Zambon SpA's Phase 3 PROMIS-I and PROMIS-II study results, published in The Lancet Respiratory Medicine, reveal that inhaled colistimethate sodium, delivered via the I-neb® Adaptive Aerosol Delivery System (CMS I-neb), significantly reduces pulmonary exacerbations and improves the quality of life for patients with non-cystic fibrosis bronchiectasis (NCFB) chronically colonized with Pseudomonas aeruginosa. These findings offer a potential new treatment option for a condition with limited approved therapies.
The PROMIS trials, both global, multicenter, randomized, double-blind, and placebo-controlled, enrolled adult patients with bronchiectasis and chronic P. aeruginosa colonization who had a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year. In PROMIS-I, 377 patients were randomized, while PROMIS-II included 287 patients, each receiving either inhaled colistimethate sodium or a placebo via the I-neb device twice daily for up to 12 months. The primary efficacy endpoint was the annual pulmonary exacerbation rate.
Key Findings from PROMIS-I and PROMIS-II
The PROMIS-I trial met its primary endpoint, demonstrating a 39% reduction in the annual pulmonary exacerbation rate (rate ratio 0.61; 95% CI 0.46–0.82; p=0.0010) compared to the placebo group. Furthermore, severe exacerbations were reduced by 59%, and patients treated with CMS I-neb experienced a clinically significant improvement in quality of life, as measured by the St. George's Respiratory Questionnaire, alongside a reduction in P. aeruginosa density.
Although the PROMIS-II study was prematurely halted due to the COVID-19 pandemic, a pre-pandemic sub-analysis showed results consistent with those of the PROMIS-I trial. Both trials indicated that CMS I-neb was generally well-tolerated, with no major safety concerns identified. Bronchospasm occurred in fewer than 5% of patients.
Clinical Significance
"The results of the PROMIS program represent an important breakthrough for patients with NCFB, a population that has long suffered from chronic respiratory infections without any approved treatments," said Dr. Charles Haworth, Respiratory Physician at the Cambridge Centre for Lung Infection at Royal Papworth Hospital, and PROMIS trials Chief Investigator. "For the first time, we have robust evidence showing that CMS I-neb can significantly reduce exacerbations and improve quality of life in patients with NCFB and chronic P. aeruginosa infection, offering hope where there were previously limited options."
Professor James Chalmers, Professor of Respiratory Research at the University of Dundee and PROMIS Investigator, added, "These findings underscore the importance of inhaled antibiotics, such as CMS I-neb, in reducing exacerbations and improving outcomes in patients with NCFB chronically infected with P. aeruginosa. Chronic bronchial infection plays a key role in driving inflammation and airway damage in bronchiectasis, and reducing exacerbations has been linked to better prognosis, quality of life and lung function."
About NCFB and Colistimethate Sodium
Non-cystic fibrosis bronchiectasis is a chronic lung disease characterized by recurrent infection, inflammation, persistent cough, and sputum production. Its prevalence is increasing worldwide, with estimates suggesting it affects up to 566 per 100,000 people. Chronic infection with P. aeruginosa is associated with more severe disease, accelerated lung function decline, increased exacerbations, hospitalizations, and a higher mortality rate.
Colistimethate sodium (CMS) is a pro-drug of the antibiotic colistin, effective against aerobic Gram-negative pathogens, including P. aeruginosa. It is considered a last-line therapeutic option for infections caused by multi-drug-resistant Gram-negative bacteria.
Regulatory Status and Future Directions
The PROMIS clinical program has received FDA Qualified Infectious Disease Product (QIDP), Fast Track, and Breakthrough designations for reducing pulmonary exacerbations in adult NCFB patients colonized with P. aeruginosa. Zambon is continuing to work with regulatory authorities to make colistimethate sodium delivered via a customized inhalation device available to patients with bronchiectasis and chronic P. aeruginosa infection.
