Date: 2016-05-06
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 19th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT)
Company: Oxford Biomedica (UK)
Product: ProSavin®/OXB-101
Action
mechanism: gene therapy. ProSavin® uses Oxford Biomedica's LentiVector® gene delivery technology to deliver the genes for three enzymes - AADC (aromatic amino acid decarboxylase), TH (tyrosine hydroxylase) and CH1 (GTP-cyclohydrolase 1) - that are required for the synthesis of dopamine. These genes re-programme transduced cells to manufacture and secrete dopamine. The product is administered locally to the region of the brain called the striatum, converting cells into a replacement dopamine factory within the brain, thus replacing the patient's own lost source of the neurotransmitter.
Disease: Parkinson's disease
Therapeutic area: Neurodegenerative diseases
Country: France, UK
Trial
details: The Phase I/II study evaluated three ascending dose levels of ProSavin® (1x, 2x and 5x) in a total of 15 patients with Parkinson's disease. Six patients received the 2x dose, the latter three of which were treated using an enhanced administration procedure. Six patients received the highest 5x dose. Patients were treated at two centres of excellence for neurosurgery: the Henri Mondor Hospital in Paris, France with Professor Stéphane Palfi as Principal and Coordinating Investigator, and at Addenbrooke’s Hospital in Cambridge, UK with Professor Roger Barker as Principal Investigator. The primary endpoints of the Phase I/II study were safety and efficacy as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) assessment at six months. (NCT01856439)
Latest
news: * On May 6, 2016, Oxford BioMedica announced that Professor Stéphane Palfi has presented a poster on OXB-101, a gene therapy product for the treatment of Parkinson’s disease, at the 19th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Washington DC, USA. In the Phase I/II study 15 advanced PD patients were treated with OXB-101 in three dose cohorts. OXB-101 demonstrated a favourable safety profile and a statistically significant improvement in motor function relative to baseline at six and 12 months post-treatment. The most recent follow-up data, presented this week, shows that the majority of patients continue to experience improvement in motor function relative to baseline over the four years since treatment. The Company has since developed OXB-102, a more potent version of OXB-101, and is planning to start a Phase I/II study in mid-2016. * On May 5, 2015, Oxford BioMedica announced that Professor Stéphane Palfi MD, PhD has presented a summary of the results from the 12 months and long term (three years) follow up of the 15 patients in the Phase I/II study of ProSavin®, a lentiviral vector based treatment for advanced Parkinson’s disease. Professor Palfi gave an oral presentation of the results at the American Association of Neurological Surgeons (AANS) conference on 4 May 2015 in Washington DC, USA. The Phase I/II study was designed to evaluate the safety and tolerability of ProSavin® for the treatment of advanced Parkinson’s disease at numerous time points including one, three, six, nine, 12 and 36 months post single injection. ProSavin® was administered to 15 patients by MRI-guided stereotactic injection to the striatum. The study consisted of three dose cohorts. As previously announced, and as reported in The Lancet in January 2014, ProSavin® met the endpoint of safety and tolerability at all dose levels. A significant improvement in mean unified Parkinson's disease rating scale (UPDRS) part III motor scores in the off medication was observed at six and 12 months compared to baseline in all patients, and this was sustained in the majority of patients for up to three years in the long-term follow up analysis in this progressively degenerative disease. The open-label follow-up study is running to assess long-term (up to 9 years) safety data. The data supports the continued development of an enhanced construct of ProSavin®, OXB-102, as a treatment for advanced Parkinson’s disease. * On January 10, 2014, Oxford BioMedica, a UK gene-based biopharmaceutical company, has announced the online publication of results from the previously reported ProSavin® Phase I/II study in patients with advanced Parkinson’s disease in The Lancet . According to the published findings in The Lancet, ProSavin® has demonstrated a favourable safety profile and a statistically significant improvement in motor function relative to baseline at six and 12 months post-treatment. Highlights from the Phase I/II study: Table 1:Summary of independently verified improvements in motor function to date * On August 4, 2011, Oxford BioMedica has announced positive interim data from the on-going Phase I/II trial of ProSavin® for the treatment of Parkinson’s disease (PD). The first three patients in the current six-patient cohort were treated with a 5x dose of ProSavin®, the scaled equivalent to the maximum dose in pre-clinical studies, and have reached their three-month assessment.
• Safety:ProSavin® has demonstrated a favourable safety profile with no serious adverse events, related to ProSavin® or the surgical procedure, observed to date.
• Efficacy:A statistically significant improvement in motor function relative to baseline was observed at six and 12 months in all patients. Long-term follow-up data showed favourable tolerability and evidence of continued clinical benefit for up to four years post-treatment. However, the magnitude of effects does fall within the placebo range reported in other clinical trials for PD utilising surgical techniques and must therefore be interpreted with caution. Although it is difficult to assess efficacy in small patient populations, there are indications that the highest 5x dose of ProSavin® provided the greatest level of dopaminergic activity. Patients in the highest 5x dose cohort demonstrated the greatest mean improvement in motor scores; a consistent reduction in requirement for oral dopaminergic medication; and possible dopamine provision attributable to ProSavin® from functional imaging data.
