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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

Palfi, Stéphane; Gurruchaga, Jean Marc; Ralph, G Scott; Lepetit, Helene; Lavisse, Sonia; Buttery, Philip C; Watts, Colin; Miskin, James; Kelleher, Michelle and Deeley, Sarah, et al. (2014) In The Lancet 383(9923). p.46-1138
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... (More)

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.

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keywords
Aged, Antiparkinson Agents, Dopa Decarboxylase, Dopamine, Dopaminergic Neurons, Follow-Up Studies, GTP Cyclohydrolase, Genetic Therapy, Genetic Vectors, Humans, Infectious Anemia Virus, Equine, Injections, Intralesional, Male, Middle Aged, Parkinson Disease, Putamen, Transfection, Transgenes, Tyrosine 3-Monooxygenase, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
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The Lancet
volume
383
issue
9923
pages
9 pages
publisher
Elsevier Limited
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  • scopus:84897076939
ISSN
1474-547X
DOI
10.1016/S0140-6736(13)61939-X
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English
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25685e23-bab9-478f-943f-15080e669170
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2017-11-12 04:26:28
@article{25685e23-bab9-478f-943f-15080e669170,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.</p><p>FUNDING: Oxford BioMedica.</p>},
  author       = {Palfi, Stéphane and Gurruchaga, Jean Marc and Ralph, G Scott and Lepetit, Helene and Lavisse, Sonia and Buttery, Philip C and Watts, Colin and Miskin, James and Kelleher, Michelle and Deeley, Sarah and Iwamuro, Hirokazu and Lefaucheur, Jean Pascal and Thiriez, Claire and Fenelon, Gilles and Lucas, Cherry and Brugières, Pierre and Gabriel, Inanna and Abhay, Kou and Drouot, Xavier and Tani, Naoki and Kas, Aurelie and Ghaleh, Bijan and Le Corvoisier, Philippe and Dolphin, Patrice and Breen, David P and Mason, Sarah and Guzman, Natalie Valle and Mazarakis, Nicholas D and Radcliffe, Pippa A and Harrop, Richard and Kingsman, Susan M and Rascol, Olivier and Naylor, Stuart and Barker, Roger A and Hantraye, Philippe and Remy, Philippe and Cesaro, Pierre and Mitrophanous, Kyriacos A},
  issn         = {1474-547X},
  keyword      = {Aged,Antiparkinson Agents,Dopa Decarboxylase,Dopamine,Dopaminergic Neurons,Follow-Up Studies,GTP Cyclohydrolase,Genetic Therapy,Genetic Vectors,Humans,Infectious Anemia Virus, Equine,Injections, Intralesional,Male,Middle Aged,Parkinson Disease,Putamen,Transfection,Transgenes,Tyrosine 3-Monooxygenase,Clinical Trial, Phase I,Clinical Trial, Phase II,Journal Article,Multicenter Study,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {03},
  number       = {9923},
  pages        = {46--1138},
  publisher    = {Elsevier Limited},
  series       = {The Lancet},
  title        = {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},
  url          = {http://dx.doi.org/10.1016/S0140-6736(13)61939-X},
  volume       = {383},
  year         = {2014},
}