A randomized, double-blind, Phase 1 study of IN-006, an inhaled antibody treatment for COVID-19

RationaleAlthough COVID-19 is predominantly a respiratory tract infection, current antibody treatments are administered by systemic dosing. We hypothesize that inhaled delivery of a muco-trapping monoclonal antibody would provide a more effective and convenient treatment for COVID-19. ObjectiveWe investigated the safety, tolerability, and pharmacokinetics of IN-006, a reformulation of regdanvimab, an approved intravenous treatment for COVID-19, for nebulized delivery by a handheld nebulizer. MethodsA Phase 1 study was conducted in healthy volunteers. Study staff and participants were blinded to treatment assignment, except for pharmacy staff preparing the study drug. The primary outcomes were safety and tolerability. Exploratory outcomes were pharmacokinetic measurements of IN-006 in nasal fluid and serum. ResultsTwenty-three participants were enrolled and randomized across two single dose and one multiple dose cohorts. There were no serious adverse events (SAEs). All enrolled participants completed the study without treatment interruption or discontinuation. All treatment-emergent adverse events were transient, non-dose dependent, and were graded mild to moderate in severity. Nebulization was well tolerated and completed in a mean of 6 minutes in the high dose group. Mean nasal fluid concentrations of IN-006 in the multiple dose cohort were 921 {micro}g/g of nasal fluid at 30 minutes after dosing and 5.8 {micro}g/g at 22 hours. Mean serum levels in the multiple dose cohort peaked at 0.55 {micro}g/mL at 3 days after the final dose. ConclusionsIN-006 was well-tolerated and achieved concentrations in the respiratory tract orders of magnitude above its inhibitory concentration. These data support further clinical development of IN-006. RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621001235897

Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 support its development as a potent, dose-saving inhaled therapy for COVID-19

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID-19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self-dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc-mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID-19 in several countries around the world, can effectively trap SARS-CoV-2 virus-like-particles in fresh human airway mucus. IN-006, a reformulation of Regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN-006 resulted in 100-fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN-006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS-CoV-2 and other respiratory pathologies.