• Oral dopaminergic medication:Eleven out of 15 patients required a reduction in levodopa equivalent daily dose (LEDD) at 12 months compared to baseline. Of the four patients that did not require a decrease at 12 months, three showed no change and one had a small increase in LEDD compared to baseline. In what is usually a progressively degenerative disease requiring an increase in LEDD, these data are encouraging. The need for LEDD reduction was most evident in the highest 5x dose cohort, in which all six patients experienced an increase in “on-medication dyskinesias” at six weeks post-treatment with ProSavin® resulting in an immediate clinical decision to reduce LEDD. In comparison, only four out of nine patients experienced an increase in “on-medication dyskinesias” at the same time point in the lower dose cohorts.
• Patient diaries:The patient diary data indicate a decrease in the mean time spent in the “OFF” (unresponsive to medications) state and an increase in the “ON” (responsive to medication without dyskinesias, or with non-troublesome dyskinesias) state in 13 out of 15 patients. There was no overall difference between the differently dosed cohorts with respect to this.
• Positron Emission Tomography (PET) data: PET scan functional imaging data were generated in France using the tracer [11C] Raclopride. Dopamine competes with the binding of the PET tracer, therefore the more dopamine produced by ProSavin® the lower the PET signal. The three patients treated at the Paris clinical site, receiving the highest 5x dose of ProSavin®, exhibited a significant decrease in [11C] Raclopride binding potential relative to baseline in the putaminal sub-regions, suggesting a partial restoration of striatal dopamine tone in a dose-related fashion.
Oxford BioMedica is currently evaluating a more potent formulation of ProSavin®, called OXB-102, to ensure the greatest chance of success in future randomised studies. OXB-102 will also increase the commercial opportunity by offering extended patent protection and a relative reduction in cost of goods.
* On April 16, 2012, Oxford BioMedica has announced that it has successfully completed a Phase I/II study to assess the safety, efficacy and dose evaluation of ProSavin® in patients with mid-stage Parkinson’s disease (PD) who are experiencing reduced benefit on L-DOPA "equivalent" therapy.
The primary endpoint of the Phase I/II study is safety, and the secondary endpoint is efficacy as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) assessment at six months. All six patients in the fourth and final cohort have reached their six-month assessment time point, the results of which have been independently verified.
Highlights of fourth cohort at six months (n=6 at 5x dose, enhanced administration)
• Favourable safety profile with no serious adverse events related to ProSavin® or the enhanced administration technique;
• Average motor function1 improvement of 30%, with a maximum of 41% in one patient;
• L-DOPA “equivalent” therapy has reduced in all six patients, in what is usually a progressively degenerative disease requiring an increase in dose.
In summary, ProSavin® has demonstrated a long-term safety profile, now up to 48 months post treatment for the first two patients treated with a 1x dose. All 15 patients treated have shown an improvement in motor function at the six-month efficacy endpoint relative to baseline. As previously announced on 15 December 2011 (See below), population analysis of the first nine patients (cohorts 1-3) revealed that ProSavin® significantly improves motor function relative to baseline, with improvements remaining statistically significant up to 12 months post-treatment. The study’s independent Data Monitoring Committee also confirmed that the signals of improvements in motor function with decreased oral dopaminergic therapy observed to date are encouraging, particularly at the 5x dose.
* On December 15, 2011, Oxford BioMedica has announced new data from its Phase I/II study to assess the safety, efficacy and dose evaluation of ProSavin®in patients with mid-stage Parkinson’s disease .
Summary of efficacy analysis of all 15 patients treated:
• ProSavin®mediates improvement in UPDRS Part III “OFF”scores1in all cohorts at six-month primary efficacy endpoint;
• Population analysis of cohorts 1-3 indicates that ProSavin®significantly improves motor function relative to baseline, with statistically significant improvements up to 12 months;
• ProSavin®demonstrates efficacy across range of disease severity;
• Treatment with ProSavin®supports average reduction in L-DOPA “equivalent” therapy in all cohorts with signs of a dose-related response - cohort 4 (5x dose) indicates highest level of dopamine provision vs. earlier cohorts
ProSavin®has been evaluated in four ascending dose cohorts (1x, 2x and 5x) in a total of 15 patients. Six patients received the 2x dose, the latter three of which were treated using an enhanced administration procedure which facilitates higher dosing, and six patients received the 5x dose.
