Nor-2'-deoxyguanosine; 2'NDG; 2-Amino-1,9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one; 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one; 21+ years old; 6H-Purin-6-one, 2-amino-1,9-dihydro-9-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-; 9-((2-Hydroxyethoxy)methyl)guanine; 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine; AIDS Virus; ATP[{..}]thymidine 5'-phosphotransferase; Acicloftal; Aclovir; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Acycloguanosine; Acyclovir; Address; Adult; Age; Animals; Anthrax; Anthrax disease; Antiviral Agents; Antiviral Drugs; Antivirals; Area; Asia, Southeastern; Bioavailability; Bioavailable; Biologic Availability; Biological; Biological Availability; Bioshield; Body Tissues; CDC; CMV; Cargosil; Cells; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic Disease; Chronic Illness; Cidofovir; Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Cold Sore; Collaborations; Communicable Diseases; Cow Pox; Cow Pox Virus; Cowpox; Cowpox virus; Crab-Eating Macaque; Cytomegalovirus; DHPG; Deoxypyrimidine Kinase; Deoxythymidine Kinase; Development; Development and Research; Disease; Disorder; Dose; Double Stranded DNA Virus; Drug Kinetics; Drug resistance; Drugs; EC 2.7.1.21; Early-Stage Clinical Trials; Ensure; Evaluation; Exhibits; Face; Family; Fever Blister; Funding; Ganciclovir; Gancyclovir; Generalized Growth; Glaxo Wellcome Brand of Aciclovir; Glaxo Wellcome Brand of Aciclovir Sodium Salt; Government; Growth; HCMV; HHV-1; HHV-2; HIV; HIV Infections; HIV-1; HIV-I; HIV1; HOSP; HPMPC; HPV; HSV; HSV-1; HSV-2; HSV1; HSV2; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Herpes Genitalis; Herpes Labialis; Herpes Simplex Virus; Herpes Simplex Virus 1; Herpes Simplex Virus 2; Herpes Simplex Virus Type 1; Herpes Simplex Virus Type 2; Herpes Simplex, Genital; Herpes Simplex, Labial; Herpes labialis Virus; Herpesviridae; Herpesvirus 1 (alpha), Human; Herpesvirus 1, Human; Herpesvirus 2 (alpha), Human; Herpesvirus 2, Human; Herpesvirus hominis; Herpesvirus progenitalis; Herpesviruses; Hospitalization; Human (alpha) herpes virus 2; Human Herpesvirus 2; Human Immunodeficiency Viruses; Human Papillomavirus; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human herpes simplex virus type 1; Human herpes simplex virus type 2; Human herpesvirus 1; Human herpesvirus type 1; Human immunodeficiency virus 1; Human, Adult; Immunocompromised; Immunocompromised Host; Immunocompromised Patient; Immunodeficiency Virus Type 1, Human; Immunosuppressed Host; In Vitro; India; Individual; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Infectious Human Wart Virus; Investments; Journals; Kaposi - Kaposi's Sarcoma; Kaposi Sarcoma; Kaposi?s Sarcoma; Kidney; LAV-HTLV-III; Lead; Legislation; Licensing; Life; Lymphadenopathy-Associated Virus; Lytotoxicity; Macaca fascicularis; Magazine; Mammals, Mice; Mammals, Primates; Marketing; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Medical; Medication; Mice; Mission; Monkey, Crab-Eating; Monkey, Cynomolgus; Monkeys; Multiple Hemorrhagic Sarcoma; Murine; Mus; N-methanocarbathymidine; Nordeoxyguanosine; Oral; Orthopoxvirus; Papilloma Virus, Human; Papillomaviridae; Papillomavirus, Human; Parke Davis Brand of Aciclovir; Pb element; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phosphorylation; Physiologic Availability; Population; Poviral; Poxviridae; Poxvirus officinale; Poxviruses; Predisposition; Prevention Measures; Primates; Process; Prophylactic treatment; Prophylaxis; Protein Phosphorylation; Public Health; R & D; R&D; Recurrence; Recurrent; Reporting; Research Resources; Resistance; Resources; Risk; Route; STD; Safety; Sales; Salivary Gland Viruses; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Simplexvirus; Smallpox; Southeast Asia; Southeastern Asia; Staging; Statutes and Laws; Susceptibility; T-Lymphotropic Virus Type III Infections, Human; Testing; Therapeutic; Thymidine Kinase; Tissue Growth; Tissues; Toxic effect; Toxicities; Toxicology; Translating; Translatings; United States; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Urinary