Interview with CEO of Australian venture firm
A medical treatment project using donated induced pluripotent stem cells (iPS cells) has been promoted by a Japanese team led by Riken, and an Australian regenerative medicine bioventure firm in which Fujifilm has invested. The Australian bioventure firm – Cynata Therapeutics – plans to conduct clinical trials in the U.K. and elsewhere on graft-versus- host disease (GVHD) patients, which is manifested in an excessive response by immune cells. Their Chief Executive Officer (CEO), Dr Ross Macdonald, was exclusively interviewed by the Yomiuri Shimbun in Japan at the beginning of this month, and revealed, “We hope to make this practically available, possibly as soon as 2019.” (Yusuke Toyama)
Interviewer (I): How do you plan to proceed with the clinical trial?
Macdonald (M): GVHD is a condition in which the patient’s body is attacked due to an excessive response by immune cells contained in bone marrow that has been transplanted into patients suffering from leukaemia and suchlike. The most severe cases often prove fatal. The intention is to administer donated iPS cell-derived mesenchymal stem cells , which appear to restrain excessive immune function, to GVHD patients. A total of 16 patients will participate in the trial in the U.K. and Australia.
I: What is the advantage of using donated iPS cells?
M: GVHD treatment using mesenchymal stem cells derived from donated bone marrow has a proven track record, and in Japan, JCR Pharma (based in Ashiya City, Hyogo prefecture) also brought it to market in 2015. However, it is difficult to cultivate mesenchymal stem cells, so many donors need to be found. There is no limit to cultivating iPS cells though.
I: What is the basis for your tie-up with the Fujifilm Group?
M: We have been provided with iPS cells from Fujifilm’s subsidiary in America. They were the first company in the world to cultivate iPS cells of a quality that can be used for clinical applications, so the benefits are substantial.
I: There are reportedly over a thousand GVHD patients a year in Japan that develop severe conditions, of whom several hundred are considered to be the most severe cases and could be considered as subjects for this clinical trial.
M: If beneficial results can be obtained through the clinical trials conducted in the U.K., we are considering seeking authorization (for this treatment) by conducting further clinical trials in Japan in the future.
I: What are the future prospects?
M: Phase 1 clinical trials are currently underway to verify safety. If beneficial results can be obtained within 100 days of administration, we would like to proceed to the next step of confirming the treatment’s efficacy. We are working hard to ensure that we can make this treatment available as quickly as possible for patients.
Illustration of GVHD therapy based on donated iPS cellsMesenchymal stem cells: Inherent in bone marrow and body fat, these cells can be transformed into a variety of tissues, such as bone, muscle, and fat. Numerous projects are being conducted to find ways to be able to use them for regenerative medicine.
A “gold rush” for the next wave of regenerative medicine therapies. But what are MSCs? And what do they do? Let us break it down for you.
Mesenchymal stem cells (MSCs) are multipotent stem cells that naturally occur in adult tissues such as bone marrow and fat. They are also found in placental tissues. MSCs are able to produce a wide range of biologically active chemicals that stimulate the body’s own healing systems. Around 650 clinical trials around the world are investigating MSCs as a treatment for a diverse range of illnesses, including immune disorders, heart disease, stroke, arthritis, fractures, degenerative disc disease, diabetes, lung disorders and eye disease. To date, all the MSC products tested have been isolated from human tissue, mostly bone marrow.
MSCs can be derived from Induced Pluripotent stem cells (iPSCs) which are a type of pluripotent stem cell that can be generated directly from adult cells. It all started in 2006, when Japanese researchers identified conditions that allowed specialised adult cells to be genetically ‘reprogrammed’ to an embryonic stem cell-like state. This was a profound discovery as it enabled a solution to the controversy over using pluripotent stem cells from human embryos. There has been enormous interest globally in the development of iPSC-derived therapies for a number of years.
MSCs are free from ethical concerns and can come from numerous sources, so why aren’t MSC’s more widely used? Well they are the most commonly used stem cells in current clinical trials and applications, however a major hurdle that scientists face has been the ability to produce a consistent commercial supply of clinical quality MSCs for use in clinical trials and eventually for commercial therapeutic use. Current methods of producing MSCs reply on traditional means of extraction from the donor’s bone marrow or other tissue, this is costly, not efficient or sustainable for commercial development of MSC-based therapeutics.
