Trial of Inhaled Molgramostim in CF Subjects With NTM Infection

Methodology:

The Screening period will begin up to 10 weeks prior to the Baseline visit for collection of
the sputum sample, but the remainder of the assessments including Safety labs will be
completed within 6 weeks of Baseline, to determine eligibility. Adult subjects with a history
of cystic fibrosis (CF) and chronic pulmonary NTM infection will be considered for
enrollment. Chronic pulmonary NTM infection will be defined by at least three positive NTM
cultures (sputum or broncho-alveolar lavage (BAL)) for the same species/subspecies within the
past 2 years, with at least one positive within the past 6 months and a minimum of 50% of NTM
cultures positive over the past 2 years. Subjects should additionally provide a positive
sputum culture with the same species/subspecies within 10 weeks prior to Baseline during the
Screening period.

Three subgroups of subjects will be recruited:

- Group 1: Subjects who have not consistently achieved negative NTM sputum cultures while
currently on a multidrug NTM guideline-based antimycobacterial regimen, which has been
ongoing for at least 9 months prior to the Baseline visit.

- Group 2: Subjects who remain sputum culture positive but have stopped a multidrug NTM
guideline-based antimycobacterial regimen at least 28 days prior to Screening due to
lack of response or intolerance.

- Group 3: Subjects with chronic NTM infection not meeting recommendations for treatment
with a multidrug NTM guideline-based antimycobacterial regimen based on failure to meet
American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for
NTM pulmonary disease (i.e. absence of radiologic findings and clinical symptoms beyond
what is expected from underlying CF).

All subjects will have Screening, Baseline, Week 1, 2 and followed by monthly Treatment
visits from week 4 during the Treatment period. The Treatment period will be 48 weeks.
Following the End of Treatment (Week 48), subjects will have Follow-up visits at 4 and 12
weeks for assessment of durability of effect, and a final End of Study visit 24 weeks after
the End of Treatment. At the Baseline visit, eligible subjects will start treatment with
inhaled molgramostim. A detailed Schedule of Assessments is outlined in Table 1. At each
visit any changes in concomitant medication will be recorded. Participating subjects will be
encouraged to contact the clinic between visits if they experience adverse events (AE),
worsening of their condition or have any other concerns. If needed, unscheduled visits will
be conducted at the Investigator's discretion. All subjects will be maintained on their
standard CF treatment and medications independent of NTM treatment status.

Treatment with inhaled molgramostim will be given at a dosage of 300 μg once daily for 48
weeks. Dosing will be done in the morning, after completion of the subject's normal airway
clearance routine, where medications should be taken in the following order: bronchodilator,
dornase alfa (Pulmozyme), inhaled antibiotics (e.g. TOBI) and lastly inhaled molgramostim.

Subjects on a cyclical on-off anti-Pseudomonal regimen will have their trial visits (Baseline
and subsequent visits in the Treatment Period) scheduled during a week after at least three
weeks off treatment or after at least one week on-treatment of the antibiotic. Subjects on a
continuous inhaled regimen, including continuous alternating therapy (CAT), should have been
on a stable regimen for at least 28 days prior to Baseline.

A data review will be conducted after the first 6 subjects have completed 12 weeks of
treatment. If safety concerns or poor tolerability are identified in this review, the review
committee may decide on less frequent dosing for subsequent subjects in the study. Additional
safety reviews will be conducted at regular intervals thereafter. During the study, subjects
in Group 1 will continue use of antimycobacterial treatment, whereas subjects in Groups 2 and
3 will receive inhaled molgramostim as monotherapy for their NTM infection. For subjects in
Group 1, the antimycobacterial therapy should preferably not change during the treatment
period except in case of drug toxicity or adverse reactions. Antibiotics discontinued due to
toxicity may be replaced, with drug selection and dose modification at the discretion of the
treating physician. All changes in antimycobacterial treatment will be recorded, including
reasons for each change. In the event the Investigator has evidence of infection while on
treatment which requires more intensive therapy (i.e. additional antibiotics in Group 1 or
addition of antibiotics to Group 2 or 3) the subject may be allowed to continue after
discussion with the Sponsor medical monitor.

Number of subjects (planned):

A minimum of 30 subjects will be included. No formal sample size calculation was done as this
is an initial pilot study. To be able to assess response in each of the three subgroups, a
minimum of 4 and maximum of 7 subjects with MAC, and a minimum of 4 and a maximum of 7
subjects with MABSC, will be recruited in each subgroup. Thus, up to 14 subjects may be
included in each subgroup, i.e. 42 subjects may be included in total.

Inclusion Criteria:

1. Written informed consent obtained from participant.

2. Confirmed diagnosis of CF according to the Cystic Fibrosis Foundation (CFF) 2017
Consensus Guidelines.

3. History of chronic pulmonary infection with M. avium complex (MAC) or M. abscessus
complex (MABSC) (defined as at least three positive NTM cultures (sputum or BAL for
the same species (MAC) or subspecies (MABSC) within the past 2 years, with at least
one positive within the past 6 months and a minimum of 50% of NTM cultures positive
over the past 2 years) that does not demonstrate response to current treatment course
based on decreasing NTM burden or frequency of positive cultures, and in the opinion
of the Investigator is unlikely to resolve with current treatment course.

