Research Update Meeting - November 2017 Research Update Meeting We presented our research update to a packed audience kindly hosted by Deloittes, London. The meeting featured presentations from Dr Dilan Athauda, clinical research fellow at University College London, who conducted the exenatide trial with Professor Tom Foltynie, and Dr Simon Stott, Cambridge University. Dr Athauda presented the exenatide trial results in some detail and highlighted the additional ongoing work to further analyse the trial data in terms of identifying why some people responded better than others to exenatide. Long term further extensive analysis will be vital as it will show who will benefit most from this potentially disease modifying therapy. Dr Athauda also discussed the next stage, this being the phase III trial, which is currently being planned. A Q&A session led by CPT’s Dr Joy Duffen, allowed the audience (some of whom were on the trial) the opportunity to share their views and opinions of the trial results and importantly, whether the team at UCL should wait for a better drug or press ahead to verify their findings. The audience was unanimously keen to see next steps undertaken. Cambridge University’s Dr Simon Stott presented his perspective on the three main components required for a cure for Parkinson’s: Disease halting mechanisms - Multiple experimental options of both direct and indirect approaches Neuroprotective agents - Numerous clinically available drugs and novel compounds being tested as well as neurotrophic trials Cell replacement therapies - Multiple groups around the world going to the clinic with alternative approaches Disease halting mechanisms: This is a treatment that will slow or disrupt the spread of the condition within the brain. One key feature of Parkinson’s is the aggregation of the toxic protein alpha-synuclein and its spread throughout the brain. A key question here is ‘Does Parkinson’s spread through brain cells via alpha-synuclein? If it does, how can we stop this? Two crucial areas of research within this investigative field are 1) direct approaches and 2) indirect approaches. Directly, research into boosting the immune system to target the toxic form of alpha synuclein in the Parkinsonian brain: See Affiris – 2 phase II trials – results due 2018/19. Indirectly, by tackling alpha-synuclein by introducing ‘repurposed’ drugs which have shown potential to stop alpha-synuclein toxicity – the Ambroxol trial which is underway and the Nilotinib trial which has begun recruiting. Neuroprotective agents: Where a compound or compounds could help nurture and rejuvenate the remaining neurons in the Parkinsonian brain. The following repurposed drugs are being trialled, or trials are currently being outlined, through CPT’s Liked Clinical Trials initiative: Bydureon/Exenatide (this drug is already used to treat diabetes) - https://www.ncbi.nlm.nih.gov/pubmed/28777758 Phase II trials of Lixisenatide and Liraglutide (diabetes treatments) trials are underway in France and California. Ursodiol/UDCA (currently used to treat gallstones) – University of Minnesota; Phase I safety trial –https://clinicaltrials.gov/ct2/show/NCT02967250 results are due in 2018 Isradipine (used to treat high blood pressure)- this trial is currently underway in the US - STEADY‐PD III Phase III – https://www.ncbi.nlm.nih.gov/pubmed/28589163 - results due 2019 Simvastatin (a cholesterol lowering drug) - STAT-PD Phase II trial - https://clinicaltrials.gov/ct2/show/NCT02787590 - results due in 2019/20 There are also a large number of novel compounds being trialled for efficacy in Parkinson’s: EPI-589 - Phase IIA trial run by Edison Pharmaceuticals; results are due in 2018 IkT-148009 (Abl kinase inhibitor) - Inhibikase Therapeutics 2x Phase-2 clinical trials in Parkinson’s disease – currently recruiting Future combination clinical trials: Bydureon/Exenatide with MSDC-0160 - MSDC-0160 is an mTOR inhibitor and autophagy activator. Currently in preclinical concept testing - Neurotrophic factors: Glial cell-derived neurotrophic factor (or GDNF) - This Bristol based trial is now complete and although the initial results have been disappointing, we are awaiting the final report once all of the outcomes data has been collated and interpreted. In August 2017, Herantis Pharma began recruiting subjects for their CDNF (Cerebral Dopamine Neurotrophic Factor) gene therapy trial. A total of 18 people with Parkinson’s disease will be involved. Cell replacement therapy : Introducing new cells to take up the lost function: TRANSEURO headed by Professor Roger Barker and part-funded