Trial of Inhaled Molgramostim in Cystic Fibrosis Subjects With Nontuberculous Mycobacterial Infection

A 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 participants with a history of CF and chronic pulmonary NTM infection will be considered for enrollment. Chronic pulmonary NTM infection will be defined by at least 3 positive NTM cultures (sputum or broncho-alveolar lavage (BAL)) for the same species/subspecies of mycobacterium avium (MAC) or mycobacterium abscessus complex (MABSC) within the 2 years prior to screening, with at least one positive within the past 6 months prior to screening and a minimum of 50% of NTM cultures positive over the past 2 years. Participants must additionally provide a positive sputum culture with the same species/subspecies obtained from the central laboratory during the Screening period to be eligible.

Three groups of participants will be recruited:

• Group 1: Participants with chronic pulmonary MAC or MABSC infection 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: Participants with chronic pulmonary MAC or MABSC infection 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: Participants with chronic pulmonary MAC or MABSC 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 participants 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 a Follow-up visit at 4 and 12 weeks, and the End of Study visit 24 weeks after the End of Treatment. At the Baseline visit, eligible participants will start treatment with inhaled molgramostim.

At each visit any changes in concomitant medication will be recorded. Participants 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 participants 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.

Participants 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. Participants 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 participants 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 participants in the study. Additional safety reviews will be conducted at regular intervals thereafter. During the study, participants in Group 1 will continue use of antimycobacterial treatment, whereas participants in Groups 2 and 3 will receive inhaled molgramostim as monotherapy for their NTM infection. For participants 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 participant may be allowed to continue after discussion with the Sponsor medical monitor.

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 groups, a minimum of 8 participants with MAC or MABSC will be enrolled into each of the 3 groups, and a minimum of 30 participants will be enrolled across all 3 groups. The maximum number of participants enrolled into each group will be 12, and the maximum number of participants enrolled into the study will be 34.