IMPAHCT: A randomized phase 2b/3 study of inhaled imatinib for pulmonary arterial hypertension.

AV-101 (imatinib) powder for inhalation, an investigational dry powder inhaled formulation of imatinib designed to target the underlying pathobiology of pulmonary arterial hypertension, was generally well tolerated in healthy adults in a phase 1 single and multiple ascending dose study. Inhaled Imatinib Pulmonary Arterial Hypertension Clinical Trial (IMPAHCT; NCT05036135) is a phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging, and confirmatory study. IMPAHCT is designed to identify an optimal AV-101 dose (phase 2b primary endpoint: pulmonary vascular resistance) and assess the efficacy (phase 3 primary endpoint: 6-min walk distance), safety, and tolerability of AV-101 dose levels in subjects with pulmonary arterial hypertension using background therapies. The study has an operationally seamless, adaptive design allowing for continuous recruitment. It includes three parts; subjects enrolled in Part 1 (phase 2b dose-response portion) or Part 2 (phase 3 intermediate portion) will be randomized 1:1:1:1 to 10, 35, 70 mg AV-101, or placebo (twice daily), respectively. Subjects enrolled in Part 3 (phase 3 optimal dose portion) will be randomized 1:1 to the optimal dose of AV-101 and placebo (twice daily), respectively. All study parts include a screening period, a 24-week treatment period, and a 30-day safety follow-up period; the total duration is ∼32 weeks. Participation is possible in only one study part. IMPAHCT has the potential to advance therapies for patients with pulmonary arterial hypertension by assessing the efficacy and safety of a novel investigational drug-device combination (AV-101) using an improved study design that has the potential to save 6-12 months of development time. ClinicalTrials.gov Identifier: NCT05036135.

AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study.

Background: Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs. Methods: This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days. Results: 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%). Conclusions: AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.

Safety and toxicology of cyclosporine in propylene glycol after 9-month aerosol exposure to beagle dogs.

BACKGROUND: Cyclosporine inhalation solution (CIS) delivered via nebulization is under evaluation for the prevention of chronic rejection post-lung transplant. A 300-patient randomized, controlled clinical trial (CYCLIST) is expected to be completed late in 2011. In support of this trial, a chronic inhalation toxicology study in dogs has been completed. METHODS: To mimic the clinical setting, animals (four/sex/dose plus two/sex/dose in the control and high dose recovery groups) were exposed to aerosolized CIS, via nose-only exposure, three times per week for 9 months at targeted inhaled doses of 0 (air), 4, 12, and 24 mg/kg. In addition, the potential for persistence or reversibility of any toxic effects were assessed after a 6-week recovery period. The toxicological endpoints included clinical observations, body-weight, food consumption, toxicokinetics, clinical chemistry, and histopathology. RESULTS: All dogs receiving CIS completed the study with the only consistent observations being excessive salivation and changes in minute ventilation. There was no limiting lung or systemic toxicity associated with exposure to CIS, and the only possible drug-related effect was an observation of benign fibroadenoma tissue in the mammary glands of the high-dose female recovery group. Toxicokinetic data showed that cyclosporine is initially absorbed rapidly with little drug remaining in lung tissue or blood 24 h after the end of dosing. CONCLUSION: The study supports the pulmonary and systemic safety of aerosolized CIS at expected lung dose levels/kg of up to 12 times greater than the average dose patients are receiving in the CYCLIST trial.

Toward managing chronic rejection after lung transplant: the fate and effects of inhaled cyclosporine in a complex environment.

The fate and effects of inhaled cyclosporine A (CsA) are considered after deposition on the lung surface. Special emphasis is given to a post-lung transplant environment and to the potential effects of the drug on the various cell types it is expected to encounter. The known stability, metabolism, pharmacokinetics and pharmacodynamics of the drug have been reviewed and discussed in the context of the lung microenvironment. Arguments support the contention that the immuno-inhibitory and anti-inflammatory effects of CsA are not restricted to T-cells. It is likely that pharmacologically effective concentrations of CsA can be sustained in the lungs but due to the complexity of uptake and action, the elucidation of effective posology must ultimately rely on clinical evidence.

KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice.

KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.