Evaluation of a Single Dose of Inhaled Sargramostim in Patients With Autoimmune Pulmonary Alveolar Proteinosis

PAP is a rare syndrome of surfactant accumulation and resulting hypoxemic respiratory failure
that occurs in a number of diseases classified pathogenically 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 surfactant
dysfunction-related PAP (caused by mutations in genes required for normal surfactant
production). In current clinical practice, PAP is diagnosed based on a lung biopsy; an
approach that is not able to identify the etiology of the PAP. Current therapy involves the
physical removal of surfactant by a procedure in which the lungs are repeatedly filled with
saline and emptied - whole lung lavage, which is invasive, inefficient, and not widely
available, especially for children. Importantly, research advances have elucidated the
pathogenesis of diseases causing PAP in most patients and have identified new diagnostic and
therapeutic approaches. Simple blood-based research tests can now identify the PAP-causing
disease in about 95% of patients. Further, several promising potential disease-specific
therapies are currently in development. Preliminary clinical trials of inhaled rhGM-CSF in
autoimmune PAP patients show promising results, 62%-96% therapeutic response rate at two
doses (250 and 500 mcg/day) without any identified safety concerns. At least 73 people with
autoimmune PAP have been reported to have received inhaled sargramostim with no identified
drug-related adverse effects. However, the PK, PD, optimal dose, and treatment duration
needed to maximize efficacy are unknown. The short-term goal is to address knowledge gaps for
inhaled sargramostim for autoimmune PAP patients in the following clinical study: a pilot
safety and PK/PD study (TPSC-110). A major goal of this protocol is to evaluate the local and
systemic safety, PK, and PD one dose of inhaled sargramostim in autoimmune PAP. The central
hypothesis is that in patients with autoimmune PAP, aerosol inhalation of sargramostim will
be well-tolerated and safe because the GM-CSF autoantibody will limit detection of free
GM-CSF thereby preventing local and systemic toxicity. The specific objectives of this study
are to: 1) evaluate the safety profile of one dose of inhaled sargramostim in patients with
autoimmune PAP 2) estimate the PK profile of inhaled sargramostim following single dose
administration in patients with autoimmune PAP 3) measure the PD effects of inhaled
sargramostim following single dose administration in patients with autoimmune PAP.

The target population is adults with autoimmune PAP 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, multi-site study. Sargramostim will be administered to autoimmune PAP patients
via aerosol inhalation one time at a dose of 125 mcg or 250 mcg. Adverse events (AEs),
serious AEs (SAEs), PK, and PD parameters will be evaluated (see Appendix 3 Schedule of
Events). The experimental approach will evaluate 1) safety of inhaled sargramostim by
documenting occurrence of treatment-emergent AEs and SAEs, 2) PK profile of GM-CSF in serum
and BAL fluid, 3) local and systemic PD effects of inhaled GM-CSF and 4) effects of inhaled
GM-CSF on the quality of life for participants. Anticipated results will determine the safety
profile of inhaled sargramostim in patients with autoimmune PAP, will evaluate total and free
GM-CSF levels in blood and lung, effects of sargramostim on blood and BAL cell counts,
differentials, baseline- and GM-CSF-responsiveness of blood leukocytes and BAL cells, and
biomarkers of PAP in patients with autoimmune PAP after single dose administration. These
results will impact the field by 1) confirming existing published data, 2) monitoring local
effects of inhaled sargramostim in autoimmune PAP patients, 3) demonstrating a safe starting
dose to evaluate the efficacy of inhaled sargramostim for autoimmune PAP.

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 use hand held nebulizer

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

Diagnosis of autoimmune PAP 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 autoimmune PAP

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 ≥ 15 mm Hg

Exclusion Criteria:

Diagnosis of any other PAP-causing disease

Autoimmune PAP complicated by:

- Severe disease at screening/enrollment (A-aD02<50)

- Clinically significant pulmonary fibrosis

History of any clinically significant:

- Other lung disease

- Cardiovascular disease

- Disease requiring use of systemic steroids in past year

- Coagulopathy or other hematologic disease

- Active / serious lung or systemic infection

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

- Use of any immunosuppressive medication within 3-6 months of screening

- Women who are pregnant or plan to become pregnant

- History of active tobacco/e-cig/marijuana use

- Concomitant or recent use of specific medicines