Oxford BioMedica plc, a gene therapy company, announces new data from the on-going Phase I/II trial of ProSavin for the treatment of Parkinson’s disease (PD).
Three-month data from the third patient cohort show that ProSavin continues to be safe and well-tolerated following treatment with a 2x dose using an enhanced administration technique developed by the Company. The enhanced technique has been shown to reduce the surgical delivery time, will facilitate higher dosing and has the potential to provide better reproducibility of administration as study centres expand.
By way of background, the current Phase I/II study is designed to assess the safety, efficacy and dose evaluation of ProSavin in patients with mid-stage PD who are experiencing reduced benefit on L-DOPA “equivalent” therapy. To date, nine patients have been treated in cohorts of three.
In June 2010, Oxford BioMedica reported 24-month results from the first cohort which received a 1x dose of ProSavin®, in addition to 12-month results from the second cohort which received a 2x dose of ProSavin. Motor function is assessed according to the Unified Parkinson’s Disease Rating Score (UPDRS) in patients’ “OFF” state (ie after withdrawal of PD medication). Quality of life is assessed based on a standard measure of clinical benefit using a patient questionnaire known as PDQ-39. Patients from the third cohort who received a 2x dose of ProSavin® using the Company’s enhanced administration technique have now reached their three-month assessment:
Highlights of third cohort at three months (2x dose, enhanced administration)
Favourable safety profile with no serious adverse events related to ProSavin or the enhanced administration technique;
Average motor function improvement of 26%, consistent with 28% improvement using the old administration technique at the 2x dose, with a maximum of 52% improvement in one patient;
All three patients show improvements in at least one indicator of clinical benefit; and
Surgery delivery time for the 2x dose reduced by approximately 50%.
Highlights across all treatment cohorts (total of nine patients)
Patient diary data show an increase in “ON” time (when PD symptoms are not present) in all three cohorts; L-DOPA “equivalent” therapy has either reduced or remained stable in all three cohorts, in what is usually a progressively degenerative disease requiring an increase in dose; Quality of life has either improved or remained stable in all three cohorts, again where it would usually be expected to worsen; and ProSavin continues to have a favourable safety profile 30 months post-treatment (1x dose) and 18 months post-treatment (2x dose); As previously reported, 1x dose data showed average motor function improvement of 20% at 24-months (with a maximum of 30% in one patient) and 2x dose data showed average motor function improvement of 29% at 12-months (with a maximum of 56% in one patient).
The study’s independent Data Monitoring Committee (DMC) has reviewed the data and supports the Company’s proposal to proceed to a 5x dose, facilitated by the enhanced administration technique, in a six-patient cohort. Importantly, the 5x human dose is the allometrically-scaled equivalent (ie a dose that is scaled for the difference in brain size between humans and the pre-clinical model) to the highly efficacious pre-clinical dose published in Jarraya et al. Sci Transl Med. 2009 Oct 14;1(2). The DMC also gave its approval to open the second site in the UK at Addenbrookes Hospital, Cambridge, with Dr Roger Barker as Principal Investigator, which will recruit some of the six patients into the 5x dose cohort.
Oxford BioMedica plans to initiate treatment of the 5x dose cohort in Q1 2011. To date, nine patients have been treated at the Henri Mondor Hospital, Paris, with Professor Stéphane Palfi as Principal Investigator. The first patient in the 5x dose cohort will be treated in Paris, one month after which subsequent patients can be treated in parallel at both sites which is expected to increase the rate of recruitment and treatment. Results from the first three patients in the 5x dose cohort are expected in mid-2011. Depending on the efficacy seen with the 5x dose, a Phase II trial of ProSavin could be initiated in the EU/US in 2012 and planning is underway for this stage of the development programme.
Commenting on the nine patients treated, Professor Stéphane Palfi said: “The safety of the new administration method and the continued safety profile of ProSavin are both very favourable and the data from the earlier cohorts provide encouraging signs of long-term benefit. We can now be confident to administer ProSavin at a dose which showed the best benefit in a severe pre-clinical model of Parkinson’s disease.”
John Dawson, Chief Executive Officer of Oxford BioMedica, said: “This first-in-man Phase I/II study is an appropriately cautious approach to a potentially revolutionary treatment for Parkinson’s disease. With the excellent safety profile and sustained, positive signs of clinical benefit we have seen at the lower doses, we are confident that progressing ProSavin to the 5x dose could further enhance efficacy and therefore significantly increase the product’s value. We are making the necessary preparations to advance ProSavin into Phase II development as rapidly as possible including site expansion, regulatory guidance and manufacturing and we look forward to continuing our discussions with potential partners as we generate more data from this increasingly valuable asset.”
Oxford BioMedica's LentiVector gene delivery technology is one of the most advanced gene delivery systems currently available, which has many applications in product development and discovery research. It is the system of choice for gene-based treatments addressing chronic and inherited diseases. Oxford BioMedica has established a dominant intellectual property estate in the field of lentiviral-vector mediated gene delivery through its in-house research and from work conducted by the Company's co-founders at Oxford University.
Parkinson's disease is a disorder of the central nervous system that results from the loss of cells in various parts of the brain, including a region called the substantia nigra. The substantia nigra cells produce dopamine, a chemical messenger responsible for transmitting signals that allow for coordination of movement. Loss of dopamine causes neurons to fire without normal control, leaving patients less able to direct or control their movement (source: www.michaeljfox.org). On average, Parkinson’s disease affects one person in 1,000 of the population but for people in their seventies and eighties this rises to at least one in every 50. Parkinson’s disease currently affects 4.1 million patients globally which is projected to rise to 8.7 million by 2030. The current treatment market for Parkinson’s disease is approximately US$3.5 billion (source: Datamonitor 2007).
ProSavin uses the company'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. ProSavin has the potential to address an unmet medical need in Parkinson’s disease, offering long-lasting benefit from a single administration with an excellent safety profile.
Oxford BioMedica plc
