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.
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.