October 15, 2008 (Vol. 28, No. 18)

Initiatives Include Treating Diseases and Conditions by Restoring or Repairing Genetic and Cellular Defects

Advances in stem cell research and tissue engineering are evolving into a new generation of regenerative therapies to treat diseases and conditions by restoring or repairing genetic and cellular defects.

The clinical development stakes are high, but the results have been some fruitful collaborations between pharma and biotech. At Arrowhead-Spectra’s “International Clinical Development Congress in Cell Therapies and Tissue Engineering,” to be held in London later this month, researchers will discuss the progress of clinical-phase candidates and technologies that have the potential to succeed in the highly competitive global marketplace.

“This is a very timely meeting,” notes Robert Deans, Ph.D., senior vp of regenerative medicine at Athersys, “and a multibillion dollar opportunity. There will certainly be deals and collaborations to announce in the near future as well.”

The talks will range in scope from challenges in the service-provider sector, funding sources for further development, and case studies and preliminary data from ongoing trials.

Know Your Product

Robert Preti, Ph.D., president and CSO, Progenitor Cell Therapy, says that his company’s philosophy is to know as much as possible about the product and the process as is practical before embarking on serious development efforts with a client.

“It seems obvious, but as the product evolves, there is a great need to understand the product as much as possible,” Dr. Preti points out. “Looking at particularly heterogeneous cell products, you need to understand how the cells work as much as possible. A well-defined product and process allows for a solid comparability profile around which to make process and related testing changes through the development process, while limiting the amount of retesting for effectiveness and toxicity.”

Dr. Preti describes successful development approaches to achieve a risk-based balance of time and resources. “If you spend too much time and money up front to understand the product, it may be difficult to stretch funding to continue the development process through preclinical, Phase I, and Phase II trials. You may never really know the mechanism of action of one cell or cell type,” he says.

“At first, if you inject undifferentiated cells into muscle, what happens? Does it turn into muscle? Does it automatically differentiate to what you want it to turn into? What is the cell actually doing? So it is critical to get as educated an answer as you can, and proceed from there with your development efforts.”

Cell therapy is different from drug development in that it is both system-based and organ-based. “When you enter into product development, you need to have some understanding of how your product works,” adds Dr. Preti. “In Phase III trials and in commercial distribution, it would be most effective to have a real-time readout of potency.”

“There needs to be a balance. We tend to think that the action of the cell is obvious,” he continues, “and, as a consequence, things get moved along faster than they should. Your venture capital partner will likely favor milestones based on clinical trial progression over advances in cell product characterization. But if a therapy gets pushed through too quickly, it can all fall apart.

“When critical process changes that need to be made are made and one has been unable to verify that those changes have not affected the therapeutic or toxicity profile, a worst-case scenario is that one might need to repeat a clinical trial.”

Dr. Preti will discuss how working with a client is crucial to the success of the enterprise. “It’s a holistic process,” he explains. “For instance, the design and validation of the facility, the distribution logistics, and the release testing are all interrelated and tailored to the product. Putting quality systems in place, understanding critical parts of the process, these are things that factor into the final product. In fact, it’s almost impossible to separate the product from the process. The process is the product. The product is the process.”

Stem Cell Neurogenesis

“We work mainly in the field of growth factors, not transplants,” says Markus Jerling, Ph.D., CMO, NeuroNova. “We were previously taught that we could not regenerate cells in the central nervous system, but new research has shown that’s not true. We have screened a number of compounds to stimulate neuronal growth and regeneration.”

Dr. Jerling will be presenting on two projects: the first looks at a proposed treatment for Parkinson’s disease wherein platelet-derived growth factor, a protein that promotes neuronal stem cell proliferation, is infused with a pump directly into a fluid filled cavity in the brain. He points out that NeuroNova is working closely with Medtronic, which supplies the implantable pumps and catheters.

“What has been administered locally in the brain can stimulate brain cells in this area,” remarks Dr. Jerling. “Our next step is to show results in typically affected Parkinson’s patients. We have good animal models—we’ve administered this in monkeys and demonstrated by PET imaging increased dopamine turnover and symptom relief patterns. Treatment is short, approximately two weeks, but the effects are long-lasting. By kick-starting the process, it will continue on its own.”

Dr. Jerling says his group suspects that further treatment periods may be necessary, but the option to retreat in a similar fashion is open.

“Currently, the study proposal is under regulatory review, and we expect to start in patients with relatively advanced Parkinson’s,” states Dr. Jerling. “So part of my talk will also cover some of the methods for assessing disease activity and designing such a trial in man.”

An advantage of stem cell stimulation using an implanted pump is that dosing can be stopped or modified, in contrast to stem cell transplantation where cells become independent. Similar approaches have been tested previously, but technologies have advanced considerably in the last ten years.

Dr. Jerling will also discuss a similar project that involves the delivery of the growth factor VEGF to ALS patients. “The catheter will be in the same place, but it will be continuous treatment—24/7. The ALS disease mechanism is not well known, and it affects a wider area of the brain. ALS patients have less of a capacity to increase VEGF production when needed, and our aim is for all patients with a diagnosis to get treatment.”

