Cynata in the Japanese Media

Nihon Keizai Shimbun

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.


Osaka Yomiuri Shimbun (Evening edition)

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.


Nikkei Biotech Online

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.

Aya Kubota

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).

You are focusing on technology enabling large-scale differentiation culturing of iPS cell-derived MSCs.

(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.”

What is the status of Cynata’s Phase I trials?

(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.”

Your firm uses iPS cells manufactured by U.S.-based Cellular Dynamics International (CDI, a Fujifilm subsidiary, as raw material. Is it correct to understand that human leukocyte antigen (HLA) 3 iPS cells collected from healthy donors are used? The National Institute of Health (NIH) also manufactures iPS cells, so why do you use cells from CDI?

(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.”

In Japan, cellular therapeutics containing donated MSCs are currently marketed by JCR Pharma through a joint-venture with U.S.-based Osiris Therapeutics. Are such products also already available in the U.K. and Australian markets?

(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.”

iPS cell-derived cells carry a risk of tumorization.

(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.”

In addition to receiving a third-party allocation of shares of Cynata’s stock in September 2016, Fujifilm Group also received an option to acquire the rights to the global development, manufacturing, and marketing of iPS cell-derived MSC products. Is there a possibility of development activities in Japan or the U.S.?

(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”

iPS cell-derived MSC therapeutic development for other indications, such as asthma, cardiac infarction, idiopathic pulmonary fibrosis, and others is advancing.

(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 was added as a director in February 2017.

“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”


Nikkei Biotech Online

Industry talk

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.”