Design of Idiopathic Pulmonary Fibrosis Clinical Trials in the Era of Approved Therapies

• Published in: American journal of respiratory and critical care medicine 2019-07, Vol.200 (2), p.133-139
• Main Authors: Kaner, Robert J, Bajwa, Ednan K, El-Amine, Moustapha, Gorina, Eduard, Gupta, Renu, Lazarus, Howard M, Luckhardt, Tracy R, Mouded, Majd, Posada, Kaity, Richeldi, Luca, Stauffer, John, Tutuncu, Ahmet, Martinez, Fernando J
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Clinical trials; Clinical Trials as Topic; Drug Approval; Drug Development; Drug dosages; Drug Interactions; Drug Therapy, Combination; FDA approval; Glycoproteins; Humans; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - physiopathology; Indoles - therapeutic use; Medicine; Patient Outcome Assessment; Protein Kinase Inhibitors - therapeutic use; Pulmonary fibrosis; Pyridones - therapeutic use; Quality of Life; Regulatory agencies; Standard of Care; Vital Capacity; Walk Test
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201903-0592PP

Conversely, strong inducers could reduce levels of the antifibrotic drugs. [...]potential for DDIs should be evaluated in the early phases of new drug development and preferably starting early in phase I. For example, in the PANORAMA trial (A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of the Safety and Tolerability of N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis with Background Treatment of Pirfenidone; EudraCT identifier 2012-000564-14), adding N-acetylcysteine to pirfenidone was associated with the loss of efficacy of pirfenidone and an increase in side effects (6). FibroGen’s anti-CTGF (connective tissue growth factor) monoclonal antibody pamrevlumab (Evaluate the Safety and Efficacy of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis; www.clinicaltrials.gov identifier NCT01890265) (15), Promedior’s recombinant human pentraxin 2 (A Trial to Evaluate the Efficacy of PRM-151 in Subjects with Idiopathic Pulmonary Fibrosis; www.clinicaltrials.gov identifier NCT02550873) (16), Prometic Life Science’s mixed agonist of GPR40 (G protein–coupled receptor 40) and antagonist of GPR84 PBI-4050 (A Phase 2 Study to Evaluate the Safety and Tolerability of PBI-4050 in Patients with Idiopathic Pulmonary Fibrosis; www.clinicaltrials.gov identifier NCT02538536) (7), and Galapagos’s autotaxin inhibitor (17). Study Design Considerations for New Idiopathic Pulmonary Fibrosis Drugs Monotherapy Add-on to SOC Noninferiority/Superiority to SOC Pros Cons Pros Cons Pros Cons True comparison with placebo; ideal for testing new agent with efficacy similar to, but fewer and/or less severe side effects than, SOCAllows inclusion of patients intolerant of SOCJustified only in short-duration evaluations Will not evaluate DDI with SOCWill not evaluate side effect profile with SOCPatients receiving SOC will be excluded from participationDelay in starting SOC for newly diagnosed patientsWill require a stronger rationale to exclude SOC as the duration of the study increases No ethical concerns about lack of SOCPermits evaluation of DDI and side effectsPermits evaluation of potential additive or synergistic efficacy effects Potential improvements in the safety and tolerability profile and/or quality of life could be overlooked for the new agent over the current SOC for use in monotherapy A head-to-head comparison with SOC is ideal to understand efficacyAvoids ethical concerns about a placebo-only arm For superiority: narrow window to improve FVC decli