Innovative Therapeutics in Pulmonology: Meeting Unmet Needs

In a field where innovation seeks to meet persistent needs, two therapies are drawing attention. Brensocatib and mepolizumab are emerging options in non-CF bronchiectasis and eosinophilic COPD, respectively, with benefits and risks still being defined through ongoing studies and careful patient selection.

Brensocatib represents a potential advance in non-CF bronchiectasis as a selective DPP-1 inhibitor and remains investigational; it is being evaluated for its ability to mitigate chronic neutrophilic inflammation that exacerbates disease, addressing an unmet need pending regulatory review.

Mechanistically, it aligns care toward focused inflammatory control.

Building on early signals, a phase 2 trial reported a longer time to first exacerbation and fewer exacerbations with brensocatib, while subsequent phase 3 findings have been mixed; taken together, the evidence warrants cautious optimism rather than claims of a paradigm shift, as summarized in a review of DPP-1 inhibition with brensocatib.

As precision approaches evolve across airway diseases, attention is turning to distinct inflammatory endotypes—shifting from neutrophil-driven pathways targeted by DPP-1 inhibition to eosinophil-driven pathways modulated by IL-5–targeted therapies such as mepolizumab.

From data to practice, mepolizumab has been evaluated for COPD with an eosinophilic phenotype and may be considered for patients with frequent exacerbations despite optimized inhaled therapy when blood eosinophil counts are elevated, aligning selection with guideline-based criteria rather than media reports.

Biomarkers such as blood eosinophil count play an instrumental role in personalizing COPD treatment, particularly when considering IL-5–pathway therapies.

In practice, benefits are most evident in patients with a history of exacerbations despite optimized inhaled therapy and elevated blood eosinophils (for example, at or above commonly used thresholds in guidelines), reinforcing the role of targeted selection.

In clinical studies, reductions in exacerbation rates have been observed in selected patients with eosinophilic COPD receiving mepolizumab, reinforcing the importance of applying therapy within evidence-based selection criteria.

Despite encouraging progress, challenges remain—for example, mixed late-phase results for brensocatib, questions about optimal eosinophil thresholds and payer coverage for mepolizumab, and the need to better define long-term safety and ideal candidates.

Looking ahead, optimizing use should remain anchored to current evidence-based criteria and labeling, with any expansion to broader populations contingent on results from ongoing and future trials.

Key Takeaways:

• Targeted therapies addressing distinct inflammatory endotypes (neutrophilic and eosinophilic) are informing care pathways in bronchiectasis and COPD.
• Evidence for brensocatib is evolving, with encouraging phase 2 data and mixed phase 3 findings warranting cautious interpretation.
• Selection for mepolizumab in COPD should be guided by exacerbation history and elevated blood eosinophil counts within evidence-based criteria.
• Practical considerations include safety monitoring, payer coverage, and ongoing trials that may refine indications and patient selection.