IND-enabling development for IN-003, an inhaled mAb therapy against human metapneumovirus infection

Project Summary Human metapneumovirus (MPV) is the second leading cause of lower respiratory tract infections (LRTI) in infants and young children, and a major cause of respiratory illness among the immunocompromised and the elderly. Unfortunately, there is currently no effective therapy or vaccine for MPV. A pathogen-specific, safe and effective antiviral would undoubtedly address the current gap in pharmacological interventions. MPV, like many common respiratory viruses, spreads in the respiratory tract by shedding progeny (i.e. daughter) virions back into airway mucus (AM); viruses must then diffuse through AM to reach and infect the next cell. Thus, the infection remains restricted to the apical side of the airways as it spreads from the upper respiratory tract to the lower respiratory tract, making it difficult to target by systemically dosed antivirals. Indeed, while neutralizing monoclonal antibodies (mAbs) offer a safe and likely effective antiviral intervention, their use is greatly limited by inconvenient dosing and limited distribution into the respiratory tract. Inhalon has been advancing a platform of inhaled mAb treatments capable of achieving very high concentrations of mAb directly in the respiratory tract (i.e. the site of infection) nearly instantly. Specifically, we have developed methods that enable stable and efficient delivery of mAbs via handheld vibrating mesh nebulizers, with dosing completed within minutes per day in the comfort of a patient’s own home. Inhalon has also developed a platform of muco-trapping mAbs, based on tuning sugars on the Fc domain of mAbs that enable effective crosslinking of virion/mAb complexes to mucins. Muco-trapping mAbs can directly block progeny viruses from diffusing through AM, and can quickly remove them from the airways by harnessing natural mucus clearance mechanisms. We have validated our topical mAb therapy approach in hamsters infected with MPV, as well as in lambs infected with RSV (another virus that, like MPV, propagates exclusively by apical shedding). Recently, we completed a Phase 1 human clinical study of the safety, tolerability, and pharmacokinetics of an inhaled mAb against SARS-CoV-2, and found excellent safety and high concentrations of drug in the airways in humans, despite using a far lower dose compared to typical IV doses. Inhalon is advancing IN-003, comprised of a pair of potent neutralizing mAbs against MPV F protein, as an inhaled mAb therapy against hMPV. By delivering IN-003 directly to the airways, we expect to enable efficacious and cost-effective treatment for MPV, with limited risk of adverse side effects. In this project, we seek to produce a GLP tox lot batch of IN-003, and conduct the key GLP IND-enabling studies required by the FDA before advancing to the clinic. The proposed work, based on our recent regulatory experience advancing inhaled mAbs for SARS-CoV-2 and RSV, represents the critical path to advance IN-003 into the clinic. Successful completion of this work will put us in a position to quickly file an IND following GMP manufacturing of clinical trial materials, leading to the first clinical study of an inhaled mAb therapy for MPV.