IND-enabling development for IN-005, an inhaled muco-trapping mAb therapy against Influenza A

Inhalon Biopharma, Inc., Morrisville NC

Investigators

Abstract

Project Summary Seasonal influenza virus (INFV) infections represent a major public health burden. Although flu vaccines are broadly available, they only offer modest effectiveness and have limited uptake. Current antivirals are only modestly effective if given soon after symptoms emerge (~24-48hrs), which is achievable in less than half of infected patients due to delays in seeking care and confirming diagnosis. Several neutralizing monoclonal antibodies (mAb) against INFV have been advanced into Phase 2 studies over the past 2 decades. However, they have all failed in clinical studies due to inability to consistently achieve therapeutic concentrations in the respiratory tract (RT) following IV dosing. Indeed, in clinical studies, the subset of patients who experienced the greatest clinical benefit were those with the highest levels of mAb in nasal swab samples. This suggests that prior clinical failures were primarily due to insufficient distribution of mAb into respiratory fluids after IV administration, not due to deficiencies of the mAbs themselves. Inhalon is advancing a pipeline of antiviral mAbs to treat various acute respiratory infections, to be dosed directly into the RT via nebulization. Direct inhaled delivery allows us to achieve far higher mAb concentrations in the RT than IV dosing. Inhalon also incorporates into its mAb pipeline a largely underappreciated mAb effector function in mucus – trapping individual viruses in mucus – which blocks the local spread of the infection and facilitates rapid elimination of virions from the RT, removing a key source of antigens that can propagate infection-induced inflammation. We believe Inhalon’s approach to combine localized delivery with optimized mucosal effector function is uniquely well-suited to treat various acute respiratory infections, including INFV. To quickly advance this concept into the clinic, we have in-licensed a broadly neutralizing mAb against INFV-A from large pharma, with a well-established CMC package, existing GMP master cell bank, and excellent safety profile across multiple clinical studies. We have termed this reformulated molecule IN-005, and have developed formulations that support stable nebulization at high concentrations while maintaining physical stability and functional binding. In Aim 1, we will verify whether inhaled dosing of IN-005 can improve survival and reduce lung viral titers relative to oseltamivir standard of care, particularly when withheld until after oseltamivir’s efficacious treatment window. We will, in parallel, submit a pre-IND to the FDA (Aim 2A) to confirm the necessary preclinical and clinical pathway, and produce tox materials using an existing master cell bank CHO cell line (Aim 2B). This will enable us to complete the key additional preclinical studies (inhalation tox, nebulization characterization, Aim 3) that, in our experience with other mAbs in our pipeline, will support advancing IN-005 into clinical studies. Successful completion of these studies will put IN-005 at the doorstep of clinical studies as the first inhaled mAb therapy for INFV.