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Interstitial lung disease
Original research
Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose–response trial
  1. Alex West1,
  2. Nazia Chaudhuri2,
  3. Adam Barczyk3,
  4. Margaret L Wilsher4,
  5. Peter Hopkins5,
  6. Ian Glaspole6,
  7. Tamera Jo Corte7,8,
  8. Martina Šterclová9,
  9. Antony Veale10,
  10. Ewa Jassem11,
  11. Marlies S Wijsenbeek12,
  12. Christopher Grainge13,
  13. Wojciech Piotrowski14,
  14. Ganesh Raghu15,16,17,
  15. Michele L Shaffer18,
  16. Deepthi Nair18,
  17. Lisa Freeman18,
  18. Kelly Otto18,
  19. A Bruce Montgomery18
  1. 1Guy's and St Thomas' Hospital, London, UK
  2. 2University of Ulster, Magee Campus, Londonderry, UK
  3. 3Department of Pneumonology, Medical University of Silesia, Katowice, Slaskie, Poland
  4. 4Respiratory Services, Auckland District Health Board, Auckland, New Zealand
  5. 5The Prince Charles Hospital, Brisbane, Queensland, Australia
  6. 6Department of Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia
  7. 7Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
  8. 8Department of Respiratory Medicine, Royal Brompton Hospital, London, UK
  9. 9Department of Respiratory Medicine, Thomayer Hospital, Praha, Praha, Czech Republic
  10. 10Department of Respiratory Medicine, Queen Elizabeth Hospital, Woodville South, South Australia, Australia
  11. 11Gdanski Uniwersytet Medyczny, Gdansk, Poland
  12. 12Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
  13. 13Hunter Medical Research Institute, University of Newcastle, New Castle, New South Wales, Australia
  14. 14Department of Pneumonology and Allergy, Medical University of Lodz, Lodz, Lodzkie, Poland
  15. 15CENTER for Interstitial Lung Diseases, University of Washington, Seattle, Washington, USA
  16. 16Department of Medicine, University of Washington, Seattle, Washington, USA
  17. 17Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
  18. 18Avalyn Pharma Inc, Seattle, Washington, USA
  1. Correspondence to Dr A Bruce Montgomery, Avalyn Pharma, Seattle, WA, USA; bruce.montgomerymd{at}gmail.com

Abstract

Introduction Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression.

Methods This phase 1b, randomised, open-label, dose–response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%–90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.

Results We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were −2.5 (95% CI −5.3 to 0.4, −88 mL) and −4.9 (−7.5 to −2.3,–188 mL) in the 50 mg once per day and 0.6 (−2.2 to 3.4, 10 mL) and −0.4 (−3.2 to 2.3, −34 mL) in the 100 mg two times per day group.

Discussion Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted.

Trial registration number ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.

  • idiopathic pulmonary fibrosis
  • cough/mechanisms/pharmacology

Data availability statement

Data are available on reasonable request. Data are available from Avalyn Pharma on reasonable request.

http://dx.doi.org/10.1136/thorax-2022-219391

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    Data availability statement

    Data are available on reasonable request. Data are available from Avalyn Pharma on reasonable request.

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    Footnotes

    • Twitter @ILDIPFDoc_NI

    • Contributors All authors had the ability to access the data. The authors assume responsibility for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The initial draft of this manuscript was written by the authors without outside assistance. MLS and ABM have both verified the underlying data, and ABM is acting as guarantor. AW, NC, AB, MLW, TJC, MŠ, AV, EJ, MSW, WP and GR contributed to study conduct, data interpretation and manuscript writing. PH, IG and CG contributed to study design, study conduct, data interpretation,and manuscript writing. DN contributed to data collection, data interpretation and manuscript writing. KO contributed to study design, data analysis, data interpretation and manuscript writing. MLS contributed to data analysis, data interpretation and manuscript writing. LF and ABM contributed to study design, data interpretation and manuscript writing.

    • Funding Avalyn Pharma sponsored the study and was involved in the study design, the analysis and interpretation of data, the writing of this report and in the decision to submit the paper for publication.

    • Competing interests NC received a grant from Boehringer Ingelheim and consulting fees from Boehringer Ingelheim, Carrick, Redex, UCB, and Novartis; speaker fees and travel sponsorship from Boehringer Ingelheim and Roche; and payment for participation on data 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 and 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. MW 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. MW 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.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.