SBIR-STTR Award

HIV/AIDS remains a formidable global epidemic with 33 million infections worldwide, including over 1 million patients in the US. In 2008, there were 2.7 million new infections and 2 million AIDS-related deaths. Current HIV treatment combines drugs from several classes of HIV inhibitors and has dramatically extended the lives of many HIV patients, but serious side effects and rapidly increasing drug resistance are significant concerns. Thus, there is a continuing need to develop HIV inhibitors with new mechanisms of action and more robust resistance profiles. Navigen Pharmaceuticals is a pharmaceutical development company targeting infectious diseases. Using a combination of discovery and design, we have identified a novel type of HIV entry inhibitor (protease-resistant D-peptide) that targets HIV's conserved extracellular entry machinery and overcomes the limitations of existing HIV entry inhibitors (e.g., frequent and high dosing, narrow breadth, injection site reactions, and susceptibility to resistance). Our lead prototype (PIE12-trimer) potently inhibits diverse strains from all major subtypes of HIV and is extraordinarily elusive to resistance. We have developed multiple variants of PIE12-trimer in an effort to minimize dosing frequency and have selected two that we expect to be superior. In this one-year grant application, Navigen proposes to (1) develop a bioanalytical assay to support preclinical development of PIE12-trimer, (2) measure pharmacokinetic (PK) properties, and (3) conduct acute, 7-day, and 28-day rat toxicity studies on the two most promising lead candidates. This information will allow Navigen to select an ideal PIE12-trimer variant with low toxicity and PK properties compatible with weekly dosing for advancement into IND-enabling studies and ultimately clinical trials.

Public Health Relevance:
Navigen Pharmaceuticals is developing a potent and novel inhibitor of HIV entry. The goal of this study is to optimize our lead candidate for weekly dosing and low toxicity. If successful, this new inhibitor will improve the health of HIV/AIDS patients by providing them with a safe and highly effective new therapeutic option.

Thesaurus Terms:
Aids;Aids Virus;Aids/Hiv;Aids/Hiv Problem;Acquired Immune Deficiency;Acquired Immune Deficiency Syndrome;Acquired Immune Deficiency Syndrome Virus;Acquired Immuno-Deficiency Syndrome;Acquired Immunodeficiency Syndrome;Acquired Immunodeficiency Syndrome Virus;Acquired Immunologic Deficiency Syndrome;Acute;Adverse Effects;Applications Grants;Assay;Bioassay;Biologic Assays;Biological Assay;Blood Serum;Cdc;Cells;Centers For Disease Control;Centers For Disease Control And Prevention;Centers For Disease Control And Prevention (U.S.);Cessation Of Life;Cholest-5-En-3-Ol (3beta)-;Cholesterol;Clinic;Clinical Research;Clinical Study;Clinical Trials;Combined Modality Therapy;Common Rat Strains;Communicable Diseases;Data;Death;Development;Dose;Drug Kinetics;Drug Resistance;Drugs;Ec 2.7.7.49;Epidemic;Esteroproteases;Evaluation;Fda Approved;Fret;Fluorescence Resonance Energy Transfer;Frequencies (Time Pattern);Frequency;Future;Fuzeon;General Viruses;Goals;Grant Proposals;Hiv;Hiv Entry Inhibitors;Hiv Protease;Hiv Proteinase;Hiv/Aids;Hiv/Aids Problem;Htlv-Iii;Htlv-Iii Protease;Half-Life;Health;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Infection;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Injection Site Reaction;Integrase Inhibitors;Lav-Htlv-Iii;Loinc Axis 2 Property;Lead;Link;Lymphadenopathy-Associated Virus;Measures;Medication;Multimodal Therapy;Multimodal Treatment;Multimodality Treatment;Patients;Pb Element;Peptidases;Peptide Hydrolases;Peptides;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacokinetics;Pharmacologic Substance;Pharmacological Substance;Phase;Predisposition;Property;Proteases;Proteinases;Proteins;Proteolytic Enzymes;Rna Transcriptase;Rna-Dependent Dna Polymerase;Rna-Directed Dna Polymerase;Rat;Rats Mammals;Rattus;Resistance;Resistance Profile;Resistant Profile;Rest;Reverse Transcriptase;Revertase;Roche Brand Of Pentafuside;Serum;Subcutaneous Injections;Surface;Susceptibility;Therapeutic;Toxic Effect;Toxicities;Toxicology;Treatment Side Effects;United States Centers For Disease Control;United States Centers For Disease Control And Prevention;Variant;Variation;Viral Diseases;Virus;Virus Diseases;Virus-Hiv;Base;Clinical Investigation;Combination Therapy;Combined Modality Treatment;Combined Treatment;Design;Designing;Developmental;Drug Resistant;Drug/Agent;Extracellular;Gene Product;Heavy Metal Pb;Heavy Metal Lead;Improved;Inhibitor;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Multimodality Therapy;New Therapeutics;Next Generation Therapeutics;Novel;Novel Therapeutics;Pre-Clinical;Pre-Clinical Study;Pre-Clinical Trial;Preclinical;Preclinical Study;Preclinical Trial;Prevent;Preventing;Prototype;Resistance To Drug;Resistant;Resistant To Drug;Side Effect;Therapy Adverse Effect;Treatment Adverse Effect;Viral Infection;Virus Infection;Virus-Induced Disease

