Regenerative medicine is one of the most promising fields of medical research, offering the prospect of disease reversal. Europe currently leads the world in the therapeutic applications of a swathe of technologies that fall under regenerative medicines banner, ranging from patches of decellularised pig tissue for use in repairing veins, to patient-specific cell therapies for repairing damaged knee cartilage, and human embryonic stem cell-based treatments for degenerative eye diseases.
Special Report: Experts debate the future of stem cells (PDF)Europe is currently a world leader in the fundamental science underpinning regenerative medicine and cell therapy, and in its therapeutic use and regulation. But how can Europe build on its leading position?
View from Europe: Delivering on the vision of regenerative medicine and stem cells
Talking to the experts: Why the EU should support human embryonic stem cell research in Horizon 2020
Europe has also put in place a science-based regulatory pathway for clinical development, manufacturing and approval of these complex products. Now the first European clinical trial involving a human embryonic stem cell (hESC) line is underway at sites in London and Aberdeen, where cells developed by the U.S. company Advanced Cell Technology Inc. are being tested in the treatment of Stargardt’s Macular Dystrophy, a cause of blindness.
The first European-developed therapy based on hESCs is due to enter the clinic in 2013. The product, which has been developed in a collaboration between Pfizer Inc and University College London, is a treatment for age-related macular degeneration, a cause of sight loss and blindness.
However, attempts to force through cuts to embryonic stem cell funding in the European Union’s (EU) next five-year R&D programme Horizon 2020, coupled with the Brüstle ruling on 24 October 2011 by the Court of Justice of the European Union that an invention involving the destruction of a human embryo cannot be patented, threaten to undermine progress - not only in treatments based on embryonic and foetal cells - but in regenerative medicine as a whole.
On 18 October Science|Business brought together business, politicians, research funders, patients’ representatives and scientists to debate the challenges that exist for Europe to maintain its lead in the field and translate excellent publicly-funded science into marketed products - providing significant health benefits and delivering on the commercial potential of regenerative medicine.
Welcoming delegates to the meeting at the British Embassy in Brussels, the UK Ambassador to Belgium, Jonathan Brenton noted that the award of this year’s Nobel Prize for Medicine to John Gurdon, for the discovery in 1962 that the specialisation of cells is reversible, and to Shinya Yamanaka for demonstrating in 2006 that adult skin cells can be reprogrammed to pluripotent cells with the potential to develop into any cell type, has put the spotlight on the therapeutic promise of stem cells.
Ambassador Brenton said this is an appropriate time to have an “honest and searching debate” as discussions on the exact shape of the Horizon 2020 R&D programme move towards a conclusion. Not only is there huge potential in terms of the medical applications, there is a growing commercial opportunity, with the cell therapy market forecast to reach €5 billion in 2014, and the prospect of further growth as more products are developed and come into use.
This debate should focus on what kind of legislative framework Europe needs to unlock the medical and commercial potential, and what level of research funding is required to maintain Europe’s lead, Ambassador Brenton said.
Maintaining the ‘Triple-Lock’
Some EU member states and pro-life Members of the European Parliament (MEPs) are lobbying for the existing restrictive rules on funding embryonic stem cell research in the current Framework Programme 7 (FP7) to be further tightened in its successor, the proposed €80 billion Horizon 2020 programme, which currently is under consideration by the European Parliament.
The EU Research Commissioner Máire Geoghegan-Quinn has made it clear she intends to resist any change, noting that a great deal of time and effort was spent sorting out the existingg “triple-lock” agreement negotiated for FP7. The triple-lock states that any EU-funded embryonic stem cell research must conform with the laws of the country in which it is undertaken; that the research is subject to ethical review; and that EU money cannot be used for the derivation of new human embryonic stem cell lines, or any research involving the destruction of human embryos.
The European Council supports retaining the triple-lock agreement in Horizon 2012.
Marina Yannakoudakis, a UK MEP representing London told delegates at the Science|Business meeting that this is an area where Europe “should not attempt to devise a one-size-fits-all policy”. Instead, the subsidiarity principle operating in FP7 should be maintained: where it is permitted by member state legislation it should continue to be possible to get funding in Horizon 2020 for stem cell research. “Horizon 2020 should fund the best stem cell science, but it cannot, and it should not, seek harmonisation,” Yannakoudakis said.
This is also the position of the ITRE (Industry, Research and Energy) Committee in the European Parliament, noted another MEP Amelia Andersdotter. The issue of funding embryonic stem cell research, “has not been particularly controversial”, with ITRE more or less supporting the status quo in FP7.
Sweden’s Pirate Party, of which Andersdotter is a member, also supports maintaining the status quo in FP7. However, the Green group of MEPs to which the Pirate Party belongs, is of the opinion that European Union money should not be used for research that would be illegal in some member states.
