Inhaled molgramostim safe in nontuberculous mycobacterial infection

Key takeaways:

• The OPTIMA trial included adults with Mycobacterium avium complex and patients with Mycobacterium abscessus.
• Researchers did not find any serious safety concerns with inhaled molgramostim.

A quarter of adults with a refractory nontuberculous mycobacterial infection had culture conversion during a 48-week daily inhaled molgramostim treatment period, according to results published in Annals of the American Thoracic Society.

“The OPTIMA cohort of patients had refractory [nontuberculous mycobacterial] infection characterized by poor prognostic factors, such as long duration of infection before enrollment (7 ± 7.4 years), elevated [C-reactive protein] at screening (16.9 ± 23.5 mg/L), low BMI (median, 19.5 kg/m²) and the presence of radiological cavities in 46.9% of patients,” Rachel M. Thomson, MBBS, PhD, head of the Greenslopes Clinical Unit and thoracic physician at Greenslopes Private Hospital and The Prince Charles Hospital, and colleagues wrote.

“The likelihood of any intervention having an impact in this group is low, and the overall sputum conversion rate of 25% is encouraging,” Thomson and colleagues continued.

In the open label, noncomparative pilot OPTIMA trial, Thomson and colleagues evaluated 32 adults (mean age, 67 years; 22 women) with a severe refractory nontuberculous mycobacterial infection — Mycobacterium avium complex (MAC; n = 24; mean age, 68.4 years; 15 women) or Mycobacterium abscessus (MABS; n = 8; mean age, 61.4 years; seven women) — to find out how many patients achieve sputum culture conversion (three monthly negative cultures in a row) while receiving 300 μg of inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) molgramostim (Savara Inc.) per day for 48 weeks.

As Healio previously reported, daily administration of inhaled molgramostim for 24 weeks had beneficial effects on pulmonary gas transfer and functional health status compared with placebo in patients with autoimmune pulmonary alveolar proteinosis.

Within the total OPTIMA cohort, half (n = 16; 12 MAC, four MABS) received inhaled molgramostim plus ongoing guideline-based therapy (GBT), whereas the other half (n = 16; 12 MAC, four MABS) only received inhaled molgramostim.

Researchers had 48-week data for 23 patients. Reasons for not reaching the end of the set treatment period included death, an adverse event and lack of efficacy.

During the 48-week treatment period, culture conversion was observed in seven patients in the MAC group (29.2%; n = 3 receiving molgramostim plus GBT; n = 4 receiving only molgramostim) and one patient from the MABS group (12.5%) who was receiving molgramostim plus GBT.

When assessing this endpoint at 12 weeks following the end of the treatment period, four patients (n = 3 MAC group; n = 1 MABS group) continued to have culture conversion.

In addition to culture conversion, researchers captured monthly positive/negative sputum smears.

A partial response, which researchers defined as “converting from smear positive at baseline to smear negative at the end of treatment,” was found in four patients from the MAC group, and two had negative cultures at the 48-week mark and the 12-week follow-up.

Further, researchers found a longer time to positivity in liquid culture media vs. baseline in the two remaining patients with a partial response.

Clinical outcomes including 6-minute walk distance, symptom scores, Quality of Life-Bronchiectasis Questionnaire score and body weight did not change with 48-week inhaled molgramostim.

In terms of safety, treatment-emergent adverse events occurred in every patient. Cough was reported by 22 patients, followed by dyspnea in 18 patients, nausea in 12 patients and peripheral blood eosinophilia in 10 patients.

Of the total cohort, five patients discontinued inhaled molgramostim due to a treatment-emergent adverse event.

Researchers also noted a total of 31 serious adverse events from 14 patients, which frequently were reports of pulmonary exacerbation hospitalizations or nontuberculous mycobacterial infection worsening.

“Overall, no safety concern was identified on the basis of evaluation of the [serious adverse event] data,” Thomson and colleagues wrote.

Lastly, none of the three deaths were related to the treatment, according to researchers.

“Further studies are needed to evaluate the mechanism of action of GM-CSF in this disease, using an integrated multiomics approach to evaluate the transcriptomic characteristics of macrophages (alveolar and monocyte derived) in patients with NTM infection, before and after treatment with GM-CSF,” Thomson and colleagues wrote.