by CPT is a consortium with the principal objective to develop an efficacious and safe treatment methodology for Parkinson’s using foetal cell based treatments. To date 7.5 people have been transplanted in Cambridge and 2.5 people in Sweden (where .5 is one side of the brain). A total of 13 people will receive the transplant cells and followed up long term. Planning is also underway for an embryonic stem cell-based clinical trial of cell transplantation in Parkinson’s between Sweden and the UK led my Professor Malin Parmer. A follow-on project from Transeuro is planned involving a screened and well characterised cohort ready for trial and tried-and-tested surgical/clinical evaluation protocols. Embryonic stem cells are derived from the blastocyst. They can be expanded in cell culture and turned into any cell type we desire. Cyto Therapeutics (subsidary of ISCO) is conducting a Phase I clinical trial to evaluate the safety of neural stem cells in people with PD - they are using human parthenogenetic stem cells for their study. These are stem cells derived from ‘parthenotes’ or chemically activated unfertilized female eggs. The reasoning is that this avoids the ethical problem of destroying a potentially viable human embryo. Read more in the Science of Parkinson's blog here. A Phase I/II, open-label study to assess the safety and efficacy of transplantation of embryonic stem cells-derived neural precursor cells in people with Parkinson’s at the First Affiliated Hospital of Zhengzhou University in Henan province. Thus far, the company has transplanted 6 of the 12 people who are enrolled in the study. Results are expected in 2019/20. Read more here - https://www.nature.com/news/trials-of-embryonic-stem-cells-to-launch-in-china-1.22068 What does the future hold? Personalising cell transplantation therapy: Versant Ventures and pharmaceutical giant Bayer AG plan to submit an Investigational New Drug (IND) application to the FDA in 2018, with the goal of transplanting IPS cells into the first patient within that year. See Lorenz Studer’s work. Prof Jun Takahashi – Plans are underway for an IPS cell-based transplantation clinical trial for Parkinson’s in 2018. Read more here. We are still some years away from the clinic, but this technology is very exciting. Personalised combinations of one or all components of these therapies for PD will be used in future treatment of Parkinson’s. ____________________________________________________________________________________________ Rallying to the Challenge Survey CPT’s Leah Mursaleen and Helen Matthews presented the results of a survey which was run before the annual advocacy conference 'Rallying to the Challenge' which is hosted annually by the Van Andel Institute in September. The survey was designed to explore different perspectives to risk and benefit. Read more here. Focus groups held during the meeting highlighted some practical steps and recommended developing a simple tool to help people ask questions when considering making changes to their Parkinson’s treatment (incl. off-label use). They also recommended creating a linked tool to assist in decision making for taking part. In the coming months, the CPT team will be seeking people with Parkinson's to help us create these tools. ___________________________________________________________________________________________ The final session was a panel discussion led by CPT’s Lyndsey Isaacs and involving David Jones, Vicki Dillon and Richard Windle all of whom have taken part in research - the aim of this session was to stimulate discussion about ways people with Parkinson's can get involved in research. Members of the audience raised the need for a national register of patients interested in taking part in research, and there was a call for Parkinson’s centres to make their research efforts more joined up by listing all current studies seeking participants on a flyer distributed via clinical appointments. ** It is important for all readers to note that cell transplantation therapies are all still at the clinical trial stage of this technology and could have serious consequences for the individuals receiving any such procedures with potential negative ramifications for future research in the stem cell transplantation area. Also, the repurposing of drugs for Parkinson’s is still within the trial phase and even though these drugs and therapies are available and may have been tested in healthy human volunteers, repurposed drugs have to undergo additional clinical testing to evaluate safety, tolerability and efficacy in people with Parkinson's.