The primary efficacy end-point of the Phase I/II trial is the six-month UPDRS assessment and results from all six patients in the fourth (5x dose) cohort are expected in H1 2012. Results from the latest assessment of all four cohorts have now been verified and reviewed by the study’s independent Data Monitoring Committee (DMC):
DMC highlights of all four patient cohorts (n=15)
• Favourable safety profile with no serious adverse events related to ProSavin®or the enhanced administration technique;
• Cohort 4 (5x dose) shows most promising signs of efficacy to date including improved UPDRS Part III “OFF” scores, improved UPDRS Part III “ON” scores2despite a reduction in L-DOPA “equivalent” therapy and a reduced Positron Emission Tomography (PET) scan signal implying a higher level of dopamine provision;
• Average L-DOPA “equivalent” therapy has either reduced or remained stable in all four cohorts, in what is usually a progressively degenerative disease requiring an increase in dose; and
• Long-term safety profile 36 months post-treatment (1x dose)
Oxford BioMedica and its clinical experts believe that the interim ProSavin data set continues to support planning for a sham-controlled Phase II study. During 2011, the Company has identified and developed an enhanced product construct based on the ProSavin®dopaminergic enzymes. The new construct can potentially provide more than a 10-fold increase in dopamine production capacity, allowing further dose escalation without impacting volume or rate of administration. In addition, the new construct offers extended patent protection and a relative reduction in cost of goods, thus increasing the commercial opportunity for ProSavin®. The Company looks forward to six-month results from all six patients in the fourth (5x dose) cohort in H1 2012, and given the potential of the new construct will evaluate a strategy to move it into development as part of a Phase II programme.Cohort3 Dose Admin. method 3 months
(UPDRS)6 months
(UPDRS)1 year
(UPDRS)2 years
(UPDRS)1, n=3 1x Original Mean 27%
Max. up to 30%Mean 30%
Max. up to 48%Mean 29%
Max. up to 44%Mean 20%
Max. up to 30%2, n=3 2x Original Mean 28%
Max. up to 53%Mean 34%
Max. up to 53%Mean 29%
Max. up to 56%Mean 27%
Max. up to 47%3, n=3 2x Enhanced Mean 26%
Max. up to 52%Mean 43%
Max. up to 61%Mean 28%
Max. up to 48%- 4, n=6 5x Enhanced Mean 26%
Max. up to 49%Mean 24%
Max. up to 31%
(n=3 of 6) - -
Highlights of fourth patient cohort at three months (n=3, 5x dose) are:
- Favourable safety profile with no serious adverse events related to ProSavin® or its method of administration;
- Data Monitoring Committee (DMC) supports current planning for randomised studies;
- Highest average motor function1 improvement of 29% at this time point, with a maximum of 49% improvement in one patient; and
- Reduction in average daily dose of L-DOPA “equivalent” therapy.
*On May 23, 2011, Oxford BioMedica plc has announced that new data from the on-going Phase I/II trial of ProSavin® for the treatment of Parkinson’s disease were presented at the American Society of Gene & Cell Therapy (ASGCT) 14th Annual Meeting held in Seattle, USA by Professor Stéphane Palfi, Principal Investigator at the Henri Mondor Hospital in Paris, on Saturday 21 May 2011.
Highlights of third cohort at six months (2x dose, enhanced administration)
• Average motor function1 improvement of 43%, with a maximum of 61% in one patient;
• Patient diary data2 show an increase in functional “ON” time (when PD symptoms are not present) of approximately 3 hours;
• Patient diary data2 show a decrease in “OFF” time (after withdrawal of PD medication) of approximately 4 hours;
• Daily dose of L-DOPA “equivalent” therapy has either reduced or remained stable;
• Quality of life has either improved or remained stable on the PDQ-39 questionnaire3 and these findings are consistent with the UPDRS activities of daily living (ADL) subscore4; and
• Continued favourable safety profile with no serious adverse events related to ProSavin® or the enhanced administration procedure developed by the Company.
A further higher (5x) dose of ProSavin® is being assessed in the current six-patient cohort; the scaled equivalent to the optimal dose in pre-clinical studies. Three-month results from the first three patients in the 5x dose cohort are expected mid-2011 and will be announced in H2 2011 following a review by the study’s independent Data Monitoring Committee (DMC). Planning is on-going for a sham-controlled Phase II study that will recruit up to 50 patients. Depending on the results from the 5x dose cohort and the independent opinion from the study’s DMC, a randomised Phase II trial of ProSavin® could be initiated in the EU/US in 2012.
* On May 3, 2011, Oxford BioMedica has announced that new data from the on-going Phase I/II trial of ProSavin® for the treatment of Parkinson’s disease (PD) will be presented on Saturday 21 May, 2011 at the American Society of Gene & Cell Therapy (ASGCT) 14th Annual Meeting in Seattle, USA by the study’s Principal Investigator, Professor Stéphane Palfi of the Henri Mondor Hospital in Paris. The third patient cohort consists of three patients treated with a 2x dose of ProSavin® using an enhanced administration method. The top-line results at six months, which have been independently validated, are:
• Average motor function1 improvement of 43%, with a maximum of 61% in one patient
• Continued favourable safety profile with no serious adverse events related to ProSavin® or the enhanced administration procedure developed by the Compa
