Brensoctib: Managing Side Effects of the Novel DPP-1 Inhibitor for Bronchiectasis

Brensoctib is a novel oral inhibitor of dipeptidyl peptidase-1 (DPP-1), designed to treat bronchiectasis and other neutrophil-driven inflammatory conditions by reducing acute exacerbations. While it offers significant therapeutic promise, its mechanism of suppressing neutrophil activation requires careful management of specific safety signals.

1. Mechanism and Safety Overview

By inhibiting DPP-1, Brensoctib blocks the activation of neutrophil serine proteases (NSPs), thereby reducing airway inflammation. However, because neutrophils are vital to innate immunity, this suppression can lead to increased susceptibility to infections and specific effects on the skin and gums. Understanding these risks is the foundation of safe long-term use.

2. Dermatological Reactions and Management

Clinical trials report skin-related issues such as dryness, scaling, follicular hyperkeratosis, and palmoplantar keratoderma. These are linked to epithelial differentiation changes due to DPP-1 inhibition.

• Management:​ Daily use of emollients containing urea or ceramides is essential. Mild keratolytics can address thickening skin. If painful fissures occur, temporary dose reduction or interruption may be necessary. Most patients adapt over time with consistent skincare.

3. Periodontal and Oral Health

A notable safety signal is the increased risk of periodontitis and gingivitis, stemming from altered oral microbial homeostasis.

• Prevention & Management:​ A dental baseline evaluation is recommended before starting therapy. Patients must maintain rigorous oral hygiene, including brushing after meals and using chlorhexidine mouthwash. Any progressive periodontal issues warrant immediate dental intervention and possible drug interruption.

4. Infection Risk Mitigation

Due to partial suppression of pathogen clearance, there is a slight increase in the risk of upper respiratory tract infections, bronchitis, and skin infections.

• Strategy:​ Most mild-to-moderate infections can be treated without stopping Brensoctib. However, pneumonia or recurrent deep infections require discontinuation and immune assessment. Prophylactic non-live vaccines (e.g., flu, pneumococcal) are advised.

5. General Tolerability and Monitoring

Other common reactions include headache, nasopharyngitis, and mild gastrointestinal upset (nausea, loose stools). These are typically transient. Routine monitoring should include complete blood counts and liver/kidney function tests to detect any rare organ-specific toxicities.

6. Dose Adjustment and Long-Term Strategy

For Grade 3 or intolerable toxicities (severe infection, severe keratosis), temporarily hold the drug until recovery, then restart at a lower dose if appropriate. Flexibility in dosing is key to balancing efficacy with safety. Patient education on recognizing early signs and maintaining preventative care is crucial for sustained therapy.