Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis Autoimmune Pulmonary Alveolar Proteinosis
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Infectious Disease, Pulmonary |
| Therapuetic Areas: | Immunology / Infectious Diseases, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 2/3/2019 |
| Start Date: | August 17, 2017 |
| End Date: | June 2020 |
First in Human Study of Pioglitazone Therapy of Autoimmune Pulmonary Alveolar Proteinosis
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.
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.
PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure
that occurs in multiple diseases that can be classified on the basis of pathogenesis into
three groups: primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP,
hereditary PAP), secondary PAP (caused by reduction in alveolar macrophage numbers and/or
functions), and metabolic disorders of surfactant production-related PAP (caused by mutations
in genes required for normal surfactant production). Blood tests are capable of identifying
the PAP-causing disease in about 95% of patients.
Research has demonstrated that aPAP is caused by a high level of GM-CSF autoantibodies, which
block GM-CSF signaling. Normally, alveolar macrophages clear (remove) about half of the used
surfactant from air sacs (alveoli) in the lungs. Without GM-CSF, alveolar macrophages have a
reduced ability to clear surfactant, which builds up in the alveoli and the blocks delivery
of oxygen into the blood, resulting in a low blood oxygen level and a reduced oxygen delivery
to tissues of the body. This macrophage defect is thought to occur because loss of GM-CSF
stimulation causes reduced activity of PPAR-gamma, a molecule present within alveolar
macrophages that they require to simulate the ability to clear surfactant: the reduction in
PPAR-gamma activity cause a functional impairment of surfactant clearance by alveolar
macrophages.
Currently, no pharmacologic agent has been FDA-approved as therapy aPAP: it is currently
treated by whole lung lavage, a procedure requiring general anesthesia and a breathing
machine the lungs are individually filled with saline and drained repeatedly to physically
remove the excess surfactant. Recent research has shown that pioglitazone, a drug that
activates PPAR-gamma, is able to increase the ability of cultured macrophages to clear
surfactant in the laboratory and that oral administration is able to reduce lung disease
severity and be well-tolerated in a mouse model of aPAP. Currently, pioglitazone is approved
by the FDA for treatment of increased blood sugar in patients with diabetes.
This study is a pilot phase I/II human clinical trial of oral pioglitazone as therapy for
autoimmune PAP. The target population is adults with aPAP who have measurable, clinically
significant disease satisfying all of the inclusion and exclusion criteria. The study design
will involve recruitment, screening, and enrollment of participants into a phase I,
open-label, dose-escalating, single site study. Oral pioglitazone will be administered to
autoimmune PAP patients with a personalized dose escalation plan beginning at 15 mg per day,
advancing to 30 mg per day and then 45 mg per day, if tolerated, in 12 week increments.
Adverse events (AEs), serious AEs (SAEs), and pharmacodynamics (PD) parameters will be
evaluated. The experimental approach will evaluate 1) safety of oral pioglitazone by
documenting occurrence of treatment-emergent AEs and SAEs, 2) physiological effects of oral
pioglitazone by measuring changes in the physiological, clinical, and quality of life
parameters and 3) biochemical effects of pioglitazone on the transcriptome, phenotype, and
function of mononuclear phagocytes (alveolar macrophages and monocytes) from autoimmune PAP
patients. Anticipated results will determine the safety, efficacy, and biochemical effects of
oral pioglitazone in patients with autoimmune PAP. These results will impact the field by 1)
monitoring safety of oral pioglitazone in autoimmune PAP patients, 2) translating existing
preclinical data in humans, and 3) demonstrating the results of pioglitazone in a
personalized treatment plan with dose escalation in a pilot trial to evaluate the efficacy of
oral pioglitazone for aPAP.
that occurs in multiple diseases that can be classified on the basis of pathogenesis into
three groups: primary PAP (caused by disruption of GM-CSF signaling - autoimmune PAP,
hereditary PAP), secondary PAP (caused by reduction in alveolar macrophage numbers and/or
functions), and metabolic disorders of surfactant production-related PAP (caused by mutations
in genes required for normal surfactant production). Blood tests are capable of identifying
the PAP-causing disease in about 95% of patients.
Research has demonstrated that aPAP is caused by a high level of GM-CSF autoantibodies, which
block GM-CSF signaling. Normally, alveolar macrophages clear (remove) about half of the used
surfactant from air sacs (alveoli) in the lungs. Without GM-CSF, alveolar macrophages have a
reduced ability to clear surfactant, which builds up in the alveoli and the blocks delivery
of oxygen into the blood, resulting in a low blood oxygen level and a reduced oxygen delivery
to tissues of the body. This macrophage defect is thought to occur because loss of GM-CSF
stimulation causes reduced activity of PPAR-gamma, a molecule present within alveolar
macrophages that they require to simulate the ability to clear surfactant: the reduction in
PPAR-gamma activity cause a functional impairment of surfactant clearance by alveolar
macrophages.
Currently, no pharmacologic agent has been FDA-approved as therapy aPAP: it is currently
treated by whole lung lavage, a procedure requiring general anesthesia and a breathing
machine the lungs are individually filled with saline and drained repeatedly to physically
remove the excess surfactant. Recent research has shown that pioglitazone, a drug that
activates PPAR-gamma, is able to increase the ability of cultured macrophages to clear
surfactant in the laboratory and that oral administration is able to reduce lung disease
severity and be well-tolerated in a mouse model of aPAP. Currently, pioglitazone is approved
by the FDA for treatment of increased blood sugar in patients with diabetes.
This study is a pilot phase I/II human clinical trial of oral pioglitazone as therapy for
autoimmune PAP. The target population is adults with aPAP who have measurable, clinically
significant disease satisfying all of the inclusion and exclusion criteria. The study design
will involve recruitment, screening, and enrollment of participants into a phase I,
open-label, dose-escalating, single site study. Oral pioglitazone will be administered to
autoimmune PAP patients with a personalized dose escalation plan beginning at 15 mg per day,
advancing to 30 mg per day and then 45 mg per day, if tolerated, in 12 week increments.
Adverse events (AEs), serious AEs (SAEs), and pharmacodynamics (PD) parameters will be
evaluated. The experimental approach will evaluate 1) safety of oral pioglitazone by
documenting occurrence of treatment-emergent AEs and SAEs, 2) physiological effects of oral
pioglitazone by measuring changes in the physiological, clinical, and quality of life
parameters and 3) biochemical effects of pioglitazone on the transcriptome, phenotype, and
function of mononuclear phagocytes (alveolar macrophages and monocytes) from autoimmune PAP
patients. Anticipated results will determine the safety, efficacy, and biochemical effects of
oral pioglitazone in patients with autoimmune PAP. These results will impact the field by 1)
monitoring safety of oral pioglitazone in autoimmune PAP patients, 2) translating existing
preclinical data in humans, and 3) demonstrating the results of pioglitazone in a
personalized treatment plan with dose escalation in a pilot trial to evaluate the efficacy of
oral pioglitazone for aPAP.
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
We found this trial at
1
site
3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
Cincinnati, Ohio 45229
1-513-636-4200
Phone: 513-636-8916
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
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