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FREDERICK, MD, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 442.16K | Year: 2007

DESCRIPTION (provided by applicant): The goals of this Phase II research proposal focus on the further development of a topical microbicide for vaginal and rectal use from a small group of highly potent pyrimidinedione molecules identified in our Phase I research. Topical microbicides represent an important strategy for preventing the sexual transmission of HIV, the predominant mode by which HIV is transmitted worldwide, especially in the developing world. The specific rationale for the development of the pyrimidinedione series of molecules includes the observation that the compounds exhibit subnanomolar activity against clinical strains of HIV-1 and HIV-2, including subtypes found throughout the world, the compounds inhibit HIV infection and replication through two distinct mechanisms of action, including inhibition of reverse transcription and viral entry, and they display a significantly high level of activity in cervical explant models of sexual transmission. The specific aims of the proposal are constructed to identify our primary lead pyrimidinedione microbicide for clinical development from among a series of highly potent molecules which were selected based on the results of our Phase I microbicide testing. We propose to utilize this agent, either alone or in combination with another microbicide, for advancement to IND submission and clinical trials. The selection criteria used to identify the superior microbicide candidate will be based on an algorithm using established and novel in vitro assays developed to examine compound efficacy, toxicity, stability, and formulation in a microbicide-like environment. These assays will examine the efficacy of the pyrimidinediones alone and in combination with each other or other microbicide compounds against multiple clinical strains of HIV-1 and HIV-2 in the presence of vaginal and seminal simulates in primary and established cell lines hypothesized to represent models of the sexual transmission of HIV. In addition, the efficacy of the pyrimidinediones against other STIs and their toxicity to Lactobacilli and normal human vaginal and cervical cells will also be examined in an environment that mimics that of the vagina at the time of intercourse and HIV transmission. Following in vitro analysis, a lead compound will be advanced to toxicology evaluations in well established animal model systems. These animal models will utilize rabbits and rodents to examine the contact hypersensitivity and adsorption potential of the lead compounds alone and in combination. Additional studies will also be performed using the cervical explant model to confirm the efficacy and lack of toxicity of the candidate microbicide in its formulated state. These assays are designed to address the FDA's points to consider in the preclinical development of anti-infective agents, and are specifically tailored to address the requirements of an effective topical microbicide as defined by the International Working Group on Microbicides. The results of this research will be used as a basis for Phase III preclinical research and the submission of an Investigatory New Drug (IND) application to the FDA for the use of pyrimidinediones as single or combination topical microbicides. In the absence of an effective vaccine to prevent HIV infection, the development of a low cost and effective barrier to the sexual transmission of HIV is one of medicine's most pressing issues in light of the high rates of virus transmission occur in the developing world, especially in women in social settings where the negotiation of condom use is problematic. It has been estimated that a microbicide product that is only 60% effective could prevent millions of new infections by HIV each year. The pyrmidinediones have characteristics that make them superior microbicide candidates, including the fact that they are highly potent inhibitors of HIV infection, inhibit both virus entry and reverse transcription, are highly active in cervical explant models of sexual virus transmission, and they can be easily synthesized at low cost.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 141.37K | Year: 2009