With 33 million people living with HIV/AIDS (including 1.2 million in the US), and 1.8 million AIDS-related deaths annually, HIV/AIDS remains a formidable global epidemic (UNAIDS, CDC). Modern HIV therapy combines drugs from different classes to form "cocktail" therapies that have significantly prolonged the lives of many HIV patients. However, side effects and drug resistance remain serious concerns. Thus, there is an enduring need for novel HIV inhibitors with new mechanisms of action and stronger barriers to resistance. Navigen is a pharmaceutical development company targeting infectious diseases. Through an innovative discovery and design process, we have identified a novel HIV entry inhibitor (protease-resistant D-peptide) that targets HIV's conserved entry machinery and overcomes the current limitations of this inhibitor class. Our lead candidate (chol-PIE12-trimer) inhibits diverse strains from all major subtypes of HIV with high potency and possesses an unprecedented barrier to resistance. Further, chol-PIE12-trimer appears from our Phase I SBIR preclinical studies to possess pharmacokinetic (PK) and physicochemical properties that would support development of a once-weekly, and perhaps once-monthly (with depot formulation) subcutaneous injectable. In this three-year grant application, we propose the following specific aims to advance chol-PIE12-trimer towards IND filing, as well as continue to explore potential backup candidates including PIE12-trimer, should problems with chol-PIE12-trimer arise: (1) advance the manufacturing and formulation of chol-PIE12-trimer, (2) investigate the ADME properties of chol-PIE12-trimer, (3) hold a pre-IND meeting with the FDA to discuss our nonclinical and early clinical plans, (4) evaluate the in vivo proof-of-concept efficacy of chol-PIE12-trimer in a standard nonhuman primate (NHP) model of HIV infection, and (5) further characterize the safety of chol- PIE12-trimer in toxicology and safety pharmacology studies in rats and NHPs. These data will be used to select a final candidate for advancement to IND and ultimately to the clinic as a marketable entry inhibitor. This proposal will also provide valuable toxicology data that will advance D-peptides as a therapeutic platform against diverse viral infections and other diseases.

Public Health Relevance:
Navigen is developing a novel D-peptide inhibitor of HIV entry with remarkable potency, breadth, and an unparalleled barrier to resistance. The goal of this proposal is to establish the in vivo efficacy of our lead candidate, chol-PIE12-trimer, and advance it towards IND filing and human clinical trials. Chol-PIE12-trimer has the potential to offer an exciting new therapeutic option to HIV/AIDS patients.

Public Health Relevance Statement:
Navigen is developing a novel D-peptide inhibitor of HIV entry with remarkable potency, breadth, and an unparalleled barrier to resistance. The goal of this proposal is to establish the in vivo efficacy of our lead candidate, chol-PIE12-trimer, and advance it towards IND filing and human clinical trials. Chol-PIE12-trimer has the potential to offer an exciting new therapeutic option to HIV/AIDS patients.

Project Terms:
absorption; Acquired Immunodeficiency Syndrome; Adverse effects; AIDS/HIV problem; analytical method; Animal Model; Applications Grants; Autopsy; Centers for Disease Control and Prevention (U.S.); Cessation of life; chemical synthesis; Chemistry; Clinic; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Cytochrome P450; Data; design; Development; Disease; Dose; Drug Exposure; Drug Formulations; Drug Kinetics; Drug resistance; Ensure; Enzymes; Epidemic; Evaluation; Excretory function; experience; FDA approved; Feces; Future; Goals; HIV; HIV Entry Inhibitors; HIV Infections; HIV therapy; Human; in vivo; Infection; inhibitor/antagonist; Injectable; innovation; Investigation; irritation; Lead; Life; Liver Microsomes; manufacturing process; meetings; Metabolism; Methods; microbicide; Modeling; monomer; mouse model; Mus; Nature; nonhuman primate; novel; novel therapeutics; Oryctolagus cuniculus; Parents; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma Proteins; preclinical study; Predisposition; Process; Production; Program Development; Property; Protein Binding; Rattus; Research Design; Resistance; response; Roche brand of pentafuside; Rodent; Safety; Small Business Innovation Research Grant; subcutaneous; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Urine; Virus Diseases; Work