The study objectives are to assess safety, tolerability and gene expression after a single dose of non-viral CFTR gene therapy (pGM169/GL67A) administered to the nose and lungs of patients with cystic fibrosis.

Start Date01 Nov 2008

Sponsor / Collaborator

Imperial College London

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100 Clinical Results associated with pGM169-GL67A gene therapy(The National Heart & Lung Institute)

100 Translational Medicine associated with pGM169-GL67A gene therapy(The National Heart & Lung Institute)

100 Patents (Medical) associated with pGM169-GL67A gene therapy(The National Heart & Lung Institute)

Literatures (Medical) associated with pGM169-GL67A gene therapy(The National Heart & Lung Institute)

01 Dec 2015·American Journal of Respiratory and Critical Care MedicineQ1 · MEDICINE

A Phase I/IIa Safety and Efficacy Study of Nebulized Liposome-mediated Gene Therapy for Cystic Fibrosis Supports a Multidose Trial

Q1 · MEDICINE

Article

Author: Boyd, A. Christopher ; Davies, Jane C. ; Higgins, Tracy E. ; Innes, J. Alastair ; Alton, Eric W. F. W. ; Hyde, Stephen C. ; Griesenbach, Uta ; Davies, Gwyneth ; Gill, Deborah R. ; Porteous, David J.