DESCRIPTION (provided by applicant): The goals this Phase I SBIR grant are focused on the development of PG 301029 and chemically related compounds as therapeutics for treatment of hepatitis C virus infection. PG 301029 is a small molecule inhibitor of hepatitis C virus (HCV) replication that has been shown to be less toxic and have a larger therapeutic index than the approved therapeutic ribavirin in in vitro assays using the HCV surrogate bovine viral diarrhea virus (BVDV). The relative decrease in toxicity of PG 301029 compared to that of ribavirn was also observed when studies were extended to include a panel of primary and established cell lines, suggesting the potential of PG 301029 as a safer and more efficacious drug than ribavirin for the treatment of HCV. Additionally, preliminary in vivo toxicology studies indicate that the compound is well tolerated and has a pharmacokinetic profile appropriate for drug development. We will perform a structure activity relationship (SAR) based examination of an additional fifteen compounds previously identified as inhibitors of BVDV replication in a screen of 155 near neighbor related compounds for their ability to inhibit replication of an HCV replicon. These studies will provide insight into the functional structural features of PG 301029 which contribute to the antiviral activity and will be the basis for chemi- informatic studies to develop second generation PG 301029 based inhibitors as a component of the Phase II SBIR proposal. PUBLIC HEALTH RELEVANCE: The goal of this Phase I SBIR is to identify and characterize novel inhibitors of hepatitis C virus replication. The lead compound for development, PG 301029, is a small molecule that acts through a novel mechanism of action to reduce viral RNA accumulation in BVDV-infected and HCV replicon and has a therapeutic index greater gt 500 against BVDV. Structure activity relationship (SAR) analysis with 15 chemically related molecules that have shown antiviral activity against BVDV will be performed using a HCV replicon cell line to define the structural features of PG 301029 which contribute to their functional antiviral activity . The collective data will be the basis for chemi-informatic studies to develop second generation inhibitors as a component of the Phase II SBIR proposal. We will also use hypothesis directed research to define the mechanism of action of the antiviral activity by examining alterations in macromolecular interactions and gene expression in PG 301029 treated cells.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 272.48K | Year: 2008

DESCRIPTION (provided by applicant): The goal of this project is to define the mechanism of anti-HIV activity of the small molecule pyrimidinedione HIV inhibitor IQP-0410. IQP-0410 inhibits HIV replication by two distinct mechanisms, acting as a nonnucleos ide reverse transcriptase inhibitor while also potently suppressing virus entry. Unlike other NNRTIs, IQP-0410 inhibits both HIV-1 and HIV-2. The ability of IQP-0410 to prevent HIV entry into target cells occurs through a unique mechanism and the compound has been found to be more potent against clinical strains of HIV than against laboratory-derived viruses. The proposed research will utilize in vitro assays for selection and genotypic and phenotypic characterization of viruses resistant to IQP-0410. The p rogram will focus on resistance engendering mutations within the viral gag, pol and envelope genes. A series of chimeric viruses containing wild type HIV-1 and HIV-2 sequences and sequences from resistant viruses at early, mid, and late stages of the selec tion process will be engineered to examine the contribution of the individual domains to IQP-0410 resistance and fitness of the virus. Pseudotype viruses possessing envelope glycoproteins from wild type and IQP-0410-resistant HIV-1 and HIV-2 viruses will b e evaluated for their ability to infect target cells in the presence and absence of IQP-0410 and to quantify the effects of env mutations on the antiviral activity of IQP-0410. Pseudotype viruses with site-specific mutations engineered into envelope gp120 and gp41 domains identified by resistance selection will be utilized to define the conformational epitope within the envelope structure targeted by IQP-0410 in entry inhibition. Additionally, experiments will be performed to further understand the role of mutations in the gag gene and evaluate potential effects of IQP-0410 on virus maturation from infected cells. The impact of resistance mutations on the activity of viral RT and protease will also be examined using biochemical analysis. PUBLIC HEALTH RELEVA NCE The goal of this grant proposal is to define the mechanism of action of a small molecule inhibitor of human immunodeficiency virus (HIV). The HIV inhibitor (IQP-0410) is known to inhibit two essential stages of virus infection and replication (reverse transcription and virus entry), and thus has the potential for providing a combination therapy with administration of a single drug. The proposed research will define the molecular targets of the compound within the virus, the mechanism by which the compou nd inhibits virus replication, and mutations that occur in the virus that make it resistant to the compound and the effects of these mutations on virus replication and infectivity.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 301.47K | Year: 2010

