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Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.
Lancet. 2014 Mar 29; 383(9923):1138-46.Lct

Abstract

BACKGROUND

Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease.

METHODS

We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439.

FINDINGS

15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline.

INTERPRETATION

ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.

FUNDING

Oxford BioMedica.

Authors+Show Affiliations

AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France. Electronic address: stephane.palfi@hmn.aphp.fr.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.Oxford BioMedica, Oxford, UK.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.Oxford BioMedica, Oxford, UK.Oxford BioMedica, Oxford, UK.Oxford BioMedica, Oxford, UK.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; INSERM U955, E01, Institut de Recherche Biomédicale, Créteil, France.Oxford BioMedica, Oxford, UK.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.Gene Therapy, Centre of Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Hammersmith Hospital Campus, London, UK.Oxford BioMedica, Oxford, UK.Oxford BioMedica, Oxford, UK.Oxford BioMedica, Oxford, UK.CIC9302 and UMR 825, INSERM and Department of Pharmacology and Neurosciences, University Hospital and University of Toulouse III, Toulouse, France.Oxford BioMedica, Oxford, UK.John van Geest Centre for Brain Repair and Addenbrooke's Hospital, Cambridge, UK.CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; CEA, DSV I(2)BM, MIRCen and CNRS URA2210, Fontenay-aux-Roses, France.AP-HP, Groupe Hospitalier Henri-Mondor, DHU PePsy, UF Neurochirurgie Fonctionnelle, Neurologie, Neurophysiologie, Anesthésie, Centre d'Investigation Clinique 006, Plateforme de Ressources Biologiques, Créteil, France; Université Paris 12, Faculté de Médecine, Créteil, France; INSERM U955, E01, Institut de Recherche Biomédicale, Créteil, France.Oxford BioMedica, Oxford, UK.

Pub Type(s)

Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24412048

Citation

Palfi, Stéphane, et al. "Long-term Safety and Tolerability of ProSavin, a Lentiviral Vector-based Gene Therapy for Parkinson's Disease: a Dose Escalation, Open-label, Phase 1/2 Trial." Lancet (London, England), vol. 383, no. 9923, 2014, pp. 1138-46.
Palfi S, Gurruchaga JM, Ralph GS, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014;383(9923):1138-46.
Palfi, S., Gurruchaga, J. M., Ralph, G. S., Lepetit, H., Lavisse, S., Buttery, P. C., Watts, C., Miskin, J., Kelleher, M., Deeley, S., Iwamuro, H., Lefaucheur, J. P., Thiriez, C., Fenelon, G., Lucas, C., Brugières, P., Gabriel, I., Abhay, K., Drouot, X., ... Mitrophanous, K. A. (2014). Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet (London, England), 383(9923), 1138-46. https://doi.org/10.1016/S0140-6736(13)61939-X
Palfi S, et al. Long-term Safety and Tolerability of ProSavin, a Lentiviral Vector-based Gene Therapy for Parkinson's Disease: a Dose Escalation, Open-label, Phase 1/2 Trial. Lancet. 2014 Mar 29;383(9923):1138-46. PubMed PMID: 24412048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. AU - Palfi,Stéphane, AU - Gurruchaga,Jean Marc, AU - Ralph,G Scott, AU - Lepetit,Helene, AU - Lavisse,Sonia, AU - Buttery,Philip C, AU - Watts,Colin, AU - Miskin,James, AU - Kelleher,Michelle, AU - Deeley,Sarah, AU - Iwamuro,Hirokazu, AU - Lefaucheur,Jean Pascal, AU - Thiriez,Claire, AU - Fenelon,Gilles, AU - Lucas,Cherry, AU - Brugières,Pierre, AU - Gabriel,Inanna, AU - Abhay,Kou, AU - Drouot,Xavier, AU - Tani,Naoki, AU - Kas,Aurelie, AU - Ghaleh,Bijan, AU - Le Corvoisier,Philippe, AU - Dolphin,Patrice, AU - Breen,David P, AU - Mason,Sarah, AU - Guzman,Natalie Valle, AU - Mazarakis,Nicholas D, AU - Radcliffe,Pippa A, AU - Harrop,Richard, AU - Kingsman,Susan M, AU - Rascol,Olivier, AU - Naylor,Stuart, AU - Barker,Roger A, AU - Hantraye,Philippe, AU - Remy,Philippe, AU - Cesaro,Pierre, AU - Mitrophanous,Kyriacos A, Y1 - 2014/01/10/ PY - 2014/1/14/entrez PY - 2014/1/15/pubmed PY - 2014/4/16/medline SP - 1138 EP - 46 JF - Lancet (London, England) JO - Lancet VL - 383 IS - 9923 N2 - BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/24412048/Long_term_safety_and_tolerability_of_ProSavin_a_lentiviral_vector_based_gene_therapy_for_Parkinson's_disease:_a_dose_escalation_open_label_phase_1/2_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(13)61939-X DB - PRIME DP - Unbound Medicine ER -