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BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis.

King TE Jr, Behr J, Brown KK, et al. Am J Respir Crit Care Med. 2008;177(1):75-81.

Introduction:

• Pulmonary arterial hypertension (PAH) is a disease characterized by progressive remodeling of the pulmonary vasculature, and the vasoconstrictor endothelin-1 (ET-1) is involved in the regulation of this process.
• Patients with idiopathic pulmonary fibrosis (IPF) have elevated plasma concentrations of ET-1, and its expression is also elevated in their lungs. ET-1 concentration has been found to correlate with IPF disease activity, and this peptide may play a role in the pathophysiology of PAH and IPF. Some of the cellular functions that are increased by ET-1 include:
  • Proliferation of smooth muscle cells
  • Inflammation
  • Fibrosis
  • Collagen synthesis
  ET-1 may also exacerbate the fibrotic process by decreasing interstitial collagenase production.
  
• Bosentan is an antagonist of two forms of the endothelin receptor, ET_A and ET_B, and is an FDA-approved treatment for PAH.¹ The bosentan label carries a box warning for potential liver injury, as 11% of patients receiving the drug in clinical trials had elevated liver enzymes. In a rat bleomycin model of pulmonary fibrosis, bosentan reduced collagen deposition in the lungs.² IPF is a fibrotic lung disease, and bosentan is a potential candidate for treatment of this condition.

Study Design:

• BUILD-1 was a clinical study of bosentan treatment of IPF. In this double-blind, 12-month multicenter trial, data were collected on 154 IPF patients randomized to either bosentan (n = 71) or placebo (n = 83) treatment groups. Patients with IPF and severe PAH were excluded from this study.
• Primary efficacy endpoint: change from baseline to month 12 in exercise capacity, as measured by a 6-minute walk test distance (6MWD).
• Secondary endpoints:
• Time to death or disease progression (worsening pulmonary function tests (PFTs) or acute decompensation)
• Change in PFT scores
• Dyspnea
• Quality of life (QoL)

Findings:

• The 6MWD at month 12 decreased in both groups, with a mean change from baseline of –52 m in the bosentan group and –34 m in the placebo group. Thus, the study did not meet its primary endpoint.
• There were trends in delayed time to death or disease progression, and improvement in QoL with bosentan. Interestingly, bosentan significantly slowed disease progression in patients who obtained a surgical lung biopsy (SLB).
• There was an unusually high discontinuation rate both in the bosentan group (33.8%) and placebo group (28.6%), due mainly to disease progression. Similar to other trials, 12.2% of the bosentan patients withdrew due to liver function test abnormalities. Only 109 patients completed the study.

Expert Opinion:

• Even though the 6MWD appears to be a valid endpoint to evaluate disease progression and response to therapy in patients with PAH, it may not be a sufficiently reliable endpoint for IPF patients. The 6MWD is highly variable in these patients because they tend to be older and have comorbidities which affect the 6MWD. The preferred primary endpoint for IPF clinical trials is the change in FVC from baseline, which more accurately reflects disease progression.
• A positive effect of bosentan was observed in the subgroup of patients who had undergone SLB to confirm diagnosis of ILD. In these patients the combined incidence of disease progression or death was 12.2% for bosentan-treated patients and 38.0% for those who received placebo. This corresponded to a relative risk reduction of 68% (95% CI 26–86%,
  P = 0.005). Why did patients with SLB appear to do better on bosentan? Patients undergo SLB when an accurate diagnosis of IPF cannot be made by clinical and HRCT findings alone. Typically such patients lack honeycombing on HRCT. One explanation for these findings is that patients who undergo an SLB have earlier and less “destructive” IPF and are therefore more responsive to therapy. Disease severity, as measured by PFTs, was similar in the bosentan and placebo groups but patients who undergo an SLB may have a variant presentation of IPF, which is more responsive to therapy.
• It is clear that IPF is a heterogeneous disease with variations in pathology, HRCT findings, and patterns of progression. Further studies are required to validate the intriguing observation reported by King et al.

In summary, this provocative study suggests bosentan may delay disease progression and improve quality of life and dyspnea in IPF patients. An ongoing double-blind trial of bosentan versus placebo in IPF patients with SLB, the BUILD 3 study,³ is addressing this question. The primary endpoint of BUILD 3 is time to occurrence of disease worsening or death.

References

1. Tracleer Product Insert. Available at:
   http://www.fda.gov/cder/foi/label/2007/021290s010lbl.pdf. Accessed January 2008.
2. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med. 1997;156(2 pt 1):600–608.
3. BUILD 3: Bosentan Use in Interstitial Lung Disease. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00391443?term=build+3&rank=1. Accessed January 2008.

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