System, Kidney; Vaccinated; Vaccinia; Vaccinia virus; Variant; Variation; Variola; Venereal Diseases; Venereal Disorders; Venereal Infections; Viral; Viral Diseases; Virorax; Virus; Virus Diseases; Virus-Genital Herpes; Virus-HIV; Viruses, General; Warner Wellcome Brand of Aciclovir; Wellcome Brand of Aciclovir; Wellcome Brand of Aciclovir Sodium Salt; Zovirax; Zovirax for Injection; adult human (21+); authority; base; bio-threat; bioavailability of drug; biodefense; biothreat; chronic disease/disorder; chronic disorder; clinical investigation; cytomegalovirus group; cytotoxic; cytotoxicity; disease/disorder; drug resistant; drug/agent; dsDNA Virus; experience; facial; genital herpes; heavy metal Pb; heavy metal lead; herpes febrilis; herpes genitalia; herpes simplex i; herpes simplex ii; herpes virus; herpes virus 1, human; herpesvirus; high risk; human T cell leukemia virus III; human T lymphotropic virus III; human alphaherpesvirus 1; human alphaherpesvirus 2; human cytomegalovirus; human herpesvirus 1 group; immunosuppressed patient; in vivo; language translation; new vaccines; next generation; next generation vaccines; novel; novel vaccines; ontogeny; phase 1 study; phase 1 trial; phase I trial; pox virus; pre-clinical; preclinical; preclinical study; prophylactic; protocol, phase I; public health medicine (field); public health relevance; recombinant vaccinia virus; renal; research and development; resistance to Drug; resistant; resistant to Drug; small pox; triphosphate; tripolyphosphate; variola major; venereal herpes; viral infection; virus infection; wart virus; yaba

The antiviral market is experiencing considerable growth with a predicted market value that is expected to double in size to more than $44B by 2010. Among the drugs that are experiencing considerable growth are those targeted to HSV-1 and -2. Anti-herpes product sales in 2007 in the United States for all indications were in excess of $2 and are projected to reach $2.5 billion in the next decade. While HSV infections are usually not life-threatening, they increase susceptibility to HIV infection and pose a major risk to immunocompromised patients. This is particularly true in India and Southeast Asia where HIV and HSV infection rates are climbing, and thus on a global scale, there will be a large demand for new antiviral drugs. There are currently no antiviral drugs licensed for use by the FDA for prophylaxis against virus infection. N&N Scientific, Inc. (N&N) is an early stage pharmaceutical company whose first product candidate is N- methanocarbathymidine (N-MCT), a promising antiviral drug that has shown potent and selective activity against the Herpes and Orthopoxvirus families. N&N proposes to develop N-MCT as a therapeutic against the Herpesviridae, Papillomaviridae and Poxviridae genera of Class I dsDNA viruses, which include HSV-1, HSV-2, HSV-8, VZV, EBV, smallpox, Vaccinia, cowpox, and HPV. N-MCT is active against all dsDNA viruses, except CMV, including acyclovir (ACV)-resistant HSV-1 and cidofovir (CDV)-resistant cowpox viruses, and has not been tested as yet against HPV. N- MCT has no apparent cytotoxicity in uninfected tissues, in contrast to cidofovir, which requires hospitalization to treat its associated renal toxicity. An additional market niche for N-MCT is its use in the area of biodefense as a prophylactic and therapeutic treatment against the biological threat agent, smallpox. N-MCT has potent antiviral activity against both cowpox and vaccinia, which should translate to other Orthopoxviruses, such as smallpox. Based on the initial findings of Edward Jenner that people exposed to cowpox did not get sick from smallpox, a modified vaccinia virus was used to vaccinate against both cowpox and smallpox. Thus, the use of N-MCT as an anti-biothreat agent is potentially applicable to the emerging market of biodefense. In mid-2004, shortly after the US anthrax incidents, President Bush signed into effect Project BioShield, whose mission is to: "ensure that resources are available to pay for "next-generation" medical countermeasures." It is expected that Project BioShield will be salvaged under the pending