Those member states that allow embryonic stem cell research will continue to fund the work through national R&D budgets. The Green group of MEPs believes in a time of austerity it is better to support research that everyone has in common, rather than research that is carried out in some countries and not others, Andersdotter said.
Regenerative medicine: a high value technology
The European Commission’s approach to funding regenerative medicine research in Horizon 2020 is based on the assessment that this is potentially a high value technology that will deliver life-changing treatments. “It is a new paradigm for medicine,” said Arnd Hoeveler, Head of Unit for Advanced Therapies and Systems Medicine, DG Research and Innovation.
However, a huge barrier – in the shape of lengthy development timelines - lies in the way of moving the new technology from the bench to the bedside, manufacturing the product and meeting the requirements of the regulators. An analysis of the Advanced Therapy Medicinal Products coming before the European Medicines Agency shows they are mostly sponsored by academics, charities and SME start-ups. Few larger and better-financed companies are involved in the field. “In other words there is a need for public sector support if the promise of the new technology is to be realised,” Hoeveler said.
Such support will allow Europe to capitalise on its high knowledge base and experience that in part has been built up by the €350 million the Commission has put into regenerative medicine and stem cell research projects over the past five years. The Commission wants to support more clinical trials to take products through from preclinical development to proof of principle in humans, providing showcases for the technology – and concrete examples of its therapeutic power. However, with the wide diversity of technologies being developed, the range of potential therapeutic targets and the lack of tried and tested business models, this is no easy task.
Live-saving therapeutic power
The therapeutic power, the huge unmet medical demand, and the difficulties involved in scaling-up and commercialising regenerative medicines is highlighted by the inspiring research of Suchitra Sumitran-Holgersson, Professor of Transplant Biology at Gothenburg University.
Sumitran-Holgersson has developed a technique for removing all the cells from a vein taken from a deceased donor and repopulating it with a patient’s own endothelial and smooth muscle cells, obtained by differentiating stem cells obtained from the bone marrow of the recipient. In the case of a 10-year old girl who had an obstruction of the portal vein feeding blood between the intestines and the liver, the graft immediately provided a functional blood supply. And because the donor’s cells were replaced with her own, there is no need for the girl to take drugs to suppress her immune system.
The publicity that was attracted when details of the case were published in the medical journal The Lancet on 14 June 2012, drew thousands of emails and enquiries from around the world, convincing Sumitran-Holgersson there is a widespread need for this type of regenerative medicine. “My request is, could the EU help me to get this therapy to the rest of the world? How can I build the infrastructure and get the therapy out there?” she asked.
Intellectual property protection
As Sumitran-Holgersson acknowledged, there are many hurdles to be overcome in scaling up the vein replacement technique, not least of which are the ethical aspects surrounding the commercialisation of donor tissue.
Such ethical issues overhang the question of whether a commercial regenerative medicine product can get the intellectual property protection needed to attract investment.
In general, patents are less important in regenerative medicine than in conventional drugs because products such as cell therapies involve huge amounts of know-how and cannot readily be copied. However, intellectual property protection is very important to investors, and small companies are unlikely to get funded to start out on the long path to market unless they have patents.
The Court of Justice of the European Union ruling in the Brüstle case was upsetting for scientists working with embryonic stem cells, who found that approved and regulated research was nonetheless deemed to be unethical. The judgement also set alarm bells ringing that there would be a flight of research and scientists from Europe.
But, said lawyer Julian Hitchcock, Counsel at Lawson Davies Denoon, there was a lot of misunderstanding of the impact, which he believes is the reverse of what was feared. Although its legal basis is dubious, the ruling provides clarity - in that it is now clear there is no need to worry about infringing patents on embryonic stem cells, because the cell lines per se are not patentable. However, it will be possible to patent accompanying elements, such as delivery devices and manufacturing processes.
“It’s also important to note that everyone is equally effected by the ruling, wherever they are in the world; in other words European scientists are not at a disadvantage,” Hitchcock told the meeting.
A path to the patients
If concerns about patenting have been overdone, it is also the case that Europe has a better system of regulation for cell therapies than many give it credit for. As head of TiGenix NV, the only company to date to have had a cell therapy approved by the European Medicine Agency’s Committee for Advanced Therapies, Gil Beyen has a particular insight into the regulatory pathway. Whilst not without its problems, he said, “Europe has done a lot: we have the regulation in place which is the basis for defining products and setting out the route to making products available to patients. If well implemented now, it can be the basis for giving Europe a strong competitive position in the fast-growing field of advanced therapies.”
The requirements are onerous, but the existence of a science-based regulatory framework allowed TiGenix, as a spin-out from KU Leuven, to put a development plan in place and to raise a total of more than Euro 100 million in venture capital and on the public market. In October 2009 the company was granted approval for ChondroCelect, a treatment for injured knee cartilage which involves taking healthy cartilage cells from the patient, expanding them in the lab and administering them into the damaged area.
