Stem cell clinical trials have a certain gravitational pull for me as I’m always fascinated by them and since the new Cynata trial is moving forward, I recently did an interview their CEO, Dr. Ross A. Macdonald to find out more.
PK: Cynata’s recently initiated clinical trial aims to treat GVHD as have other stem cell-related trials such as Prochymal so I’m interested to learn more about how this product and this trial are unique. Can you fill me in?
In many ways, our trial of CYP-001 follows the trail blazed by other trials that have investigated the use of allogeneic MSCs in GvHD and as such the protocol has many similarities in patients, dosing and endpoints. However, the key difference between Cymerus™ MSCs and all other therapeutic MSC-based products lies in the starting material that we used to produce our cells. First generation methods rely on the isolation of MSCs from donated tissue (for example bone marrow), while Cynata derives its MSCs from an iPSC Master Cell Bank. The problem with the first generation approach is that only a relatively small number of cells can be isolated from each donation, so extensive culture expansion is required to produce an adequate number of cells, and it is becoming increasingly clear from the literature that such extensive expansion of MSCs interferes with their efficacy. Conversely, as the expansion step in our process is substantially undertaken at the iPSC level, and iPSCs have an essentially limitless capacity to self-renew without losing their pluripotency, we believe we can produce an effectively infinite number of MSC doses from the same iPSC Master Cell Bank, without impairing MSC efficacy. In turn, this means we will not need to source new donors, which would be associated with major logistical, regulatory and scientific challenges.
PK: The use of Mesenchymoangioblast-derived mesenchymal stem cells is an interesting aspect of the trial. What exactly are these cells and does their derivation impact their function in preclinical studies?
The finished product of our process, ie MSCs, have properties that essentially define them as MSCs in accordance with the ISCT guidelines. Mesenchymoangioblasts (MCAs) are a common precursor of both mesenchymal and endothelial cells and as such are the source of MSCs, as described by Vodyanik et al in Cell Stem Cell 7, 718–729, December 3, 2010. MCAs are a transient population of cells within APLNR+ mesodermal subset that can be identified using FGF2-dependent mesenchymal colony-forming cell (MS-CFC) assay in serum-free semisolid suspension culture. A further description of the biology of MCAs is found in Slukvin et al, Cell Reports 19, 1902–1916, May 30, 2017. Our in vitro potency assay and in vivo preclinical work indicates that the cells have similar functionality to native, donor-derived MSCs.
PK: How strong were preclinical data in terms of safety and efficacy? What were the findings?
Cynata developed a comprehensive preclinical data package for submission to the regulatory agency. The package contained extensive safety and PoC data, including the details of the humanised mouse GvHD study undertaken by Associate Professor Lisa Minter at the University of Massachusetts Amherst in which treatment with CYP-001 markedly prolonged survival with the median survival time being 48 days and 57 days, respectively, in recipients of a single dose or dual doses of CYP-001. Control animals in which GvHD was induced survived for a median of just 24.5 days. The differences between each CYP-001 group and the control group were highly statistically significant, showing that treatment with CYP-001 doubled, at least, the survival time of the treated animals. We have additional pre-clinical data in models of both critical limb ischaemia and asthma that have been published. There were no adverse safety signals in any of the pre-clinical studies, findings that confirm the safety of MSC-based therapeutic products. In addition to the pre-clinical study in GvHD we have also reported compelling data in models of asthma (now published), heart attack and critical limb ischaemia (also published).
PK: Can these cells potentially be utilized for other clinical applications and is Cynata developing such pipelines?
Yes, there is no reason to believe that Cynata’s iPSC-derived MSCs will not find clinical application in any disease target where MSCs have shown benefit. Cynata presently has ongoing programs in heart disease, asthma, organ transplantation, acute respiratory distress syndrome (ARDS) and also with modified MSCs in cancer (glioblastoma). These studies will create a very substantive body of data attesting to the potential clinical utility of our “second generation” MSCs.
PK: I saw that you recently had a pre-IND meeting with the FDA. Can you say anything about this and/or your plans in the US?
Yes, the company recently held a pre-IND meeting with the FDA. The meeting minutes are expected within the next few weeks and so it is perhaps premature to comment at this time. We definitely plan to commercialise our technology in the USA: most likely through commercial partner(s).
PK: With the Fuji deal, how are things going in Japan?
We have a strong and productive relationship with Fujifilm, one of the major commercial players in the stem cell and regenerative medicine space. We look forward to working with Fujifilm as we develop the clinical and commercial plans for CYP-001, our MSC product for GvHD, both in Japan and elsewhere. Japan remains a very exciting market and the fact that an allogeneic MSC product is already on the market in that country, and that it leads the way in iPSC-derived therapeutic products, makes it a compelling geography.
PK: What are your 1-year and 5-10-year goals for Cynata as a company?
Our near term goal is to drive the success of CYP-001, the world’s first allogeneic iPSC derived MSC product. Our current expectations are that the GvHD trial will complete this year and that this will lead to great excitement about the broader clinical potential of our technology, in turn leading to further clinical trials, perhaps in some of the indications we are presently pursuing. As our business model is to partner our technology our longer term goals are to see a number of productive and lucrative corporate alliances that will result in the launch of multiple successful products for major unmet medical needs.
PK: What do you see as the most exciting opportunities and biggest challenges in the regenerative medicine field looking ahead overall?
As always is the case with new technologies, I think our biggest challenge is to ensure we maintain the enthusiasm of investors, patients and other stakeholders through the emotional cycle of change, from uniformed optimism all the way to eventual success and fulfillment. We have seen some incredibly exciting results in the regenerative medicine space that gives us confidence that we are on the brink of greatly beneficial new medicines, but there will be peaks and toughs that we have to ride on that journey. I remain concerned about public perceptions of stem cell based therapies and how many unscrupulous participants are damaging the field by preying on the hopes and over-enthusiasm of patients and their families.
PK: Any comment on the new US law the 21st Century Cures Act with its Regenerative Medicine Advanced Therapy designation? Is that designation something that Cynata might be pursuing?
We applaud the introduction of the 21st Centuries Cures Act and believe it is a step in the right direction to streamline the process of bringing new therapeutics to patients and their families while at the same time ensuring the high standard of safety we have all come to expect. Cynata definitely intends to avail itself of all relevant aspects of this Act at the appropriate time.