Pharmacokinetics analysis from first-in-human study of IN-002, a potent inhaled muco-trapping antibody therapy for RSV

Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral hospitalization and death in infants and young children, and also a major cause of respiratory illness in immunocompromised and elderly. Unfortunately, for the millions infected with RSV each year, there is no currently no treatment option available. Like many respiratory pathogens, RSV spreads in the lungs by shedding daughter virions from infected cells exclusively back into the airways. From there, RSV must traverse the airway mucus (AM) before infecting other neighboring cells, remaining restricted to the airways with little-to-no systemic viremia. This important mechanism of spread makes RSV difficult to target by systemically dosed therapies; the antiviral drugs need to make their way to the airway mucus in order to inactivate virions and halt infection. We believe an RSV-specific, safe, and effective antiviral therapy that can be inhaled directly into the respiratory tract using a hand-held device at home would provide a powerful treatment option. To meet this goal, Inhalon has been advancing IN-002, a mAb that binds and neutralizes RSV F protein with picomolar affinity, and has minimal risks of viral escape. Importantly, in addition to the well-established IgG Fc effector functions, IN-002 is also engineered to possess Fc N-glycans optimized to trap RSV in AM. Once trapped, RSV virions are quickly purged from the airways via natural mucociliary clearance mechanisms. We have further formulated IN-002 to be stably nebulized using a portable vibrating mesh nebulizer. In a neonatal lamb model of RSV infection, nebulized IN-002 reduced RSV viral load in the lungs and BALF to almost non-detectible levels within just 3 days. Inhalon has already manufactured clinical trial materials, and completed the full range of IND-enabling studies including GLP inhalation tox, tissue cross-reactivity and nebulization characterization studies. Inhalon is thus in position to execute a Phase 1 study for IN-002 in 2024. Inhalon has strong experience carrying out clinical studies with its inhaled mAb pipeline, being the first company to successfully complete a Phase 1 study for an inhaled mAb therapy for COVID (IN-006), and more recently executed a Phase 1b study to directly compare pulmonary distribution of the same mAb given by IV vs. by inhalation. This makes Inhalon exceptionally well positioned to execute a Phase 1 study for IN-002. In this proposal, we seek to obtain support to complete the non-clinical activities associated with the Phase 1 study, including processing of collected clinical trial biospecimens to determine drug levels in nasal swabs and serum, perform biostatistics calculations and PK modeling, and perform the medical writing to complete the clinical study report. These activities would in turn put Inhalon in a position to initiate a Phase 2 study to determine the efficacy of IN-002 in RSV-infected individuals. The work will further aid the development of future generations of inhaled, mAb-based therapies for a variety of pulmonary indications.