I began our interview by asking Dr. Van Bokkelen how regenerative medicine therapies are different than traditional pharmaceuticals and biologics. He explained that regenerative medicine consists of several different types of therapies including, cell therapy, gene therapy, gene modified cell therapy, and tissue engineering approaches. Regenerative medicine is fundamentally different from traditional pharmaceuticals or approaches that have been used to develop biologic therapies. Typically biologic therapies are very specific entities or single agent therapies that act through a well-defined mechanism of action. Cells are different in that cells can actually work through multiple different mechanisms of action, so they’re multi-dimensional in that regard.
He went on to discuss how gene therapy is different because it is not meant to provide a temporary fix for a specific problem. It is meant to provide, in some instances, a permanent or long-term cure by addressing the underlying defect that is affecting the patient. While very exciting, this approach also creates some potential challenges in figuring out how we establish a reimbursement framework for therapies that might be a single administration.
Together cell and gene therapy represent a kind of a paradigm shift in terms of how people think about approaching treatment. Several regenerative medicine therapies address a range of different diseases and conditions that are really not well served under current standards of care.
Next, I asked Dr. Van Bokkelen if he could tell us about some of the most exciting clinical breakthroughs in regenerative medicine. He said there are a growing number of cell therapies that have either been validated through clinical development or are now approved by the FDA and other regulators.
CAR T therapies are modified cell therapy approaches where cells derived from the patient are genetically modified and reintroduced into the patient to help fight cancer. These are patients that have failed other forms of therapies and the progress on that front has been incredibly exciting. These treatments have improved clinical outcomes in many patient cases.
He added that several gene therapy products have been approved over the past several years that have shown exciting response levels among the patients that are being treated.
He shared that recently at the J. P. Morgan Conference in San Francisco the Alliance for Regenerative Medicine presented data to show the phenomenal progress in terms of clinical development and companies advancing through the various phases of clinical development. He said that all of the data that was presented this year really reinforced the fact that the regenerative medicine sector and community as a whole is making incredible progress that is attracting investments and partnerships.
We then discussed some of the manufacturing challenges for regenerative medicine therapies. He explained that there are three categories of challenges that relate to manufacturing. The first has to do with scalability. If you think about cell therapies that have been approved they are all autologous therapies, which involves isolating cells from the patient, sending those cells to be genetically modified, characterized and then reintroduced ultimately sometime later into the patient. But that’s not really a scalable process and it’s reflected in the economics of those therapies. What he’s been seeing is that there’s been a lot focus on shifting towards using an allogeneic approach so therapies could be available “off the shelf” and don’t have to be patient specific.
The second big challenge relates to the scalability of the manufacturing process itself. Dr. Van Bokkelen thinks that many different therapies utilized during clinical development have modest manufacturing processes and procedures that are not ideally suited towards commercial scale activity. He believes that this is changing and that there is more effort being placed on creating technologies designed to improve the manufacturing process in an effort to make it more scalable.
The third challenge has to do with capacity. One of the things that has been written about over the past few months is that there is a lack of commercial scale manufacturing capacity both in the context of companies’ direct access and also what is available through contract manufacturing organizations.
We then talked about Athersys. Dr. Van Bokkelen explained that the company was originally established about twenty-five years ago by a team of faculty members from Stanford University Medical School, Yale School of Medicine and from Case Western Reserve University School of Medicine. Their focus was on developing technologies that they felt would address substantial areas of unmet medical need. They worked to develop innovative technologies that would move the needle with respect to challenging or difficult areas of clinical medicine where current standard of care was inherently limited. For more than fifteen years, their interest has been in the emerging field of regenerative medicine and cell therapy.
Next I asked if he could tell listeners about the development of Multistem and some of the unique advantages of these cells. He explained that Multistem is based on a discovery of a unique class of cells called Multipotent Adult Progenitor Cells, or MAPC®. These cells are distinct from mesenchymal stem cells (MSCs) and other cell types. They are obtained from healthy adult bone marrow and may be expanded outside the human body using proprietary manufacturing processes. In contrast to most other cell types that can be isolated from the human body, Multistem can be expanded to an enormous quantity and have robust growth properties. Once cells are isolated from a healthy consenting donor, the equivalent of millions of clinical doses can be produced starting with a modest amount of material.
He went on to say that these cells may be administered without tissue matching or immune suppression and results show they are capable of promoting healing and tissue repair in multiple ways. For instance, they can influence healing by repairing and reducing inflammatory mediated damage and they have relevance across a range of exciting therapeutic indications. They also offer off-the-shelf utility. Stability data shows that these cells remain stable in frozen form for years if necessary. Athersys is looking at using Multistem as a way to treat patients that have suffered from a range of different events including stroke and acute respiratory distress syndrome.
