Efficacy and Safety of Inhaled Molgramostim (rhGM-CSF) in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

The trial is a randomised, double-blind, placebo-controlled multicentre clinical trial
investigating efficacy and safety of inhaled molgramostim (rhGM-CSF) in autoimmune pulmonary
alveolar proteinosis (aPAP) patients.

The primary objective is efficacy on the Alveolar-arterial oxygen difference after 24-weeks
treatment. Secondary objectives are tolerance to exercise, effect on Quality of Life, time to
Whole Lung Lavage (WLL), effect on pulmonary function, effect on dyspnea and cough, and
effect on computed tomography (CT) scoring. Number of reported adverse events (AEs), serious
AEs, and adverse drug reactions will be monitored.

The trial will include two phases; a Double-blind treatment period consisting of up to eight
trial visits (Screening, Baseline, and at Weeks 4,8,12, 16, 20 and 24 after randomisation)
and a Follow-up period consisting of up to five trial visits (at Weeks 4, 12, 24, 36 and 48
post-treatment).

In the Double-blind treatment period, eligible subjects will be randomised to treatment for
up to 24 weeks with either: 1) inhaled molgramostim (300 µg) once daily, 2) inhaled
molgramostim (300 µg) and matching placebo administered intermittently (seven days on and
seven days off) or 3) inhaled placebo once daily. During the trial, WLL may be applied as
rescue therapy in case of significant clinical worsening. In the Follow-up period, open-label
treatment with molgramostim will be provided.

Brief risk assessment:

There is currently no approved pharmacological treatment for patients with PAP, and therefore
an unmet need for further treatment modalities exists.

Results from pre-clinical studies with inhaled molgramostim nebuliser solution showed the
expected pharmacological effects on white blood cell (WBC) populations locally and
systemically in line with observed effects after IV administration of molgramostim. No
severe, serious or dose-limiting AEs were observed in the first clinical study in humans
(MOL-001). The most common AE was cough, which was reported at a similar incidence for the
molgramostim nebuliser solution and placebo. Increases of WBC populations in the blood
consistent with the known mechanism of action were observed; most of which were considered
not clinically significant. Only two cases (total WBC increased and eosinophilia) were
reported as AEs. No development of anti-drug antibodies was observed.

Inclusion Criteria:

- aPAP diagnosed by computed tomography, or by biopsy, or by Broncho Alveolar Lavage
(BAL), and by increased GM-CSF autoantibodies in serum.

- Stable or progressive aPAP during a minimum period of two months prior to the Baseline
visit.

- Arterial oxygen concentration <75 mmHg/<10 kilo Pascal (kPa) at rest, OR desaturation
of >4 percentage points on the 6 Minute Walk Test (6MWT)

- An (A-a)DO2 of minimum 25 mmHg/3.33 kPa

- Female or male ≥18 years of age

- Females who have been post-menopausal for >1 year or females of childbearing potential
after a confirmed menstrual period using a highly efficient method of contraception
(i.e. a method with <1% failure rate such as combined hormonal contraception,
progesterone-only hormonal contraception, intrauterine device, intrauterine
hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual
abstinence), during and until 30 days after last dose of double-blind trial treatment.
Females of childbearing potential must have a negative serum pregnancy test at
Screening (Visit 1) and a negative urine pregnancy test at dosing at Baseline (Visit
2) and must not be lactating

- Males agreeing to use condoms during and until 30 days after last dose of double-blind
medication, or males having a female partner who is using adequate contraception as
described above

- Willing and able to provide signed informed consent

- Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other trial procedures specified in the protocol as judged by the investigator

Exclusion Criteria:

- Diagnosis of hereditary or secondary pulmonary alveolar proteinosis (PAP)

- WLL within one month of Baseline

- Treatment with GM-CSF within three months of Baseline

- Treatment with rituximab within six months of Baseline

- Treatment with plasmapheresis within three months of Baseline

- Treatment with any investigational medicinal product within four weeks of Screening

- Concomitant use of sputum modifying drugs such as carbocysteine or ambroxol

- History of allergic reactions to GM-CSF

- Connective tissue disease, inflammatory bowel disease or other autoimmune disorder
requiring treatment associated with significant immunosuppression, e.g. more than 10
mg/day systemic prednisolone

- Previous experience of severe and unexplained side-effects during aerosol delivery of
any kind of medicinal product

- History of, or present, myeloproliferative disease or leukaemia

- Known active infection (viral, bacterial, fungal or mycobacterial)

- Apparent pre-existing concurrent pulmonary fibrosis

- Any other serious medical condition which in the opinion of the investigator would
make the subject unsuitable for the trial