4. Subject fulfills one of the following criteria:

- Subject currently on a multidrug NTM guideline-based antimycobacterial regimen,
which has been ongoing for at least 9 months prior to the Baseline visit.

- Subject who has stopped a multidrug NTM guideline-based antimycobacterial regimen
at least 28 days prior to Screening due to lack of response or intolerance.

- Subjects with chronic NTM infection not meeting recommendations for treatment
with a multidrug NTM guideline-based antimycobacterial regimen based on failure
to meet ATS/IDSA criteria for NTM pulmonary disease (i.e. absence of radiologic
findings and clinical symptoms beyond what is expected from underlying CF).

5. Ability to produce sputum or be willing to undergo an induction protocol that produces
sputum for clinical evaluation.

6. An additional sputum culture, which is positive for the same species (MAC) or
subspecies (MABSC) of NTM as before the trial within 10 weeks of Baseline.

7. CF which in the Investigator's opinion is clinically stable and not expected to
require lung transplantation within the next year.

8. FEV1 ≥ 30% of predicted that is normal for age, gender, race, and height, using the
Global Lung Function Initiative (GLI) equation.

9. Subjects who are co-infected with a respiratory pathogen, e.g. P. aeruginosa or S.
aureus, must either be stable on a regular suppression antibiotic regimen or must be,
in the opinion of the Investigator, stable despite the lack of such treatment.

10. Female or male ≥18 years of age.

11. If female, subjects who have been post-menopausal for more than 1 year or females of
childbearing potential after a confirmed menstrual period using a highly efficient
method of contraception (i.e. a method with less than 1% failure rate) during and
until 30 days after last dose of trial treatment, having 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.

For purposes of this study, the Sponsor defines "acceptable methods of contraception"
as:

- Oral birth control pills administered for at least 1 monthly cycle prior to
administration of the study drug.

- A synthetic progestin implanted rod (eg, Implanon®) for at least 1 monthly cycle
prior to the study drug administration but not beyond the 4th successive year
following insertion.

- Intrauterine devices (IUDs), inserted by a qualified clinician for at least 1
monthly cycle prior to study drug administration.

- Medroxyprogesterone acetate (eg, Depo-Provera®) administered for a minimum of 1
monthly cycle prior to administration of the study drug and continuing through 1
month following study completion.

- Hysterectomy or surgical sterilization.

- Abstinence.

Double barrier method (diaphragm with spermicidal gel or condoms with contraceptive
foam) is not considered an acceptable form of contraception.

NOTE: For subjects prescribed Orkambi: Orkambi may substantially decrease hormonal
contraceptive exposure, reducing the effectiveness and increasing the incidence of
menstruation-associated adverse reactions. Hormonal contraceptives, including oral,
injectable, transdermal, and implantable, should not be relied upon as an effective
method of contraception when co-administered with Orkambi.

12. If male, subjects who, if sexually active of reproductive potential and non-sterile
(i.e., male who has not been sterilized by vasectomy for at least 6 months and not
diagnosed with infertility through demonstration of azoospermia in a semen sample
and/or absence of vas deferens through ultrasound) are willing to use a barrier method
of contraception, or their female partner must use an acceptable method of
contraception, during the study and until 30 days after last dose of medication.

13. 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:

1. Use of non-maintenance antibiotic for a concurrent pulmonary or extrapulmonary
infection within 28 days prior to the Baseline visit.

2. Use of a maintenance antibiotic regimen containing azithromycin for a concurrent
non-NTM pulmonary infection within 28 days prior to the Baseline visit. For subjects
in Group 1, azithromycin is allowed if part of ongoing multidrug NTM guideline-based
antimycobacterial regimen.

3. Prior therapy with inhaled or systemic granulocyte macrophage colony stimulating
factor (GM-CSF).

4. Subjects with hemoptysis of ≥60 mL in a 24-hour period within 4 weeks prior to
Screening.

5. Life expectancy of less than 6 months according to Investigator's judgement.

6. History of, or present, myeloproliferative disease, leukemia or other hematological
malignancy.

7. Active pulmonary malignancy (primary or metastatic); or any malignancy requiring
chemotherapy or radiation therapy within 1 year prior to Screening or anticipated
during the study period.

8. Active allergic bronchopulmonary mycosis or connective tissue disease, inflammatory
bowel disease or other autoimmune disorder requiring therapy associated with
significant immunosuppression, such as systemic corticosteroids at a dose equivalent
of 10 mg/day or more of prednisolone, within 3 months prior to Screening or
anticipated during the study period.

9. Changes in antimicrobial, bronchodilator, anti-inflammatory or corticosteroid
medications, or changes in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
modulators, within 28 days prior to the Baseline visit.

10. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to
Screening.

11. History of human immunodeficiency virus (HIV) infection or other disease associated
with significant immunodeficiency.

12. History of lung or other solid organ transplantation or currently on the list to
receive lung or other solid organ transplantation.

13. History of congestive heart failure (CHF) New York Heart Association (NYHA) Class III
or greater in severity.

14. History of cardiovascular ischemic event within 6 months of Baseline.

15. Any change in chronic NTM multi-drug antimycobacterial regimen within 28 days prior to
Screening.

16. Treatment with any investigational medicinal product within 3 months of Screening.

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

18. Any other condition that, in the opinion of the Investigator, would preclude informed
consent or assent, make study participation unsafe, complicate interpretation of study
outcome data, or otherwise interfere with achieving the study objectives.