Just-in-Time, Single-Dose, Universal Anti-Influenza A Virus Therapeutic
Abstract
Over 200,000 people are hospitalized every year from influenza-related complications in the U.S. alone, with over 3,000 deaths per year attributed to influenza, most due to Influenza A virus (IAV). The efficacy of currently available therapies, such as Tamiflu (oseltamivir) and Relenza (zanamivir), is controversial, with some recent reviews finding little to no impact on key clinical outcomes. IAV strains can be naturally resistant to these drugs, can become resistant following exposure to these drugs, or be purposefully weaponized to be fully resistant to these drugs, which represent our only currently available therapeutic options. A more effective drug is urgently needed. Our goal is to leverage our collective academic and industry experience in antiviral research and development to advance towards an IND an exciting novel inhibitor with broad-spectrum activity against IAV for use as a just-in-time, single-dose, anti-influenza A virus therapeutic capable of providing protection against all strains of IAV, including neuraminidase inhibitor-resistant strains. As such, this project is highly relevant to two FY17 PRMRP Topic Areas, Influenza and Antimicrobial Resistance. Our lead molecule, LNA14, specifically targets an essential structure in the IAV s genome that is required to package the genome into new viral particles. The targeted structure is highly conserved across all known IAV isolates, including 1918 pandemic flu and bird flu (H5N1). LNA14 is a highly stable molecule. In cultured cells, LNA14 dramatically inhibits production of infectious IAV at very low concentrations, and a single dose given intranasally to mice multiple days before infection protects mice from a lethal IAV infection. We now seek to develop LNA14 into a clinical stage drug by: (1) Further expanding the virology data package by [a] demonstrating activity against additional highly pathogenic and drug resistant strains of IAV; [b] providing additional evidence for LNA14 s high barrier to the development of resistance compared to other anti-IAV drugs in vitro and in vivo; [c] determining the minimum in vivo effective dose, and number of days before or after infection that LNA14 administration can rescue from influenza mortality; and [d] demonstrating LNA14 s efficacy in a second validated model (e.g., ferret), including prevention of transmission; (2) Enabling the optimal delivery and monitoring methods for in vivo preclinical studies by [a] establishing the analytical methods to monitor the distribution and clearance kinetics of LNA14 following in vivo administration; [b] determining optimal formulation for clinical delivery, and demonstrating the in vivo efficacy of intravenous (IV) delivery to complement the currently proven intranasal (IN) route; and [c] performing mouse, rat, and dog single dose pharmacokinetic studies via IN and IV routes; (3) Manufacturing LNA14 to support the requisite pre-clinical and future initial clinical studies by synthesizing both non-clinical and then clinical grade LNA14; (4) Performing initial in vitro and preclinical animal safety testing; and (5) Completing the required animal safety studies, a clinical development plan, and pre-Investigational New Drug (IND) meeting package. Our multidisciplinary team, including academic and industry partners with demonstrated expertise in virology, influenza biology, oligonucleotide chemistry, pulmonary formulation and delivery, regulatory affairs, and successful early drug development, is ideally suited for this proposal. Successful accomplishment of our specific aims will yield an exciting novel drug, LNA14, capable of countering with a single dose lethal pandemics, or seasonal flu, resulting from all known clinical isolates of influenza A virus to date. LNA14 thus has the potential for tremendous clinical and medical impact, and could uniquely protect our troops and the homeland they defend against a naturally occurring or purposefully weaponized IAV pan
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810647
Entities
People
- Jeffrey Glenn
Organizations
- Stanford University
- United States Army