Discussion The results of a Phase I/II clinical trial were previously reported describing the first-in-human use of a lentiviral-based gene therapy vector. In this study, ProSavin, an EIAV-derived lentiviral vector, was shown to have a favorable safety profile and encouraging efficacy signals following injection into the motor striatum of 15 patients with Parkinson's disease.14
The data reported here describes follow-up, for up to 8 years, of patients from the Phase I/II study and provides important additional information on the long-term safety and potential efficacy of this therapeutic approach. The safety data are generally consistent with those previously reported,14 with no drug- or procedure-related serious AEs during follow-up. The majority of drug-related AEs were on-medication dyskinesias adequately managed by lowering their L-Dopa medication, and encouragingly, the majority of drug-related AEs occurred within the first 12 months after treatment.
Eight patients received treatment with DBS, as they developed worsening off periods alternating with L-Dopa dyskinesias as a result of disease progression. It should be noted that no safety issue was observed with lead implantation or high frequency stimulation of the subthalamic nucleus in any of these cases (S. Palfi, pers. commun.). There was a very similar safety profile before and after DBS (compare Table 2 and Supplementary Table S1).
In terms of efficacy, the significant improvement in motor function previously reported up to 12 months was maintained at 2 years across the 14 patients that were assessed at this time point (with one patient withdrawing consent for off assessments after 12 months of follow-up). Although statistical analyses were not performed beyond this time point, as several patients were withdrawn from the efficacy part of the study by virtue of having had DBS, the majority of patients who remained in the open-label follow-up continued to show improvements in their UPDRS (III) off scores at all time points. These efficacy findings are consistent with the fact that the lentiviral vector genome is integrated into the host-cell genome and transgene expression is maintained long term,16 as has recently been shown following administration of an EIAV lentiviral vector into the retina.17 Nonetheless, Parkinson's disease is a progressive disease. So, it is encouraging that the data indicate that the levels of dopamine achieved through this gene therapy approach may be sufficient to sustain a positive motor behavioral effect for several years.
Considering only the patients who were evaluated at the longer-term follow-up time points, it is interesting to note that patients M6, M9, H12, and H13, who were diagnosed with Parkinson's disease between 9 and 26 years prior to ProSavin treatment,14 showed particularly encouraging improvements from baseline in their UPDRS III (off) scores, with changes of 12–24 points at the 4-year assessment. Patient M6 was also evaluated at 6 years, and continued to show an approximately 30% improvement in both UPDRS III on and off scores, with a sustained reduction in LEDD, and a 17-unit improvement in PDQ-39 scores from baseline.
Although these data provide strong evidence to support an efficacy benefit for ProSavin in Parkinson's disease patients, the overall magnitude of effects are within the range reported for placebo study arms, albeit over shorter time frames, in other clinical trials for PD using surgical interventions.8,13 The duration of such placebo effects have not been well studied. However, given that the improvements in motor scores were sustained for 6 years in some patients and confined to their “off” state assessments, combined with the fact that Parkinson's disease is a progressive neurodegenerative disease with an expected three- to four-point increase in the UPDRS part III (off) motor score per year,18,19 the likelihood that the findings reported are attributable to the study treatment is strong. Nonetheless, interpretation of these findings must still be viewed with caution until a larger comparator study has been undertaken with placebo treatments, especially given the extent of patient attrition over the follow-up period in this study. An attrition that is not unexpected, given that the study recruited patients at relatively advanced stages of disease.
Given the small sample populations, it is difficult to assess dose response. It was previously reported that there were indications of positive responses in patients receiving the highest dose of ProSavin. These patients had the most consistent LEDD reduction post intervention, the highest mean improvement in UPDRS III (off) motor scores at 1 year, and a significant change from baseline in 11C-raclopride binding potential.14 At 2 years of follow-up, a similar mean improvement from baseline in UPDRS III (off) scores was observed in the mid- and high-dose groups, which was higher than in the low-dose group. Again, interpretation of these observations must be made with caution due to the small patient numbers and the changes seen in the UPDRS III scores.
In conclusion, the new data demonstrate the long-term safety and promising efficacy profile of ProSavin in Parkinson's disease patients for up to 8 years of follow-up. These are the longest follow-up assessments reported in any Parkinson's disease gene therapy study. Although the results are encouraging, the data suggest that the optimal level of dopamine replacement may not have been achieved, since patients continued to require oral L-Dopa therapy to obtain maximal benefit, and some of the more severely affected patients required DBS 2–6 years following ProSavin administration. Further dose escalation using ProSavin would be challenging due to limitations on vector titers using current production processes and the volume of vector that can be safely administered into the human striatum. Therefore, a new vector (OXB-102) has been recently developed in which the configuration of three dopamine biosynthesis enzymes was further optimized to increase the capacity for dopamine production significantly compared to ProSavin.20 This vector is under preclinical development and, pending regulatory approval, will be assessed in a new Phase I/II study to determine the appropriate dose before a larger placebo-controlled Phase IIb clinical trial is undertaken.
AI
