Regenerative medicine: small steps towards the great leap forward

pharmafile | August 16, 2010 | Feature | Research and Development |  GSK, Pfizer, Stem cells, regenerative medicine 

Susan Aldridge reports on what some of the leading pharma companies are doing in the regenerative medicine and stem cells market

The concept of being able to repair, restore and regenerate human tissue and organs directly was once the stuff of science fiction, but is now becoming reality. If stem cell therapy and other regenerative medicine techniques and technlogies can realise their potential, they could offer radical new treatments for conditions such as cardiovascular disease, stroke, neurodegenerative disorders, blindness and diabetes.

Despite the promise, progress has not been quick in the field, and indeed public hope and media hype around stem cells have raised expectations far beyond what has been achieved so far.

Stem cells

The field of stem cell research, is of course, the focal point of the regenerative medicines, (although by no means the only technology – see box – Defining Regenerative Medicine).

Geron and ReNeuron are among the pioneering companies now embarking on clinical trials of stem cell therapies.

In January 2009, the FDA approved the world’s first phase I clinical trial of a stem cell therapy – Geron’s use of human embryonic cell to treat patients with spinal cord injury. However, just a few months in, the FDA called a halt to the trial after some patients developed cysts, and the trial has yet to gain clearance to resume.

Meanwhile, in April this year ReNeuron began a UK trial of its ReN001 in 12 patients who have suffered an ischaemic stroke. The treatment involves implanting neural stem cells directly into the brain with the hope of reversing the disabling effect of stroke.

From the pharma industry’s perspective, while the science remains unproven, the business strategy must also remain as yet undefined. For instance, should pharma companies invest directly in building up own expertise in regenerative medicine, or rely on academic and biotech partners to pioneer the developments and then help them develop them later? This is just one of the many conundrums facing pharma in relation to this cutting edge sector.

There are various sources of stem cells, including human embryonic stem cells, adult stem cells (mainly sourced from bone marrow) and the recently discovered induced pluripotent stem cells (iPSCs). These offer the pharmaceutical industry three possible types of application.

First, most companies are now developing and validating various stem cell-based assays for drug discovery and development, particularly for hepatoxicity and cardiotoxicity. Of most interest, perhaps, is the prospect of disease-specific cell lines from iPSCs.

Second, there is the possibility of using stem cells themselves as a therapy, either sourced from the patient (autologous) or from a donor (allogeneic). Recent advances in stem cell biology show that the cells often act as more than just a replacement – they secrete growth factors and other molecules which stimulate the body’s endogenous stem cells and tissue repair process, acting in many ways like a small molecule drug. The latter opens up the third possibility – of discovering small (or large) molecules, perhaps from within a pharma company’s own libraries, which can target the repair process by stimulating the repair processes of endogenous stem cells.

Pharma remains cautious

“Pharma companies are not yet fully engaged with regenerative medicine,” says Dr Alain Vertès, global alliance director, Roche and sloan fellow, from London Business School, who predicts that an allogeneic ‘off the shelf’ stem cell product will be easiest for the industry to develop and bring to the clinic.

“Induced pluripotent cells and human embryonic stem cells show great potential, but there are currently too many hurdles involved in their development, so this will take longer.”

Speaking recently at the World Stem Cells Congress, he observed that an estimate of the market for stem cells technology is at $2,680 million in 2012 and $5,100 million in 2014.

So far, Pfizer is the only one of the big pharma firms to set up a research unit specifically dedicated to regenerative medicine.

Set up in late 2008, Pfizer Regenerative Medicine employs around 50 full-time scientists at centres in Cambridge UK (neural, sensory disorders) and Cambridge, US (cardiac, endocrine disorders).

Pfizer recently set up a deal with stem cell company Athersys to develop and commercialise the latter’s MultiStem technology for  inflammatory bowel disease. MultiStem is a patented and proprietary cell therapy product that consists of a class of stem cells obtained from the bone marrow of healthy adult donors. As such, it is the type of stem cell therapy that big pharma is likely to be most comfortable with. The deal is worth $6 million upfront, with milestone payments and royalties to follow.

Pfizer has another agreement with University College London (UCL) on developing a stem cell-based therapy for age-related macular degeneration (AMD), which is a leading cause of blindness in older people and for which there is currently no really effective therapy. Pfizer will fund the development of therapies for AMD and other related retinal diseases. They have a further agreement with Novocell, which is developing a hESC-based therapy for diabetes, hoping to supply pancreatic cells that make insulin.

Meanwhile, GlaxoSmithKline signed a five-year $25 million deal with the Harvard Stem Cell Institute (HSCI) in late 2008, with projects in cardiovascular, obesity, oncology, neurology, muscle, and immunology now underway. HSCI represents one of the world’s largest concentrations of biomedical researchers, bringing together the University, the Medical School and 11 teaching hospitals and research institutions including Massachusetts General Hospital, Joslin Diabetes Center and the Dana Faber Cancer Institute.

Executive director Brock Reeve says the Institute therefore brings a lot of multidisciplinary expertise under one ‘virtual umbrella’, giving GSK ‘one stop shop’ access to in-depth knowledge of stem cell biology, leveraged funding, some unique cellular assays, patient populations, and world class clinical knowledge.

Meanwhile, GSK brings its compound libraries, high throughput screening, regulatory knowledge, and drug development expertise to the table. Reeve describes the arrangement as an equal partnership that goes way beyond the more traditional model of a pharma company ‘throwing money over the wall’ to an academic group. A Joint Steering Committee which meets regularly to monitor progress on the various projects. “All of our projects have developing a therapeutic as the ultimate goal,” Reeve explains.