Here at Cynata Therapeutics, we have developed and patented a therapeutic stem cell platform technology - Cymerus™. The technology is based on discoveries made at the University of Wisconsin-Madison, a world leader in stem cell research. We are utilising iPSCs as the starting material for generating mesenchymoagioblasts (MCAs) and in turn for manufacturing the MSC therapeutic product. With this technology, we can ensure that MSCs for therapeutic use can be produced consistently, economically and in virtually limitless quantities, which means we won’t need to constantly seek out fresh stem cell donors to fuel manufacturing demands. Because we can reproduce the iPSCs virtually limitlessly we also do not need to massively expand the MSCs themselves which should result in a more effective MSC product.
We have proved our that our Cymerus™ technology is effective in various animal models for specific disease targets. In a world-first, we have also been given the green light to commence a clinical trial of CYP-001, our patented Cymerus product for graft-versus-host disease (GvHD). If we demonstrate that our technology is effective in these clinical trials, this will fast track our ability to commercialise our platform technology for further diseases that represent major unmet medical needs.
Here’s a snapshot of what we are working on:
Scientists and clinical physicians are seeing the benefits of using MSCs as therapies, and we believe our technology is leading the way to enable commercial production of these therapies for patients in need. We have already reached a major milestone in the field of regenerative medicine, being the first to commence clinical trials with an MSC product derived from iPSCs. Our Cymerus™ technology has the potential to produce life-saving therapies, so we are working to make the future, the present and its exciting times ahead!
 APS 2017, percentages_of_common_diseases, image. Available from: http://www.nature.com/aps/journal/v34/n6/fig_tab/aps201350f3.html#figure-title. [7 March 2017].
 National Institutes of Health 2016, The Promise of Induced Pluripotent Stem Cells (iPSCs). Available from: https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter10.htm. [2 March 2017].
 ASX 2017, CYP: Prices and research. Available from: http://www.asx.com.au/asx/share-price-research/company/CYP. [7 March 2017].
Cynata is an exciting stem cell and regenerative medicine company with the ability to produce an unlimited number of stem cells at a low cost through its Cymerus technology. Japan-based Fujifilm recently bought a 10% stake in the company as part of its push to become a world leader in stem cell supply and technology...
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March 13, 2017
Fujifilm Group runs clinical trial of medical treatment targeting bone marrow transplant side effects using donated iPS cells in the U.K.
Cynata Therapeutics, Ltd., an Australia-based bioventure firm in which Fujifilm has invested, initiated a clinical study of a new medical treatment using donated induced pluripotent stem cells (iPS cells) this month in the U.K. The study targets patients presenting with graft-versus-host disease (GVHD) as a result of undergoing bone marrow transplantation to address leukemia. An additional study to be conducted in Japan is currently under consideration pending positive study results.
The Christie Hospital in Manchester, England has begun enrolling subjects. The experimental treatment will use high-quality iPS cells from healthy adults produced by Cellular Dynamics International, a U.S. based firm and a Fujifilm group company.
Study subjects will be injected with mesenchymal stem cells, one type of somatic stem cell capable of developing into a specific type of tissue that can be obtained from iPS cells. Subjects with intractable GVHD will receive between 106—2×106 cells/1 kg body weight on two occasions. A second study to be conducted in Australia is planned, and will enroll a total of 16 subjects from eight hospitals. Subjects will be monitored for a period of 100 days after receiving the experimental treatment in order to assess safety and efficacy.
GVHD is a condition in which the body’s natural defenses attack implanted cells after recognizing them as foreign entities. GVHD can also be fatal in some cases. While administering mesenchymal stem cells has been recognized as effective, because such cells are obtained from the bone marrow of healthy donors, obtaining large quantities of these cells presents difficulties.
iPS cells can proliferate endlessly, and it is possible to ensure availability of the quantity desired in a given instance. In addition, when stored cells obtained from donors are used, the need to cultivate cells from a patient’s own cells is eliminated. Japan’s RIKEN and affiliates initiated a clinical study in February evaluating treatments using donated iPS cells to address age-related macular degeneration, a condition recognized as a “nambyo” or “refractory disease” in Japan. The present study will continue on from this trial.
March 11, 2017, Page 10
Australian bioventure firm receiving investment from Fujifilm Group recruits subjects for U.K.-based clinical trial of donated iPS cell therapy
An Australian regenerative medicine venture firm receiving investment from Fujifilm Group has announced initiation of a U.K.-based clinical trial to assess a new therapy using donated induced pluripotent stem cells (iPS cells) to treat patients presenting with graft-versus-host disease (GVHD). Subject enrollment for the study began on March 1.
GVHD is a condition in which immune cells contained in bone marrow implanted into patients as treatment for diseases such as leukemia attack the patient’s skin or other organs.
