Preclinical Safety

Abstract

Several inhaled proteins and peptides have been developed to treat indications in the respiratory tract or systemically with varying degrees of success. This section will summarize the preclinical and clinical studies for inhaled Pulmozyme® (recombinant human deoxyribonuclease, rhDNase), insulin, human growth hormone (hGH), cyclosporine, alpha-1 antitrypsin, measles vaccine, and anti-immunoglobulin E (IgE). For Pulmozyme® (rhDNase), monkeys had positive serum antibody titers to rhDNase and allergic/hypersensitivity (type I) lung lesions in response to foreign protein likely due to differences in homology between monkey and human DNases. However, in patients, the levels of rhDNase antibodies were low and of no consequence. For inhaled insulin in rats, dogs and monkeys, there were no adverse effects related to insulin or excipients. In clinical trials, over 13,000 patients were safely treated with inhaled insulin for an average of 1 year. Some patients had higher antibody levels than comparators, but these antibodies did not decrease the effectiveness, safety or tolerability of inhaled insulin over time and/or affect clinical outcomes. Inhaled hGH had no adverse effects in monkeys, healthy volunteers or pediatric patients, but its absorption from the lungs was too low (<5%) in pediatric patients to be successful as a medical product. Inhaled cyclosporine had no unexpected systemic toxicity or clinically limiting findings in the respiratory tract in rat and dogs; it also had promising Phase 2 clinical data but failed in Phase 3. Inhaled alpha-1 antitrypsin also failed in a recent Phase 2/3 trial. A liquid inhaled measles vaccine was safe, well tolerated and produced an appropriate immune response in Phase 2/3 studies for children ages 10-35 months, but not younger. A dry powder inhaled vaccine in monkeys had no adverse effects and produced an immune response; Phase 1 trials are underway. Inhaled anti-IgE was well tolerated in monkeys and asthma patients, but systemic delivery had superior results in patients.

Keywords: Inhalation; Pulmozyme®; alpha-1 antitrypsin; anti-IgE; cyclosporine; growth hormone; insulin; measles vaccines; peptides; proteins; rhDNase.