Regenerative medicine is also an area of significant and developing interest at AstraZeneca, according to Alan Lamont, director, Science & Technology Alliances: “We are pursuing regenerative medicine projects through both internal work and external collaborations that are aligned to our existing areas of disease interest such as respiratory and inflammation, cardiovascular and metabolic and neuroscience and that offer the opportunity to address unmet medical need in different patient populations.”

The company’s New Opportunities Group can pursue potentially fruitful regenerative medicine approaches in areas outside AstraZeneca’s core interests, such as bone, muscle and ophthalmic disease.

“While these projects principally reflect our core strengths in small and large molecule development and are directed at modulation of stem cells, we are also interested to understand the progress being made in cell-based regenerative approaches to disease,” Lamont adds.

AstraZeneca also sees the opportunity to collaborate with external partners as an essential in the development of its activities in regenerative medicine: “While we bring a wealth of drug discovery and development experience, we want to work with key opinion leaders and biotechs that are leading in this field. Putting their expertise together with our own experience represents the best route to making a significant impact in developing new regenerative medicines,” says Lamont.

“We believe there are good opportunities for external deals and collaborations ranging from early discovery space through to the mid-late stage clinical development space.”

Taking aim at unmet clinical need

However, many barriers remain before regenerative medicine and stem cells become part of big pharma’s mainstream activity. In the absence of clear proof of efficacy, it is difficult to predict which would be the best market to aim for. “It would be great to tackle a large indication which is an unmet medical need, like chronic obstructive pulmonary disease,” says Vertès.

The COPD market was about $7 billion in 2008 but there is no specific therapy for the disease, which is treated with drugs that are meant for the treatment of asthma.

“In COPD, cells have the [conceptual] potential to regenerate and it might be easy to deliver a therapy that can assist this process into the lungs. Diabetes might be another promising area for a therapy that could replace insulin-producing beta cells,” Vertès added.

However, with cardiovascular disease – another potentially promising indication – the costs of clinical trials may be prohibitively high and there would also be competition with existing medical therapies.

“We need to find an indication with high value that is technically feasible where the therapy modifies the disease,” says Vertès. COPD fits this bill but getting there may not be easy. Another possibility is to go for the smaller or orphan market, where Genzyme, for instance, has been successful.

Regenerative therapies for inflammatory conditions like Crohn’s disease might be feasible in this context.

Regenerative medicine companies always mention regulatory as one of their main hurdles, for this is uncharted territory, with the therapies being neither a medicinal product nor a medical device.

Geron’s application for its hESC therapy was the largest IND the FDA had ever had, and their phase I is currently on clinical hold while they carry out further studies. ReNeuron also had a long and winding path to approval, turning to the UK after a series of setbacks and delays at the FDA.

One key issue for regulators is where stem cells go once they are in the body, and what are they doing where in vivo imaging and tracking systems for cells will be very important. Hopefully, however, the introduction of the EU’s Advanced Therapies Medicinal Products Regulations may help progress regenerative therapies into the clinic. Scale up and manufacturing is another potential barrier in regenerative medicine, for cell-based therapies are inherently more complex than small molecule.

Potential cost barriers

Cost of goods is a significantly higher part of the sales cost than it is for, say, a tablet. Regenerative medicine will fail if the cost bar is too high to offer treatments to those who need them. One company that has tackled many of these technical problems, including scalability, is Lonza, the largest contract manufacturing organisation (CMO) for cell-based therapies. At their dedicated facility in Walkersville, Maryland, they now produce 100 billion cells per batch which allows for 50-100 million cells per dose. In the UK, Angel Biotechnology is manufacturing the neural stem cells for ReNeuron’s clinical trial.

As for the future of regenerative medicine, Vertès believes there will be several clinical trials underway in the next five to ten years, but it will be at least 10 years before the hoped-for large scale indications are ready.

“The market could very much be like that for monoclonal antibodies, which took 25 years to mature,” he says.

Box: Defining Regenerative Medicine

Regenerative medicine is not one discipline, but several emerging and sometimes related fields. They can be defined as a group of biomedical techniques which restore the function of organs or tissue. This could be achieved by transplanting engineered tissue or cells as a replacement, or by inducing the body to regenerate itself, or by using medical devices to assist organ functions.

Cell therapies

This involves the injection of stem cells or progenitor cells (for specific cell types). Therapies can be either ‘autologous’ – using the patient’s own cells or ‘allogeneic’ using donated cells.

Tissue engineering

Transplantation of in vitro grown organs and tissues. The best known example of this is the growing of a new trachea for a patient in June 2008. A section of trachea was taken from a donor, which then had all of its living cells removed in a repeated ‘washing’ process. Two types of cells were then used to line the trachea to make it bio-compatible with the patient. Epithelial cells were taken from the patient’s existing trachea for the inner surface of the scaffold while chondrocytes (cartilage cells) were derived from stem cells from the patient’s bone marrow for the outer surface. The operation was a success, and no immune-suppression was needed because the cells were the patient’s own.

Biomedical engineering

The pacemaker, which helps to regulate the heartbeat, and was first used by patients in 1958, is an early example of biomedical engineering. Technological advances mean that an artificial pancreas is now being developed. The first artificial limbs which can be controlled by thought are among the exciting cutting-edge ideas in the field now being tested in patients.

Gene therapy

The insertion of genes into a cell or tissue of a patient to treat a disease with a genetic basis.
A handful of companies have pioneered gene therapy. One of these is Genzyme, which launched its first enzyme replacement therapy Ceredase (algucerase) for type I Gaucher disease in 1991. The technology could in theory be applied to cancer to replace genes which cause tumours to develop.