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has been successfully utilized in HIV-infected individuals to significantly reduce disease progression and improve the prognosis of infected individuals. However, the side-effects, toxicity, and drug-drug interactions of HAART therapies have resulted in reduced patient adherence to the drug regimens, fueling the development of drug resistance. Thus, a continuing need for new and improved antiretroviral agents exists. Current ARVs target five steps in HIV replication, and include inhibition of virus entry (CCR5 antagonism and fusion inhibition) and inhibition of the virus-specific enzymes reverse transcriptase, integrase and protease. Although improvements in the efficacy and toxicity of new generation inhibitors in these existing classes of drugs continues to occur, it is also important to consider the development of new and novel drugs targeting additional required steps in HIV replication. These new agents would be expected to remain fully active against existing drugresistant and multi-drug resistant viruses and thus might be highly effective supplements to existing HAART regimens or constituents of salvage therapy regimens in patients failing long courses of RT and protease inhibitor therapies. It is clear that the continued development of new agents with enhanced potency, reduced toxicity, and a greater genetic barrier to resistance, as well as targeting other HIV replication steps, is a critical need for the continued effectiveness of HIV therapy ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione (PYD) inhibitor of HIV-1 with a molecular weight of 352 g/mole. The compound exhibited a therapeutic index of approximately one to four million in replicate antiviral assays, indicating that it was several orders of magnitude more active against HIV-1 than nevirapine and the early NNRTIs and of similar potency to Sustiva. but without the significant toxicities reported for Sustiva.. Although the primary mechanism of action of IQP-0410 is inhibition of the viral reverse transcriptase (RT), acting as a typical third generation nonnucleoside RT inhibitor (NNRTI) at sub-nanomolar concentrations, this compound also inhibits viral entry at nanomolar concentrations. The dual mechanism of action confers a high genetic barrier to the selection of IQP-0410-resistant viruses and in vitro assays have shown significant activity of IQP-0410 against clinically relevant drug resistant virus strains and against multi-drug resistant virus strains with resistance to protease inhibitors. Due to low solubility and poor penetration through the mucosa to the target site of action, pyrimidinediones face significant obstacles as a therapeutic. Therefore, strategic drug delivery designs are essential for pyrimidinediones to advance as viable HAART products. Through conventional administration, such as injections or oral, PYD would be subjected to extensive first pass metabolism by the liver limiting its effectiveness. We propose transdermal films an innovative drug delivery strategy to enhance PYD therapeutic efficacy and delivery through polymeric formulations. Specifically, transdermal films delivery has many advantages over conventional administration such as improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. We propose that this project will identify a transdermal film formulation that will enhance efficacy and allow long term therapeutic delivery of IQP-0410. PUBLIC HEALTH RELEVANCE: ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione inhibitor of HIV-1, as a therapeutic drug. ImQuest Biosciences will utilize their expertise in HIV drug development and formulation to develop a novel delivery system transdermal films. This delivery vehicle will provide constant HIV therapeutics in a solid dosage form that has the advantage of improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. The research to be performed will include development of the transdermal film and the evaluation of its ability to deliver a therapeutic amount of IQP-0410 over long periods of time.

Ham A.S.,Imquest Biosciences | Rohan L.C.,Magee Womens Research Institute | Boczar A.,Imquest Biosciences | Yang L.,Imquest Biosciences | And 2 more authors.
Pharmaceutical Research | Year: 2012

Purpose: Polymeric quick-dissolving films were developed as a solid dosage topical microbicide formulation for the vaginal delivery of the highly potent and non-toxic, dual-acting HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) pyrimidinedione, IQP-0528. Methods: Formulated from approved excipients, a polyvinyl alcohol (PVA) based film was manufactured via solvent casting methods. The film formulations were evaluated based upon quantitative physicochemical evaluations defined by a Target Product Profile (TPP) Results: Films dosed with 0.1% (w/w) of IQP-0528 disintegrated within 10 min with over 50% of drug released and near 100% total drug released after 30 min. The IQP-0528 films were found to be non-toxic in in vitro CEM-SS and PBMC cell-based assays and biologically active with sub-nanomolar efficacy against HIV-1 infection. In a 12 month stability protocol, the IQP-0528 films demonstrated no significant degradation at International Conference on Harmonization (ICH) recommended standard (25°C/65% relative humidity (R.H.)) and accelerated (40°C/75% R.H.) environmental conditions. Conclusions: Based on the above evaluations, a vaginal film formulation has been identified as a potential solid dosage form for the vaginal delivery of the topical microbicide candidate IQP-0528. © 2012 Springer Science+Business Media, LLC. Source

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