To the Editor: The vast majority of treatments for cystic fibrosis (CF) target the downstream consequences of the disease and are incompletely effective. The success of the CF transmembrane conductance regulator (CFTR) potentiator ivacaftor has illustrated the clinical benefits arising from restoration of CFTR protein function (1). This agent is applicable as a monotherapy for a minority of patients with specific, rare mutations. CFTR gene therapy, a mutation-independent alternative, has demonstrated proof of principle for gene transfer in animal models and human trials, but only one study (using a viral vector) has unsuccessfully assessed whether clinical outcomes can be improved (2). In preparation for a phase IIb clinical trial of repeatedly administered, nonviral, liposome-mediated CFTR gene transfer assessing clinically meaningful outcomes (3), the UK CF Gene Therapy Consortium (www.cfgenetherapy.org.uk) undertook a single-application safety and dose-ranging study (NCT00789867). Some of the results of these studies have been previously reported in the form of abstracts (4, 5). The chosen plasmid DNA expresses CFTR under the control of the human cytomegalovirus enhancer/elongation factor 1α sequence (6), a modified EF1a promoter aiming for extended duration of expression (7), and was rendered CpG-free to minimize a host inflammatory response (6). The cationic lipid, GL67A, was chosen on the basis of extensive preclinical testing (8). After informed consent, adult patients with CF received a single nebulized +/− nasal dose of pGM169/GL67A. Reconstitution and preparation of pGM169/GL67A was undertaken on the day, and doses were delivered in sealed negative-pressure cubicles after pretreatment with inhaled salbutamol (albuterol). Preplanned adjunctive therapies including ibuprofen, prednisolone, or paracetamol were administered to some patients. The primary outcome of the clinical study was safety; assessment included examination, standard hematology/biochemistry, adverse events, spirometry, lung clearance index, chest computed tomography scan, gas transfer, bronchial biopsy histology, and immune markers. pGM169-specific DNA and mRNA were measured on nasal and lower airway brushings, with potential difference also measured bronchoscopically and nasally. For the latter, “responders” were defined as demonstrating chloride secretion 5 mV or more greater than their mean predose value, and greater than any of their predose responses. A total of 35 subjects (Tables 1 and and2)2) received a nebulized dose (5 ml, n = 8; 10 ml, n = 10; 20 ml, n = 17) via an AeroEclipse II (Trudell Medical International, London, ON, Canada) breath-actuated nebulizer (9). Three subjects undertook slow delivery (∼75 vs. 25 min for each 5 ml). Standard spray devices were used for nasal delivery (2 ml, n = 21). According to pre-/post-device weighing, a mean (SD) of 88.7% (2.9%) of expected nebulized dose and 94.5% (15.0%) of expected nasal dose was delivered. There were two serious adverse events: one occurred after the predosing bronchoscopy (swelling of the uvula related to intubation) and led to observation overnight in hospital, and the other was an episode of pancreatitis occurring around Day 10 after dosing (10 ml nebulized cohort). The subject was exocrine pancreatic sufficient and had likely experienced previous similar, but undiagnosed, episodes. Table 1. Baseline Demographics Table 2. Postdosing Responses Overall, in the trial, 94.3% of subjects experienced at least one adverse event, the majority of which were mild to moderate in severity and resolved spontaneously or with standard antipyretics. The most common occurred on the day of dosing and largely resolved within 24–48 hours (Tables 1 and and2):2): Typically, within the first few hours after dosing, a mild, self-limiting influenza-like systemic response was seen, most frequently in the 20-ml patients. This was not affected by slow delivery or coadministration of ibuprofen or prednisolone but was clearly dose-related and reduced by paracetamol. Symptoms of headache and/or tiredness were reported by 82, 70, and 13%, and raised serum inflammatory markers were recorded in 100, 60, and 63% of the 20-, 10-, and 5-ml groups respectively, with dose-related trends in maximal values. No patient dosed with 5 ml had a temperature higher than 38°C (Table 2). A relatively asymptomatic, dose-related, restrictive drop in spirometry was also observed, with no change in respiratory rate or oxygen saturation. No patient dosed with 5 ml showed a more than 20% relative fall in FEV1 (Table 2). The 20-ml group showed a small, significant (P < 0.05) mean (SD) drop in gas transfer (transfer factor for carbon monoxide corrected for alveolar volume and hemoglobin concentration) on Day 2 of 4.5% (6.0%), which returned to baseline values by Day 14. No changes were seen in the other cohorts. Two of the 20-ml patients had small areas of ground glass opacity reported on their Day 2 chest computed tomography scans, which resolved by Day 14. No significant changes were seen in endobronchial histology (20 ml; n = 10). Consistent with the proposed excretion route for lipids, small but significant serum creatinine rises within the normal range could be detected 8 hours after dosing in the 20- and 10-ml groups, but not the 5-ml cohort; there were no other biochemical changes. Bilirubin rose on Day 1 in all dosing groups, as with creatinine, remaining within the normal range, and normalized by Day 2. There was no evidence of immune responses based on double-stranded DNA antibodies or human CFTR-specific T cells. Lung clearance index, a sensitive marker of pulmonary dysfunction (10), was included as a safety assay. Fourteen 20-ml patients with paired predosing and 28-day postdosing values showed a small but significant increase (i.e., a deterioration; Figure 1A). In contrast, and unexpectedly, on post hoc analysis, 11 of 14 patients in the lower-dosing groups (5 and 10 ml) showed a small but significant improvement (Figure 1A). Figure 1. (A) Lung clearance index (LCI) increased (worsened) by a mean (SEM) of 0.75 (0.3) units in the 20-ml group (P = 0.03), whereas it decreased (improved) in the 5-/10-ml patients by 0.32 (0.1) (P = 0.04). The difference in ... With respect to bronchial samples, 10 patients (all 20 ml) had paired pre- and postdosing bronchoscopies. pGM169-specific DNA was detected in all bronchial brushing samples at levels ∼1000-fold higher than in the nasal samples. pGM169-specific mRNA was detected in 2 of 10 postdosing samples. Paired bronchoscopic potential difference measurements were interpretable for 8 of 10 patients. There was a trend toward an increase in chloride secretion (Figure 1B) but no changes in sodium-related parameters. With respect to nasal samples, pGM169-specific DNA was detected in all 15 brushing samples taken between Day 2 and Day 14 after dosing and in two of six samples at Day 28. pGM169-specific mRNA was detected in 3 of 21 postdosing samples, with all positive samples being observed at either Day 14 (n = 2) or Day 28 (n = 1). In keeping with previous published data, there were no changes in sodium parameters on nasal potential difference. In contrast, 6 of 16 subjects (37.5%) demonstrated a “response” in terms of chloride secretory capacity. Responses were seen most commonly in the zero chloride perfusion phase and at the 14-day point; they were of sustained duration in one subject (Figure 1C). These data were important in informing the design of the phase IIb trial. Thus, based on these findings, 5 ml was selected as the optimal dose, with paracetamol being used as an adjuvant to minimize the risk of unblinding. Although well-tolerated, the adverse effects of the 20-ml doses were considered prohibitive for use in a repeated administration trial. We consider that the efficient delivery of large volumes of viscous fluid into the airways led acutely to both the influenza-like and restrictive responses, analogous to those seen after bronchoalveolar lavage, and masking the effect of plasmid DNA CpG depletion. At lower volumes, the latter effect was “revealed,” allowing safe dosing of 5 ml. The unexpected improvement in lung clearance index after only one administration at the lower doses was intriguing; larger numbers and longer follow-up are needed to confirm or refute this finding. The variable responses both in molecular and CFTR functional terms underscore the technical challenges inherent in these assays and the limited sensitivity to low levels of gene expression (11). The clean safety profile and encouraging improvements in a sensitive measure of airway health lend support to progression to a phase IIb multidose trial designed to detect clinical improvements after prolonged administration.