Aligning regulatory requirements
Early pioneers of stem cell therapy, including TiGenix and the UK company ReNeuron plc, - which is developing a cell therapy treatment for the after-effects of stroke based on neuronal cells that were originally derived from foetal cells - have found themselves caught between the divergent requirements of the FDA and the EMA. However, Janice Soreth, Deputy Director of the FDA Europe Office and Liaison to the European Medicines Agency, said that on the back of regular meetings of experts from the two agencies, along with representatives of the national competent authorities from member states, there is now much more communication and cooperation with a view to more alignment. "The bottom line is that there is a great deal of collaboration between the [FDA and EMA] and member states under the umbrella confidentiality arrangements of the two agencies," Soreth said.
As a result, more companies are taking parallel scientific advice from EMA and FDA when designing studies and applying for permission to carry them out. These moves to align the regulatory pathway draw on the research base in cell therapies. "The aim of this joint approach is to reduce the regulatory overhead, while at the same time ensuring that the science drives the process, in the best interests of the public we serve," Soreth told the meeting.
Regulatory framework attracts investment
In 2008 when Pfizer Inc became one of the first big pharmaceutical companies to move into cell therapies, it chose to establish a research unit – now called Neusentis - in Europe because of the strong regulatory framework and positive public attitude to stem cell research, Ruth McKernan, Chief Scientific Officer of Neusentis told delegates.
In April 2009 Pfizer signed an agreement to work with Professor Peter Coffey of University College London, to translate his research in differentiating human embryonic stem cells to form retinal pigmented epithelial (RPE) cells, into a treatment for age-related macular degeneration. The condition leads to the loss of RPE cells and is a leading cause of blindness.
University College and Pfizer have worked together on the production of RPE cells, the safety studies needed to underpin the clinical trial, and partnering with regulators. Clinical trials are due to start next year. “After several years of research, we are excited to get our retinal epithelial cells into patients,” McKernan said.
“The collaboration with Peter Coffey is an important one for us,” McKernan said. Pfizer collaborates extensively with academic researchers in many areas and has over 200 research agreements in Europe. One challenging area for life sciences at the moment is starting new companies. “It is important to encourage spin outs and support new biotech companies. Many great ideas come from them,” said McKernan.
Supporting SMEs
To build a sustainable regenerative medicine sector, Europe needs to complete all the links in the chain from basic research to market. In particular it is critical to support university spin-outs and SMEs that can take academic research and push it through to clinical proof of principle. Public support is needed for these very early steps on the path to commercialisation.
There are a couple of role models in member states. One is CellforCure, a consortium of French biotechnology companies and academic centres that has a €30 million contribution from the government innovation agency OSEO towards the construction of a €80 million pharmaceutical-grade facility for the production of cell therapy products. This will allow companies to move away from their current dependence on university or hospital-based production facilities. The facility, based in Les Ulis, on the southwestern suburbs of Paris, will initially take on the production of cells for five clinical-stage products that members of the consortium are developing.
A second example is the UK’s Cell Therapy Catapult Centre, which in common with CellforCure has been set up to provide the missing pieces in the commercialisation jigsaw, by providing SMEs with help in scaling-up, repeatability, quality control, quality assurance, developing manufacturing processes, establishing supply chains, and so on.
The CEO of the Cell Therapy Catapult Centre, Keith Thompson told the meeting the aim is to address unmet medical need and provide demonstrations of the potential of stem cells to improve health and wealth. “We don’t have all the answers for cell therapies as yet, but we do have the collective will to get the field going and I’m confident we will help bring an array of therapies to market over time,” Thompson said.
In support of this, Thompson cited some small-scale - but highly effective - examples of existing cell therapies, including a diabetic patient who was able to stop administering insulin within two weeks of a pancreatic islet cell transplant, and the use of autologous corneal epithelial stem cell transplants to repair injuries to the cornea.
These examples hint at the imminent clinical and commercial potential of stem cells, and underline the importance of maintaining a consistent approach and providing clarity on stem cell research, both for SMEs and academics, in Horizon 2020. “We don’t want to see any particular cell type excluded, that would limit the potential benefits for patients,” said Thompson.
Basic research is still needed
The discovery of induced pluripotent stem cells makes it possible to turn an adult (somatic) differentiated cell, for example, a skin cell, back into a pluripotent cell. While these are embryonic stem cell-like, this feat of re-programming requires the addition of DNA in the form of oncogenes, making induced pluripotent stem cells unsuitable as the starting point for cell therapies.
Similarly, while induced pluripotent stem cells are important in opening out research into the mechanisms behind pluripotency and are providing powerful new tools for drug discovery, they cannot fully substitute for human embryonic stem cells in the basic research that is still needed to support the development of commercial products.
