Abstract Rationale KIT2014 is a peptide designed to interfere with the scaffold function of phosphoinositide 3 kinase gamma (PI3Kγ) and enhance β-adrenergic receptor (β-AR)/cAMP signaling. Preclinical studies show that KIT2014 disrupts the interaction of PI3Kγ with its partner, PKA, leading to type 3 and 4 phosphodiesterase (PDE3/4) inhibition and, in turn, enhanced and sustained intracellular cAMP levels. KIT2014 is being developed as an inhalation therapy for the treatment of patients with airway diseases including chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFBE) and cystic fibrosis (CF). Methods In this Phase 1, double-blind, randomized, placebo-controlled study (NCT06659757), healthy participants received single doses of nebulized KIT2014 (0.1, 0.3, 1.0, or 2.0 mg) or placebo in the Single Ascending Dose (SAD) part, and multiple once a day doses of KIT2014 (0.75, 1.5, or 2.0 mg) or placebo in the 7-days Multiple Ascending Doses (MAD) part. The primary objective evaluated the safety and tolerability of KIT2014, and the secondary objective characterized the pharmacokinetics of the peptide. Safety and tolerability were assessed through adverse events, vital signs, 12-lead electrocardiograms, spirometry, and clinical laboratory parameters. The pharmacokinetics of KIT2014 were evaluated in both parts of the study. Results All 56 healthy participants (32 in SAD and 24 in MAD) completed all doses and the study. Treatment with inhaled KIT2014 was safe and well tolerated. There were no serious treatment-emergent adverse events (TEAEs) and no TEAEs reported as severe. TEAEs were mostly mild, including TEAEs related to the respiratory system deemed related to the administration of the study drug, all of which were mild and transient. Safety and tolerability assessments, including comprehensive spirometry, demonstrated no safety signals during treatment, nor at the follow-up. Plasma levels of KIT2014 were below the lower limit of quantification at all dose levels, both in SAD and MAD, demonstrating that the inhalation route of administration results in negligible/low systemic exposure. Conclusions Treatment with KIT2014 at doses ranging from 0.1 to 2 mg for up to 7 days was safe and well tolerated in healthy participants, in this first-in-human Phase 1 study. The unique ability of KIT2014 to increase cAMP in the different airways cell types, leading to bronchodilator and anti-inflammatory effects, as seen in preclinical studies, has the potential to offer a promising new therapy for a number of airway diseases including COPD, NCFBE, and CF. The safety and pharmacokinetic profile in this study warrant further clinical development. This abstract is funded by: Kither Biotech
Uslenghi et al. (Fri,) studied this question.