While a number of companies have dabbled in this space, the following players are facilitating the development of iPS cell therapies: Cellular Dynamics International (CDI), Cynata Therapeutics, RIKEN, and Astellas (previously Ocata Therapeutics).
While each iPS cell therapy group is considered in detail below, Cellular Dynamics International (CDI) is featured first, because it dominates the iPSC industry. CDI also recently split into two business units, a Life Science Unit and a Therapeutics Unit, demonstrating a commercial strategy for its iPS cell therapy development.
1) Cellular Dynamics International, Owned by FujiFilm Holdings
Founded in 2004 and listed on NASDAQ in July 2013, Cellular Dynamics International (CDI) is headquartered in Madison, Wisconsin. The company is known for its extremely robust patent portfolio containing more than 900 patents.
According to the company, CDI “is the world’s largest producer of fully functional human cells derived from induced pluripotent stem (iPS) cells.” Their trademarked, iCell® Cardiomyocytes, derived from iPSCs, are human cardiac cells used to aid drug discovery, improve the predictability of a drug’s worth, and screen for toxicity. In addition, CDI provides: iCell® Endothelial Cells for use in vascular-targeted drug discovery and tissue regeneration, iCell® Hepatocytes, and iCell® Neurons for pre-clinical drug discovery, toxicity testing, disease prediction, and cellular research.
Induced pluripotent stem cells were first produced in 2006 from mouse cells and in 2007 from human cells, by Shinya Yamanaka at Kyoto University, who also won the Nobel Prize in Medicine or Physiology for his work on iPSCs. Yamanaka has ties to Cellular Dynamics International as a member of the scientific advisory board of iPS Academia Japan. IPS Academia Japan was originally established to manage the patents and technology of Yamanaka’s work, and is now the distributor of several of Cellular Dynamics’ products, including iCell Neurons, iCell Cardiomyocytes, and iCell Endothelial Cells.
Importantly, in 2010 Cellular Dynamics became the first foreign company to be granted rights to use Yamanaka’s iPSC patent portfolio. Not only has CDI licensed rights to Yamanaka’s patents, but it also has a license to use Otsu, Japan-based Takara Bio’s RetroNectin product, which it uses as a tool to produce its iCell and MyCell products.
Furthermore, in February 2015, Cellular Dynamics International announced it would be manufacturing cGMP HLA “Superdonor” stem cell lines that will support cellular therapy applications through genetic matching. Currently, CDI has two HLA superdonor cell lines that provide a partial HLA match to approximately 19% of the population within the U.S., and it aims to expand its master stem cell bank by collecting more donor cell lines that will cover 95% of the U.S. population. The HLA superdonor cell lines were manufactured using blood samples, and used to produce pluripotent iPSC lines, giving the cells the capacity to differentiate into nearly any cell within the human body.
On March 30, 2015, Fujifilm Holdings Corporation announced that it was acquiring CDI for $307 million, allowing CDI to continue to run its operations in Madison, Wisconsin, and Novato, California as a consolidated subsidiary of Fujifilm. A key benefit of the merger is that CDI’s technology platform enables the production of high-quality fully functioning iPSCs (and other human cells) on an industrial scale, while Fujifilm has developed highly-biocompatible recombinant peptides that can be shaped into a variety of forms for use as a cellular scaffold in regenerative medicine when used in conjunction with CDI’s products.
Additionally, Fujifilm has been strengthening its presence in the regenerative medicine field over the past several years, including a recent A$4M equity stake in Cynata Therapeutics and an acquisition of Japan Tissue Engineering Co. Ltd. in December 2014. Most commonly called “J-TEC”, Japan Tissue Engineering Co. Ltd. successfully launched the first two regenerative medicine products in the country of Japan. According to Kaz Hirao, CEO of CDI, “It is very important for CDI to get into the area of therapeutic products, and we can accelerate this by aligning it with strategic and technical resources present within J-TEC.”