I followed up by asking about acute respiratory distress syndrome (ARDS). Dr. Van Bokkelen explained that ARDS is a condition where the lung tissue has become highly inflamed and starts to fill up with fluid. The lung can’t absorb oxygen and when the ability to absorb oxygen has fallen below a critical threshold, the clinician has no other choice except to put the patient on a ventilator. When you put a patient on a ventilator, you force oxygen into the lungs at high concentration in an effort to keep the patient alive. Being on a ventilator can create many complications or other adverse events that are very challenging.
Athersys found that Multistem has relevance in treating ARDS by looking at various models, which suggested that administering Multistem intravenously would cause the cells to move to the lungs when there was active inflammation and reduce it.
I then asked why Athersys chose to pursue ARDS and about other indications for Multistem. He explained that the evidence began to mount over a period of years and in a series of studies that Multistem could have a positive impact on ARDS. In studies, when Multistem was administered, inflammatory mediated damage in the lungs could be overcome. Athersys realized that they might be able to dramatically improve outcomes in situations where there was pulmonary inflammation and current medical approaches didn’t provide an effective alternative to the ventilator. The consequences of having patients on a ventilator for an extended period of time is that you create stress on the lung tissue that can lead to fibrosis or scarring, thus causing long term damage.
Athersys was also doing work with several of the leading transplant centers in the United States at this time. Investigators at these centers came to Athersys with a problem that is widespread in the field of lung transplantation. About seventy-five percent of lungs that are isolated from organ donors become highly inflamed and start to essentially go bad before the transplant procedure can be conducted. Once the lungs are harvested from the donor they are either put on ice or stored for the subsequent transportation procedure. The pulmonary tissue begins to experience inflammation, which causes the lungs to become compromised, (very frequently within just a few hours). The lungs become highly inflamed and filled with fluid, thus rendering them unusable. Doctors can’t transplant inflamed lungs into a patient needing a transplant because essentially they would have ARDS immediately. To see if Multistem could make a difference, investigators proposed taking lungs where there was severe inflammation and infusing one side with Multistem compared to the other side to be used as control. Since Athersys had seen restoration of pulmonary function and reduced inflammatory mediated cascade pathways in animal models, they had the basis for a study on human lungs that were isolated from donors. There was a dramatic impact when one side of the lungs was perfused with Multistem. It actually caused the pulmonary function to return to normal range and dramatically reduced the inflammatory mediated damage. The transplant specialists immediately suggested a study taking human lungs from donors and perfusing them with Multistem as a way to prepare these lungs for transplant. Ultimately though this represents a limited number of patients in the United States, somewhere around fifteen hundred to two thousand patients per year. With those numbers sufficient clinical trial enrollment would be difficult.
So Athersys decided to look at ARDS because it is the same clinical process and there are more patients with this affliction per year. Athersys ran a clinical trial at about a dozen leading pulmonary critical care centers in the United States and the UK. Dr. Van Bokkelen shared that the highlights from the one-year study follow up were recently announced demonstrating that Multistem helped patients in the short term by improving clinical metrics and odds of survival. In addition, Multistem dramatically improved quality of life outcomes for many of these patients, particularly among the most severely ill.
Another indication that Dr. Van Bokkelen described was using Multistem to treat ischemic stroke patients, another huge area of unmet medical need. He explained that after ischemic stroke, there is a very tight time window for patients to get to the hospital and then undergo treatment. Furthermore there are limited treatment options currently available. Athersys conducted a phase two clinical trial using Multistem for treatment of ischemic stroke. The study showed that Multistem could effectively help patients for up to thirty-six hours after they had suffered an ischemic stroke.
For both ARDS and for ischemic stroke Athersys has received fast track designation from the FDA. They are now well into a Phase III study for stroke patients with the belief that for both ARDS and for stroke, they can improve clinical care for patients that in many instances would otherwise have no good therapeutic options. Dr. Van Bokkelen, closed by saying, that providing therapeutic options where none previously existed was exactly why Athersys was founded twenty-five years ago and that this is the type of impact that they are really committed to making.
Since our interview, Athersys announced that after the approval from the FDA, University Hospitals Cleveland Medical Center (UH Cleveland) is now open as the first clinical site for the MACOVIA (MultiStem® Administration for COVID-19 Induced Acute Respiratory Distress Syndrome) trial. You can see the press release here: Athersys and University Hospitals Cleveland Medical Center Announce Activation of the First Clinical Site for the MACOVIA Study, a Pivotal Phase 2/3 Study Evaluating MultiStem® Cell Therapy for COVID-19 Induced ARDS
This study is already enrolling patients as they announced: Athersys Announces Commencement of Patient Enrollment in the MACOVIA Study, a Pivotal Phase 2/3 Trial Evaluating MultiStem® Cell Therapy for COVID-19 Induced ARDS
Dr. Frank Jacono, MD, Associate Professor of Medicine and Pulmonary and Critical Care Medicine Physician at UH Cleveland and Cleveland VA Medical Center, will serve as principal investigator.