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Lenticlair™-ON: An extension trial examining long-term safety and efficacy outcomes associated with an inhaled F/HN-pseudotyped lentiviral vector for CF gene therapy in people with CF

J C Davies(1,2) M A Mall(3) D Polineni(4) S H Donaldson(5) I Fajac(6,7) R Jain(8) B K Rubin(9) A C Boyd(10) D R Gill(11) U Griesenbach(1) S C Hyde(11) G McLachlan(12) V Kohlbrenner(13) R Sigmund(14) A T Engel(15) A Gupta(16) E WFW Alton(1,2)

1:National Heart and Lung Institute, Imperial College London, London, UK; 2:Royal Brompton Hospital, part of Guy's & St Thomas' NHS Foundation Trust, London, UK; 3:Department of Pediatrics Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; 4:Department of Pediatrics, Division of Allergy & Pulmonary Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; 5:Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6:Université Paris Cité, Paris, France; 7:AP-HP, Hôpital Cochin, Service de Physiologie et Explorations Fonctionnelles, Paris, France; 8:Department of Internal Medicine, University of Texas Southwestern Medical Center Dallas, TX, USA; 9:Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; 10:Centre for Genomic & Experimental Medicine, Institute of Genetics & Cancer, Western General Hospital, University of Edinburgh, Edinburgh, UK; 11:Gene Medicine Group, Nuffield Division of Clinical Laboratory Science, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; 12:The Roslin Institute, University of Edinburgh, Edinburgh, UK; 13:Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT, USA; 14:Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany; 15:Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 16:Boehringer Ingelheim International GmbH, Biberach an der Riss, Germany

BI 3720931, a third-generation lentiviral vector, will be assessed in a first-in-human (FiH) Phase 1/2 trial in people with cystic fibrosis (pwCF) who are genetically ineligible for CF transmembrane conductance regulator modulator therapy. All trial participants enter an extension trial for long-term follow-up (FU; 15 years, as per regulatory guidelines) of safety and efficacy. Participants may be redosed in the extension trial to maintain efficacy (if supported by data).

Primary endpoint: occurrence of delayed adverse events (AEs) up to 15 years post-enrolment, including risks outlined by regulatory guidance documents for integrating gene therapies. Secondary endpoints: time to loss of efficacy (drop to <5% [absolute] above individual baseline in percent predicted forced expiratory volume in 1 second [ppFEV1]); change in ppFEV₁ at 8 weeks post-redosing; time to loss of efficacy post-redosing; time to first pulmonary exacerbation from last dosing; occurrence of all AEs; evidence of plasma replication-competent lentivirus. Interim analyses: at FiH trial end, then every 2 years. Long-term FU: quarterly visits Years 1–2; annual visits Years 3–15; more frequent FU in the first 2 years after redosing. Durability of clinical effect after the FiH trial dose will inform redosing in the extension trial; efficacy and safety of redosing will be determined.

This extension trial will allow seamless rollover of the first participant from the FiH trial.

This trial will investigate long-term safety and efficacy duration in pwCF treated with at least one BI 3720931 dose, and determine efficacy and safety after redosing, as applicable.

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