The clinical study was initiated by Australia-based Cynata Therapeutics. The treatment intervention for the study will involve administering mesenchymal stem cells (MSCs), which do not stimulate excessive immune system activity, to subjects via drip infusion, after conversion from iPS cells provided by a Fujifilm subsidiary company.
Cynata has also obtained permission to initiate trials in Australia as well as the U.K., and plans to treat a total of 16 subjects in both countries and evaluate safety over a 100-day monitoring period. In response to inquiries from Yomiuri reporters, Ross Macdonald, Cynata’s chief executive officer (CEO) stated that “Cynata would like start trials as soon as eligible subjects are found”, and there is a possibility that these trials could involve the world’s first therapeutic use of donated iPS cells.
Use of iPS cells collected from donors in advance is expected to result in reduced treatment costs and shorter treatment periods. RIKEN (Kobe City) and affiliates are also planning to initiate clinical studies in patients presenting with intractable ophthalmological diseases early this year, and began enrolling subjects on February 6.
March 13, 2017, 00:10
The 16th Congress of the Japanese Society for Regenerative Medicine
Australia-based Cynata Therapeutics initiates subject enrollment for Phase I clinical trial of treatment using donated iPS cell-derived mesenchymal stem cells
Permission sought from the U.S. FDA to also conduct trials in the U.S.
Australia-based Cynata Therapeutics’ CEO Ross Macdonald and Kilian Kelly, Vice President visited Japan to attend the 16th Congress of the Japanese Society for Regenerative Medicine in Sendai, Miyagi prefecture through March 9, 2017. In response to inquiries from Nikkei reporters, the pair clarified that subject enrollment has begun at some of the facilities participating in the company’s Phase I clinical trial of a new treatment using donated iPS cell-derived mesenchymal stem cells (MSC) to treat graft-versus-host disease (GVHD). This study will become the world’s first instance of transplanted cells differentiated from donated iPS cells (see related article below).
(Kelly VP) “MSCs have various functions such as regulation of the immune system, and are expected to be effective against various diseases. Approximately 650 clinical trials have been conducted to date to assess MSC-based therapies worldwide, but a considerable number of cells will be required to satisfy global demand.”
“The problem with traditional MSC manufacturing methods is that only a limited number of MSCs can be collected from healthy donors, so it is necessary to scale-up from this method to produce a large amount of cells. However, MSCs can deteriorate and become functionally impaired with repeated culturing. In addition, even if scaling-up is achieved, because the number of MSCs that can be derived from a single donor is limited, it is necessary to use MSCs collected from other healthy donors when they are lost, but this can lead to variations in cell quality between donors”
(Macdonald CEO) “We licensed the patents owned by the University of Wisconsin and mass cultured iPS cells collected from a single healthy donor indefinitely. We own technology that allows us to directly induce iPS cell differentiation into MSCs using a special culture medium. iPS cell-derived MSCs (CYP-001) do not encounter the issues described previously, and are so-called “second-generation” cells exhibiting superior quality, uniformity, price, and clinical utility.”
(Kelly VP) “We received permission to conduct clinical trials in the U.K. in September 2016 and in Australia shortly afterwards. These will be the first clinical trials using cells derived from donated iPS cells, and we believe this is a major scientific milestone. The target subjects of the Phase I trials is expected to be 16 post-bone marrow transplant patients presenting with steroid-resistant GVHD. Up to 8 medical institutions (5 in the U.K. and 3 in Australia) are planned to participate, and subject enrollment has begun at 1 facility in the U.K. (the Christie Hospital in Manchester). Enrollment at Australian facilities will begin soon.”
“The primary endpoint for the Phase I studies is safety. Secondary endpoints are efficacy after 28 days and 100 days, with efficacy defined as complete response (CR), or partial response (PR, at least grade 1 improvement) observed.”
(Kelly VP) “We use HLA 3 iPS cells manufactured by CDI. MSCs differentiated from these cells do not express HLA class II; therefore, it is not necessary for us to adapt the cells to the HLA phenotype of the recipient (patient). The reason for using cells manufactured by CDI is that during the period while we were beginning to develop this technology, CDI was the only company that produced GMP-grade iPS cells suitable for clinical use without the use of a viral vector. It was also because both of our companies were founded by researchers formerly at the University of Wisconsin, making CDI and Cynata like sibling companies.”
(Macdonald CEO) “At the time, the speed of development was limited by our ability to obtain iPS cells, but CDI iPS cells could be used from an early stage and also were of good quality.”
(Kelly VP) “iPS cells are cultured, and induction of differentiation into MSCs is outsourced to the cell processing center (CPC) at the Waisman Center of the University of Wisconsin.”
