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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI095172-03
Application #
8597326
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Conley, Tony J
Project Start
2012-12-12
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$1,000,000
Indirect Cost
Name
Navigen, Inc.
Department
Type
DUNS #
792046224
City
Salt Lake City
State
UT
Country
United States
Zip Code
84108