What is the basis for the use of nintedanib (tyrosine kinase inhibitor) in fibrotic Hypersensitivity Pneumonitis (HP)?

Evidence Basis for Nintedanib in Fibrotic Hypersensitivity Pneumonitis

The use of nintedanib in fibrotic hypersensitivity pneumonitis is based primarily on the INBUILD trial (2019), which demonstrated that nintedanib significantly reduced the annual rate of FVC decline in patients with progressive fibrosing interstitial lung diseases, including hypersensitivity pneumonitis. 1

Primary Evidence: The INBUILD Trial

The INBUILD trial is the pivotal study supporting nintedanib use in fibrotic HP:

• In the overall progressive fibrosing ILD population (which included HP patients), nintedanib reduced the annual FVC decline to -80.8 ml/year compared to -187.8 ml/year with placebo, representing a treatment difference of 107.0 ml per year (95% CI, 65.4 to 148.5; P<0.001). 1

• The trial enrolled 663 patients with various progressive fibrosing ILDs affecting more than 10% of lung volume on high-resolution CT, who had documented disease progression in the preceding 24 months despite treatment. 1

• Patients were required to have FVC ≥45% predicted and DLCO 30-80% predicted at baseline. 1

Guideline Recommendations Based on INBUILD

Following the INBUILD trial results, major respiratory societies updated their recommendations:

• The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association conditionally recommend nintedanib for progressive pulmonary fibrosis from various causes, which includes fibrotic HP when it meets progressive disease criteria. 2

• The quality of evidence supporting this recommendation is rated as low to moderate, reflecting the conditional nature of the recommendation. 3

Defining Progressive Fibrotic HP Eligible for Treatment

For fibrotic HP to qualify for nintedanib treatment based on the INBUILD criteria:

• Disease progression must be documented by either: (1) FVC decline ≥10% predicted within 24 months, OR (2) FVC decline 5-10% predicted plus worsening respiratory symptoms or increased fibrosis on imaging within 24 months. 2

• The fibrotic disease must affect more than 10% of lung volume on high-resolution CT. 1

Subgroup Analysis for Hypersensitivity Pneumonitis

While the INBUILD trial included HP patients, specific subgroup data shows variable responses:

• Real-world evidence suggests nintedanib effectively reduces FVC decline in progressive fibrosing ILD populations, though the magnitude of benefit may vary by underlying disease type. 4

• In vitro studies demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP at nanomolar concentrations, reducing PDGF-driven proliferation and migration, as well as TGF-β1-induced myofibroblastic differentiation. 5

Expected Clinical Benefits in Fibrotic HP

Based on the INBUILD trial and supporting evidence:

• Nintedanib reduces the annual FVC decline by approximately 107 ml compared to placebo in progressive pulmonary fibrosis patients. 2, 3

• The drug decreases the risk of ILD progression 2.4-fold. 2, 3

• Treatment slows disease progression but does not reverse existing fibrosis. 3

Common Pitfalls and Management

The most significant challenge with nintedanib in fibrotic HP is tolerability:

• Diarrhea occurs in approximately 62-67% of patients versus 18-24% on placebo, making it the most common adverse event. 2, 1

• For persistent diarrhea, dose reduction from 150 mg twice daily to 100 mg twice daily is recommended rather than discontinuation. 2, 3

• Liver enzyme elevations (AST/ALT) occur 3.2-3.6 times more frequently than placebo and require monthly monitoring for 3 months, then every 3 months. 2, 3

• Weight loss occurs 3.7 times more frequently and should be monitored throughout treatment. 2, 3

Treatment Algorithm for Fibrotic HP

1. Confirm progressive fibrotic HP with documented FVC decline meeting INBUILD criteria and >10% lung involvement on HRCT. 2, 1

2. Verify baseline parameters: FVC ≥45% predicted and DLCO 30-80% predicted. 1

3. Initiate nintedanib 150 mg twice daily as the standard dose. 2, 3

4. Monitor closely: Liver function tests monthly for 3 months then quarterly; assess for diarrhea and weight loss at each visit. 2

5. Manage adverse events: Reduce to 100 mg twice daily for persistent GI symptoms before considering discontinuation. 2, 3