Authors:
Prof Stéphane Palfi MD, Jean Marc Gurruchaga MD, G Scott Ralph PhD, Helene Lepetit PhD, Sonia Lavisse PhD, Philip C Buttery PhD, Colin Watts PhD, James Miskin PhD, Michelle Kelleher PhD, Sarah Deeley MSc, Hirokazu Iwamuro MD, Jean Pascal Lefaucheur MD, Claire Thiriez MD, Gilles Fenelon MD, Cherry Lucas BA, Pierre Brugières MD, Inanna Gabriel MD, Kou Abhay MD, Xavier Drouot MD, Naoki Tani MD, Aurelie Kas MD, Prof Bijan Ghaleh MD, Philippe Le Corvoisier MD, Patrice Dolphin MSc, David P Breen MRCP, Sarah Mason BSc, Natalie Valle Guzman MSc, Prof Nicholas D Mazarakis PhD, Pippa A Radcliffe PhD, Richard Harrop PhD, Susan M Kingsman PhD, Prof Olivier Rascol MD, Stuart Naylor PhD, Prof Roger A Barker PhD, Philippe Hantraye PhD, Prof Philippe Remy MD, Prof Pierre Cesaro MD, & Kyriacos A Mitrophanous PhD
Summary:
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•9×107 transducing units [TU]); mid dose (4•0×107 TU); and high dose (1×108 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.
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.
Source:
The Lancet; (01/10/14)