Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis Autoimmune Pulmonary Alveolar Proteinosis

• Status: Completed
• Trial end date: 2019-04-02
• Target enrollment: 0
• Participant gender: All

Summary

Pulmonary alveolar proteinosis (PAP) is a syndrome of surfactant accumulation, respiratory failure, and innate immune deficiency for which therapy remains limited to whole lung lavage (WLL), an invasive physical procedure to remove surfactant unavailable at most medical centers. While PAP occurs in multiple diseases affecting men, women, and children of all ages and ethnic origins, in 85% of patients, it occurs as an idiopathic disease associated with neutralizing GM-CSF autoantibodies. Basic science and translational research has shown that idiopathic PAP is an autoimmune disease in which disruption of GM-CSF signaling impairs the ability of alveolar macrophages to clear surfactant and perform host defense functions.

Recently, it has been shown that cholesterol toxicity drives pathogenesis in alveolar macrophages from GM-CSF deficient (Csf2-/-) mice and patients with autoimmune PAP. Loss of GM-CSF signaling reduces PU.1/CEBP-mediated expression of PPARγ and its downstream target ABCG1 (a cholesterol exporter important in macrophages). The cell responds by esterifying and storing cholesterol in vesicles to reduce toxicity. Eventually, vesicles fill the cell, impair intracellular transport and reduce uptake and clearance of surfactant from the lung surface resulting in disease manifestations. Recent data indicates that pioglitazone, a PPARγ agonist currently approved by the FDA for human use, increases cholesterol/surfactant clearance by alveolar macrophages from autoimmune PAP patients and Csf2-/- mice. Importantly, pioglitazone significantly reduced the severity of PAP lung disease in Csf2-/- mice after several months of therapy. Together, these observations suggest pioglitazone could be 'repurposed' as pharmacologic therapy for PAP.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Children's Hospital Medical Center, Cincinnati
• Treatments: Pioglitazone

Criteria

Inclusion Criteria:

• Male or female

• Age ≥ 18 years and ≤ 80 years

• Able to understand and willing to sign a written informed consent document

• Able and willing to complete administration of study drug at home

• Able and willing to adhere to study visit schedule and study procedures

• Diagnosis of aPAP determined by:

• History of a diagnosis of PAP with or without supporting lung histology or BAL/cytology and

• Abnormal serum GM-CSF autoantibody test (GMAb ELISA Test) and

• Chest CT findings compatible with a diagnosis of aPAP

• Evidence of impaired GM-CSF signaling demonstrated by an abnormal STAT5 phosphorylation index (STAT5-PI) test measured in heparinized whole blood at the time screening

• A-aDO2 ≥ 25 mm Hg

Exclusion Criteria:

• Diagnosis of any other PAP-causing disease

• aPAP complicated by:

• Severe disease at screening/enrollment (A-aD02<55)

• Clinically significant pulmonary fibrosis

• History of any clinically significant:

• Other lung disease

• Cardiovascular disease

• Disease requiring use of systemic steroids in past year

• History of Diabetes Mellitus

• History of untreated osteoporosis

• History of bladder cancer

• Active / serious lung or systemic infection

• Persistent or unexplained fever >101oF within 2 months of study

• Treatment with an investigational therapeutic agent for aPAP within 3 months prior to enrollment, which includes inhaled GM-CSF

• Abnormal clinical and/or laboratory parameters at screening

• Women who are pregnant or plan to become pregnant

• Concomitant or recent use of specific medicines