(Kelly VP) “No. Currently, the only countries where such products are available are New Zealand, Canada, and Japan, with MSCs only used for clinical studies in other countries.”
(Kelly VP) “We cultivated MSCs under conditions in which iPS cells cannot survive, selected only colonies of MSCs at the time of purification, and finally conducted assays on the cellular therapeutic to remove the numerous undifferentiated cells remaining.”
(Kelly VP) “Our Phase I studies will be conducted in the U.K. and Australia, but there is also a possibility of including Japan in the future, which is now under consideration. At the end of Phase I, as Fujifilm can exercise its option right, there is a possibility that Fujifilm will continue development.”
“The U.S. recently passed its ‘21st Century Cures Act’ which may be advantageous for us. We are already considering conducting clinical trials in the U.S. and plan to have a meeting with the U.S. Food and Drug Administration (FDA) in the near future”
(Kelly VP) “We are currently conducting preclinical studies to determine the best therapeutic targets for our drug candidates. For any of the indications, MSCs can be expected to exhibit immune regulatory and anti-inflammatory functions, but the specific mechanism of action for brain glioblastomas differs in that it takes advantage of the MSC characteristic of migrating to tumors as a drug delivery system (DDS)”
“Specifically, genes that metabolize the prodrugs of drugs with antitumor effects are introduced into MSCs derived from iPS cells, and the genetically modified MSCs as well as the prodrugs are then respectively administered. The MSCs accumulated in tumors metabolize the prodrugs, enabling a local antitumor effect. We are currently collaborating with Germany’s Apceth Biopharma. Apceth has developed a similar genetically-modified MSC using bone marrow-derived MSCs and is now conducting clinical trials in Europe to assess efficacy against stomach cancer, but wants to use our iPS cell-derived MSCs.”
“Paul Wotton is a physician, and served as the CEO and President of U.S.-based Ocata Therapeutics before the company was acquired by Astellas Pharma. Our Phase I trials have begun, and we invited Mr. Wotton to our board as we enter a new stage of development as a company while our clinical development programs progress”
Could RIKEN and Cynata develop the world’s first donated iPS cell therapy?
February 13, 2017, 00:39
On February 6, 2017, Takahashi Masayo, Project Leader (PL) of Japan’s RIKEN Center for Developmental Biology announced the start of subject enrollment for a clinical study to evaluate a donated iPS cell-derived retinal pigment epithelial (RPE) cell suspension product as a treatment for age-related macular degeneration (AMD). RIKEN’s plan for the provision of regenerative medical treatments was also confirmed to be in compliance with the Standards for the Provision of Regenerative Medicine Products at the Committee on Regenerative Medicine Products Assessment, Ministry of Health, Labour, and Welfare (MHLW) Health Science Working Group, held on February 1, 2017.
Anticipation of how researchers will apply the results of Japan’s groundbreaking, Nobel Prize winning research results has attracted the attention of news and media entities throughout the region. Journalists often referred to MHLW’s support of the project at the Committee as a step “towards the world’s first transplantation of donated iPS cells.” However, many participants questioned whether this development was “really the world’s first” at the announcement of the start of subject enrollment at a February 6 press conference, and subsequent coverage appeared to make this claim less liberally.
The reason for this is a Phase I clinical trial conducted by Australia-based Cynata Therapeutics in which the firm will administer its mesenchymal stem cell precursor cell (mesenchymoangioblast) CYP-001 to post-bone marrow transplant patients presenting with steroid-resistant acute graft-versus-host disease (GVHD). Apparently, some journalists reported some time after the initial media coverage that “there seems to be a company based overseas that is conducting a clinical trial involving donated iPS cells”.
CYP-001 is an experimental medical product produced from peripheral blood-derived iPS cells obtained from healthy adults by U.S.-based Cellular Dynamics International Inc., a subsidiary of Fujifilm Holdings Co., Ltd., using Cynata Therapeutics’ in-house “Cymerus” technology. Multicenter Phase I clinical trials are planned to be conducted in both the U.K. and Australia, and the firm obtained permission from Britain’s drug and medical device regulator, the Medicines and Healthcare products Regulatory Agency (MHRA) to initiate the U.K. Phase I trial in September 2016. Subject enrollment for this trial has not yet begun, and no experimental treatment has been administered to date. Meanwhile, Dr. Takahashi PL has stated that “We plan to administer the first treatment interventions during the first half of 2017”. RIKEN and Cynata are currently in a dead heat to become the first in the world to transplant cellular medicines derived from donated iPS cells into human subjects, although they become merely the focus of media sensationalism over a “world first.”
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