01 Sep 2015·The Lancet Respiratory MedicineQ1 · MEDICINE

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial

Q1 · MEDICINE

Article

Author: Rivellini, Gina ; Collie, D David S ; Boyd, A Christopher ; Carvelli, Paula ; Brand, June ; Soussi, Samia ; Calcedo, Roberto ; Nicholson, Andrew G ; Davidson, Heather E ; Spearing, Emma J ; Alton, Eric W F W ; Sumner-Jones, Stephanie G ; Ureta, Rosa P ; Hyde, Stephen C ; Soussi, Najwa ; Bayfield, Katie J ; Dewar, Maria H ; Pringle, Ian A ; Jones, Nancy ; Montero, M Angeles ; Harman, Katharine ; Greening, Andrew P ; Simmonds, Nicholas J ; Bilton, Diana ; Cheng, Seng H ; Saunders, Clare J ; Hansell, David M ; Maclean, Alan W ; Donovan, Jackie ; Smith, Keith ; Ashby, Deborah ; Osadolor, Tina ; Gea-Sorli, Sabrina ; Gill, Deborah R ; Smith, Stephen N ; Manvell, Michelle C ; Quittner, Alexandra L ; Milligan, Hazel ; Davies, Gwyneth ; Scheule, Ronald K ; Geddes, Duncan M ; Wasowicz, Marguerite Y ; Innes, J Alastair ; Wolstenholme-Hogg, Paul ; Hodges, Samantha L ; McCormick, Dominique ; Higgins, Tracy E ; Meng, Cuixiang ; Hyndman, Laura ; Porteous, David J ; McLachlan, Gerry ; Murray, Gordon D ; McGovern, Michael ; Turkkila, Minna ; Doherty, Ann ; Parra-Leiton, Javier ; Buchan, Ruaridh ; Chan, Mario ; Davies, Jane C ; Cunningham, Steve ; Armstrong, David K ; Davies, Lee A ; Keogh, Brian F ; Gibson, James S R ; Pytel, Kamila M ; Stevenson, Barbara J ; Moyce, Laura J ; Sheard, Sarah ; Jacob, Joseph ; Gavino, Jemyr ; Elgmati, Hala I ; Dwyer, Natalie S ; Waller, Michael D ; Featherstone, Rosanna F ; Bloomfield, Emily V ; Wilson, James M ; Limberis, Maria P ; Punch, Emma K ; Lloyd-Evans, Paul ; Griesenbach, Uta

BACKGROUNDLung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis.METHODSWe did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867.FINDINGSBetween June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups.INTERPRETATIONMonthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials.FUNDINGMedical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

01 Jan 2014·Gene TherapyQ3 · MEDICINE

Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung

Q3 · MEDICINE

Article

Author: Davies, L A ; Porteous, D ; Innes, J A ; Davies, J C ; Alton, E W F W ; Gill, D R ; Pringle, I ; Scheule, R K ; Cheng, S H ; Hyde, S C ; Sumner-Jones, S ; Griesenbach, U ; Boyd, A C ; McLachlan, G ; Higgins, T ; Dayan, A

For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.

100 Deals associated with pGM169-GL67A gene therapy(The National Heart & Lung Institute)

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Indication	Highest Phase	Country/Location	Organization	Date
Cystic Fibrosis	Phase 2	-	Genzyme Corp.	-
Cystic Fibrosis	Phase 2	-	Imperial College London	-
Cystic Fibrosis	Phase 2	-	The National Heart & Lung Institute	-
Cystic Fibrosis	Phase 2	-	Uk Cystic Fibrosis Gene Therapy Consortium	-

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