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.
A study has assessed 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.
Researchers 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.
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 vs 26, n=15, p=0.0001 ) and 12 months ( 38 vs 27; n=15, p=0.0001 ) compared with baseline.
In conclusion, ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. ( Xagena )
Palfi S et al, The Lancet 2014; 383:1138-1146