Pirfenidone Solution for Inhalation (AP01) for Idiopathic Pulmonary Fibrosis (ATLAS Study): A Randomized, Open-Label, Dose-Response Trial

Background: Oral pirfenidone reduces lung function decline and mortality in idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects including nausea, rash, photosensitivity, weight loss, and fatigue. Dosage reductions in response to side effects may be suboptimal in slowing the rate of disease progression. This trial (ATLAS) assessed the safety, tolerability, and efficacy of pirfenidone solution for inhalation (AP01) in patients with IPF. Methods: This phase 1b randomized, open-label, dose-response trial is being performed at 25 sites in six countries (ANZCTR: ACTRN12618001838202). Patients diagnosed with IPF within 5 years, forced vital capacity (FVC) 40–90% predicted, and intolerant, unwilling, or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulized AP01 50 mg once daily (QD) or 100 mg twice daily (BID) for 48 weeks. The primary efficacy measure was absolute change in FVC % predicted. Findings: Participants were recruited between May 31, 2019, and April 30, 2020; of 141 IPF patients screened, 91 were enrolled (50 mg QD: n=46, 100 mg BID: n=45). Changes in FVC % predicted (95% CI) over 48 weeks, estimated as slopes, were −­5·3 (−8·0, −2·7) in the 50 mg QD and −0·5 (−3·3, 2·3) in the 100 mg BID groups (evaluable n=39 and 34, respectively); difference was 4·8 (1·0, 8·7); p=0·0152. The most common treatment-related adverse events (all mild to moderate) included cough (14, 15·4%), rash (11, 12·1%), nausea (8, 8·8%), throat irritation (5, 5·5%), dysgeusia and fatigue (4 each, 4·4%), and dizziness and dyspnoea (3 each, 3·3%). Interpretation: Mean FVC % predicted was stable in the 100 mg BID group, and FVC response was significantly better than in the 50 mg QD group. Nausea and rash side effects commonly associated with oral pirfenidone were less frequent with AP01. Further study of AP01 is warranted. Trial Registration: This phase 1b randomized, open-label, dose-response trial is being performed at 25 sites in six countries (ANZCTR: ACTRN12618001838202). Funding: Avalyn Pharma Declaration of Interest: MLS, DN, LF, KO, and ABM are all employees of the sponsor, Avalyn Pharma. Authors AGW, AB, MLWilsher, PH, MS, and WP report no conflicts of interest. NC received a grant from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim, Carrick, Carrick, Redex, UCB, and Novartis; speaker fees and travel sponsorship from Boehringer Ingelheim and Roche; and payment for participation on data safety monitoring/advisory board from Boehringer Ingelheim. IG reports consulting fees from Amplia, Ad Alta, and Accendatech; speaking fees from Boehringer Ingelheim; and payment for participation in a safety review committee from Accendatech. TJC reports receiving grants/contracts from Boehringer Ingelheim, Roche, Bristol Myers Squibb, Biogen, Galapagos, and Avalyn Pharma; speaker’s honoraria from Boehringer Ingelheim and Roche; and payment for participation on data safety monitoring/advisory board from Boehringer Ingelheim, Roche, Bristol Myers Squibb, and Promedior. EJ received honoraria for lectures from Boehringer Ingelheim, Roche, AstraZeneca, MDS, Chiesi; sponsored travel to meetings from Boehringer Ingelheim and Roche; and payment for participation in advisory boards from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, MDS, Berlin-Chemie, and Chiesi. MWijsenbeek reports payments to her institution from Boehringer Ingelheim, Roche, the Netherlands Organisation for Health Research and Development, the Dutch Lung Foundation, the Dutch Pulmonary Fibrosis Patient Association, the Thorax Foundation, ErasmusMC, and Sarcoidoisis.nl. Consulting fees were paid to her institution by Boehringer Ingelheim, Roche, Galapagos, Bristol Myers Squibb, Galecto, and Respivant; honoraria were paid to her institution by Boehringer Ingelheim, Roche, and Novartis. MWijsenbeek received sponsored travel from Boehringer Ingelheim and Roche, and her institution received payment for her participation in data safety monitoring/advisory board from Savara and Galapagos. CG received consulting fees from Avalyn Pharma. GR reports receiving support from Avalyn Pharma for consulting and for chairing the Data Safety Monitoring Board during the conduct of the study; personal and consulting fees from Boehringer Ingelheim, Respivant, and Roche; grants from the NIH; and consulting fees from Bellerophon Therapeutics, Biogen, Bristol Myers Squibb, Fibrogen, Nitto, Promedior, Respivant, and Veracyte. Ethical Approval: The trial was approved by local ethics committees, and all patients provided written informed consent before trial entry.