legislation forming the Biomedical Advanced Research and Development Authority, HHS, with appropriations expected to reach $6B that would allow the government to serve as the investment partner for emerging companies focusing on new vaccines or drugs as the next generation countermeasures against anthrax, smallpox and other agents. Given the safety and efficacy profile for N-MCT against poxviruses in animal studies, it will be an ideal candidate for government support in a wide variety of viral-based biodefense initiatives. N-MCT is activated only in virus-infected cells by the HSV thymidine kinase (TK). N-MCT is converted into the active triphosphate metabolite by a three step phosphorylation process, of which only the second step is selectively accomplished by HSV-TK. The triphosphate metabolite appears to have little if any cytotoxicity to uninfected cells in vitro and in vivo in contrast to acyclic antiviral drugs, such as ganciclovir. Preclinical studies with this compound have shown the following promising characteristics: 1) It inhibits HSV-1, HSV-2, HSV-8 (Kaposi's Sarcoma Virus), as well as Vaccinia and Cowpox viruses 2) It is cytotoxic only in virus-infected cells 3) It is active against acyclovir-resistant HSV and cidofovir-resistant cowpox virus 4) It is equally or more potent than the leading antiviral drugs acyclovir, ganciclovir and cidofovir 5) It is nontoxic at dose producing potent anti-pox virus activity in infected mice, in contrast to the high renal toxicity associated with cidofovir 6) It is active and bioavailable by the oral route of administration In this application, N&N proposes to complete all preclinical studies required to advance N-MCT to Phase I clinical development as an anti-HSV and anti-pox virus drug. Specific Aim #1: To synthesize sufficient N-MCT for completion of preclinical studies. Specific Aim #2: To complete evaluation of N-MCT in vitro against smallpox, and in vivo against HSV-2-infected mice. This proposal does not include studies in monkypox-infected cynomolgus monkeys, which if successful, will require further testing in smallpox-infected primates, and will be done in collaboration with Dr. John Huggins, USAMRIID. Specific Aim #3: To complete preclinical toxicology and pharmacokinetic studies of N-MCT for filing an IND with the FDA. These studies will allow initiation of Phase I clinical trial to determine the maximum tolerated dose, toxicity, bioavailability and pharmacokinetic parameters.

Public Health Relevance:
Diseases associated with the Poxviridae genus of dsDNA viruses (smallpox, vaccinia and cowpox viruses, as well as the Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV, CMV) and Papillomaviridae (HPV) genera, represent major worldwide public health problems. The broad-spectrum orally bioavailable antiviral drug being developed by N&N Scientific, Inc. is N-methanocarbathymidine (N-MCT) that has exhibited substantial activity against herpes and pox viruses and drug-resistant variants in vivo at doses that have not produced any general cytotoxicity in mice. These unique pharmacological characteristics suggest that N-MCT would be an ideal candidate for further preclinical studies that lead to an IND and clinical trials, and the funds sought will help significantly in furthering its development.

Public Health Relevance Statement:
Diseases associated with the Poxviridae genus of dsDNA viruses (smallpox, vaccinia and cowpox viruses, as well as the Herpesviridae (HSV-1, HSV-2, HSV-8, VZV, EBV, CMV) and Papillomaviridae (HPV) genera, represent major worldwide public health problems. The broad-spectrum orally bioavailable antiviral drug being developed by N&N Scientific, Inc. is N-methanocarbathymidine (N-MCT) that has exhibited substantial activity against herpes and pox viruses and drug-resistant variants in vivo at doses that have not produced any general cytotoxicity in mice. These unique pharmacological characteristics suggest that N-MCT would be an ideal candidate for further preclinical studies that lead to an IND and clinical trials, and the funds sought will help significantly in furthering its development.