But such an undertaking requires multiple regulatory approvals—not only for the drug, but also for the device delivering the drug and the ethics. Dr. Jerling notes that some approvals have come in, and suspects the approval process will be complete by late 2008. “For ALS the medical need is extremely high,” Dr. Jerling adds. “Currently, there is no effective treatment—the only approved drug adds 2–3 months to a patient’s life.”

And the applications are broad. “We’ve selected two diseases for study, but the approach, as such, is of potential benefit for any neurodegenerative disease,” concludes Dr. Jerling.

Dr. Deans will be addressing isolation and clinical expansion of adult adherent bone marrow stem cells as well as preclinical safety and efficacy models for stem cell treatment of ischemic heart and brain injury. “Probably half the talk will deal with where we stand in clinical development,” he explains.

Athersys has been able to file with the FDA and open two clinical trials for treatment of acute myocardial infarct and limiting morbidity from graft versus host disease in allogeneic HSC transplant. Dr. Deans reports that the firm hopes to file an IND later this year for treatment of stroke.

“We covered quite a bit of ground in eight months,” he remarks. “The regulatory environment of the FDA has been supportive of adaptive clinical trials that have allowed us to test more indications in parallel. Once you are down this path you can use the same undifferentiated cell product to bring several indications forward. We’ve made significant advances, and we can leverage the safety profile proven at early stages.”

Dr. Deans also notes that Athersys has emphasized safety testing in immunodeficient animals, as well as applying new technologies looking at changes in gene-methylation patterns by microarrays, or chromosomal integrity by CGH.

“The cell has the potency and safety profile that’s required. Researchers are trying to show the safety of cell products, and it’s a significant plateau to reach. This allows for more progress in the cell therapy space, a good sign for the industry.”

There are competitive and collaborative opportunities in this space, Dr. Deans notes. “The opportunity is large, since these are coalescing technologies.” He added that he sees two primary business models: Single-channel dose from donor to patient, a personalized medicine approach that has not been a good business model.

“The other approach is a universal product from a single donor—unlimited and undifferentiated cells. This is the way the industry is headed,” he continues. “There is new attention paid to personalized medicine with the advent of IPS (pluripotent stem cells from an individual that can produce cells for a personalized medicine approach). However, this shifts the model to a banking and service-based business, which hasn’t been attractive for investors or pharma.”

Germ-Line Transmission

Stem Cell Sciences(SCS) focused on the commercialization of stem cells and stem cell technologies, recently reported that two independent laboratories in the U.K. and the U.S. have achieved germ-line transmission from embryonic stem (ES) cells in rats using technologies exclusively licensed to the company by Edinburgh University.

This is believed to be the first time that germ-line transmission from rat ES cells has been demonstrated, and full scientific reports on this breakthrough, which has been independently verified, have been submitted for publication, according to Tim Allsopp, Ph.D., CSO.

Under the terms of its agreement with Edinburgh University, SCS has global exclusive rights to commercialize the rat ES cells, the specific culture medium used to generate and grow the cells, and the rats derived. The company has exclusively licensed two patents covering this technology from the University and now plans to engage in discussions with interested parties seeking a sublicense to use rat ES cells in their commercial drug discovery programs.

“While we don’t claim to be in a pole position with the development of human cell therapeutics, our skills, technology, and intellectual property are geared to be able to support the successful translation of lab-scale cell production to the industrial scale that this exciting new modality will require,” continues Dr. Allsopp.

“We will be providing more human stem cells in the near future. One of the key challenges we see in the field right now is building an infrastructure for scaled, efficient production of cells for assays and screens—and that’s what we are looking to do.”

Cell Therapy for CVD

Amorcyte is pursuing cellular therapies for cardiovascular diseases. Andrew Pecora, M.D., chairman, will talk about cGMP production of a cell therapy for cardiovascular disease, preclinical development of a cell therapy to prevent/reduce adverse ventricular remodeling following a myocardial infarction, and preliminary Phase I trial results.

“AMR-001 is for patients with acute myocardial infarction who are at risk because of the size of the infarct,” Dr. Pecora says. “We’ll be presenting data regarding the therapy delivered and signs of biologic activity. This has given us the go-ahead for Phase II. AMR-001 is cell therapy formulated to meet pharmaceutical standards. If the therapy is found to be safe and effective, we believe it can be delivered for pharmaceutical scale and administration.”

Amorcyte’s Phase I results demonstrated proof of principle for this type of cell-based therapy. “We have shown that it is possible to take progenitor stem cells harvested and extracted from a patient’s bone marrow shortly after a heart attack and deliver these cells back into the patient’s heart with the intent of repairing the damaged heart muscle,” adds Dr. Pecora. “Cell therapies have evolved from a medical procedure to a drug—and the biggest issue is that pharma does not have the infrastructure to supply the cell lines.”

He notes that Progenitor Cell Therapy has worked hard to put these in place, and created the platform for Amorcyte, which made the creation of AMR-001 possible.

“A paradigm shift has occurred here. I’ve delivered cell therapies on scale for 20 years—when the argument that there is no business model for this, I can say it’s not true,” Dr. Pecora emphasizes. “Early trials in cell therapy were not done to the standard of drugs. Now, you can engineer cells into what they need to be. It’s a simple, elegant solution to make one’s own cells work for them.”

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