Translating the promise of stem cells is not a one-way street: as stem cell therapies make progress in development, clinicians are feeding back data from trials to prompt further -focussed - research into the basic biology of stem cells. Human embryonic stem cells are crucial here, since they represent the “gold standard” pluripotent cells. Clinicians need to access to basic research as they see how treatments play out in the clinic, so they can rationally improve a therapy.
It also clear that greater understanding of how stem cells give rise to regeneration and repair would help in applying them to treat disease.
In summary, induced pluripotent stem cells represent an important breakthrough, offering a powerful means of studying the biology of pluripotency and of disease, and providing a tool for drug discovery. But they cannot replace human embryonic stem cells.
The need continue basic research was one reason why UK medical research funding bodies reacted with alarm to the reopening of the political battle over human embryonic stem cell funding. In a joint statement sent to MEPs in June 2012, the Medical Research Council, the Wellcome Trust, the Association of Medical Research Charities (representing charities that fund over £1 billion of research each year) and other research groups, said it is important to maintain funding for all avenues of stem cell research. Any move to make human embryonic stem cells ineligible for Horizon 2020 grants would risk holding back progress across the entire field.
While the amount of funding for human embryonic stem cell research in Horizon 2020 would be only a small portion of the overall budget, axing it would have a disproportionate impact, Katherine Littler, Policy Adviser at the Wellcome Trust told delegates. This is because of the high level of international collaboration: 40 per cent of stem cell research funded by the Wellcome Trust involves researchers outside the UK.
“If there’s a negative funding environment, it will send out a negative message about the field; it will be more difficult to get funding for any type of stem cell research, and more difficult to form collaborations,” Littler said.
Supporting cross-sector and transnational research
While it is obviously important to respect the principle of subsidiarity, it is also important to improve the environment for regenerative medicine and cell therapies from a pan-European perspective, said Magda Chlebus, Director of Science Policy at the industry body, the European Federation of Pharmaceutical Industries and Associations (EFPIA). Members of EFPIA include some of the biggest investors in private sector R&D in Europe. They want to continue to do research in Europe, and to do this research in international and cross-sectoral collaborations.
As things stand, member states that favour a more restrictive approach have a disproportionate influence on the European research environment as a whole. “We want to attract research to Europe, but taking a restrictive attitude is killing off the tools,” Chlebus told the meeting.
Moral asymmetry
One of Europe’s leading patient advocates, Alastair Kent, Director of Genetic Alliance UK, believes it is “time to get off the back foot” and highlight that the moral high ground does not automatically belong to opponents of human embryonic stem cell research. “They are putting greater importance on embryos than on doing something to benefit patients with life-threatening diseases,” Kent said.
The embryos that are the source of embryonic stem cells have been generated through in vitro fertilisation and are not suitable, or are not needed, for implantation, and would be disposed of. Refusing to fund embryonic stem cell research, “is like saying people with Parkinson’s disease or Alzheimer’s disease are less important than a group of cells,” said Kent.
For Kent, there is no doubt that cell therapies will fill unmet medical needs. “The only way to scale up these treatments, guarantee their quality and make them available to any patient that needs them is through commercialisation,” he said.
Clear and unambiguous vision
There is also a risk that withdrawing from stem cell research - and so slowing commercialisation of products - will lead to an increase in rogue clinics offering unlicensed treatments. Patients are desperate and often willing to try anything. Advice and education from national health bodies, medical charities, or patients’ groups, is not credible unless there is a clear and unambiguous vision of how and when approved therapies will become available.
It is essential to continue to carry out research with human embryonic stem cells, but the focus on this is obscuring progress that is being made with other cell therapies. “This is confusing the debate and does not leave room for discussion about other types of stem cells and cell therapies,” said Emmanuelle Rial-Sebbag, Permanent Researcher in Biolaw and Bioethics, Inserm.
The best way to shift opinion and open out discussion is to showcase the progress that is being made, believes Rob Janssen, Secretary General of the Alliance for Advanced Therapies, a group launched in March 212 to promote the development of these products and attract the financial, scientific, political and regulatory support required to create a thriving sector. From a corporate perspective, a prime requirement is predictability at the national as well as the European level. “Without this, investors won’t invest,” Janssen said.
Theo Meert, Senior Director, External Innovation in Neurosciences, Janssen Pharmaceutica, agreed. If pharmaceutical companies are to invest in the commercialisation of regenerative medicine and cell therapy products there must be a supportive ecosystem. This encompasses appropriate and consistent legislation, regulation, and product definition. “It also requires a body of publicly-funded research that is open for industry to draw on,” Meert said. If academics cannot get funding for certain types of basic research in Horizon 2020, a gap will open up in European expertise.
PDF: Statement Supporting Funding for Stem Cell Research in Horizon 2020
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