Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare disorder of oculocutaneous albinism, platelet dysfunction, and in some subtypes, fatal pulmonary fibrosis. There is no effective treatment for the pulmonary fibrosis except lung transplantation, but an initial trial using pirfenidone, an anti-fibrotic agent, showed promising results. The current, randomized, placebo-controlled, prospective, double-blind trial investigated the safety and efficacy of pirfenidone for mild to moderate HPS-1 and 4 pulmonary fibrosis. Subjects were evaluated every 4 months at the National Institutes of Health Clinical Center, and the primary outcome parameter was change in forced vital capacity using repeated measures analysis with random coefficients. Thirty-five subjects with HPS-1 pulmonary fibrosis were enrolled during a 4-year interval; 23 subjects received pirfenidone and 12 received placebo. Four subjects withdrew from the trial, 3 subjects died, and 10 serious adverse events were reported. Both groups experienced similar side effects, especially gastroesophageal reflux. Interim analysis of the primary outcome parameter, performed 12 months after 30 patients were enrolled, showed no statistical difference between the placebo and pirfenidone groups, and the study was stopped due to futility. There were no significant safety concerns. Other clinical trials are indicated to identify single or multiple drug regimens that may be effective in treatment for progressive HPS-1 pulmonary fibrosis.

Figure 1. Forced vital capacity of placebo subjects plotted against time on study

Percentage of predicted forced vital capacity for 12 subjects receiving placebo is shown. Interval measurements were made every 4 months on study.

Figure 2. Forced vital capacity of pirfenidone subjects plotted against time on study

Percentage of predicted forced vital capacity for 23 subjects receiving pirfenidone is shown; interval measurements were made every 4 months on study.

Figure 3. Representative CT scan images from two HPS subjects

A–C. CT scans of subject #104, a 54-year-old man, randomized to placebo, showing worsening fibrosis (arrows) with a subpleural predominance of disease. The patient’s baseline FVC fell from 65% to 34% of predicted after 32 months on study. D–I. CT scans of subject #107, a 48-year-old woman randomized to pirfenidone. The conventional (D–F) and high-resolution (G–I) CT scans show bilateral progressive areas of fibrosis (arrows). Her baseline FVC fell from 62% to 37% of predicted after 24 months on study.