Kaz Hirao also states, “For our Therapeutic businesses, we will aim to file investigational new drugs (INDs) with the U.S. FDA for the “off-the-shelf” iPSC-derived allogeneic therapeutic products. Currently, we are focusing on retinal diseases, heart disorders, Parkinson’s disease, and cancers. For those four indicated areas, we would like to file several INDs within the next five years.”
Finally, in September 2015, CDI again strengthened its iPS cell therapy capacity by setting up a new venture, Opsis Therapeutics. Opsis is focused on discovering and developing novel medicines to treat retinal diseases and is a partnership with Dr. David Gamm, the pioneer of iPS cell-derived retinal differentiation and transplantation.
In summary, several key events indicate CDI’s commitment to developing iPS cell therapeutics, including:
- Its commitment to cGMP HLA “Superdonor” stem cell lines to support cellular therapy applications
- FUJIFILM’s interest to apply J-TEC’s knowledge to CDI technologies (J-TEC launched the first two regenerative medicine products in Japan)
- The decision to split CDI into two separate business units, Life Science and Therapeutics
- Establishing Opsis Therapeutics to pursue iPS cell-derived retinal therapies
2) Cynata Therapeutics
Australian stem cell company Cynata Therapeutics (ASX:CYP) is taking a unique approach by creating allogeneic iPSC derived mesenchyal stem cell (MSCs) on a commercial scale. Cynata’s Cymerus™ technology utilizes iPSCs provided by Cellular Dynamics International, a Fujifilm company, as the starting material for generating mesenchymoangioblasts (MCAs), and subsequently, for manufacturing clinical-grade MSCs. According to Cynata’s Executive Chairman Stewart Washer who was interviewed by The Life Sciences Report, “The Cymerus technology gets around the loss of potency with the unlimited iPS cell—or induced pluripotent stem cell—which is basically immortal.”
On January 19, 2017, Fujifilm took an A$3.97 million (10%) strategic equity stake in Cynata, positioning the parties to collaborate on the further development and commercialisation of Cynata’s lead Cymerus™ therapeutic MSC product CYP-001 for graft-versus-host disease (GvHD). (CYP-001 is the product designation unique to the GVHD indication). The Fujifilm partnership also includes potential future upfront and milestone payments in excess of A$60 million and double-digit royalties on CYP-001 product net sales for Cynata Therapeutics, as well as strategic relationship for potential future manufacture of CYP-001 and certain rights to other Cynata technology.
One of the key inventors of Cynata’s technology is Igor Slukvin, MD, Ph.D., Scientific Founder of Cellular Dynamics International (CDI) and Cynata Therapeutics. Dr. Slukvin has released more than 70 publications about stem cell topics, including the landmark article in Cell describing the now patented Cymerus technique. Dr. Slukvin’s co-inventor is Dr. James Thomson, the first person to isolate an embryonic stem cell (ESC) and one of the first people to create a human induced pluripotent stem cell (hiPSC). Dr. James Thompson was the Founder of CDI in 2004.
There are three strategic connections between Cellular Dynamics International (CDI) and Cynata Therapeutics, which include:
- Cynata uses cells from CDI/Fujifilm as its starting material.
- Fujifilm fully owns CDI and has a 10% equity stake in Cynata Therapeutics.
- CDI’s Scientific Founder Dr. Igor Slukvin is a key inventor of Cynata’s Cymerus™ technology; CDI’s Founder James Thompson was Slukvin’s co-inventor.
Recently, Cynata received advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) that its Phase I clinical trial application has been approved, titled “An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease.” It will be the world’s first clinical trial involving a therapeutic product derived from allogeneic (unrelated to the patient) induced pluripotent stem cells (iPSCs).
Participants for Cynata’s upcoming Phase I clinical trial will be adults who have undergone an allogeneic haematopoietic stem cell transplant (HSCT) to treat a haematological disorder and subsequently been diagnosed with steroid-resistant Grade II-IV GvHD. The primary objective of the trial is to assess safety and tolerability, while the secondary objective is to evaluate the efficacy of two infusions of CYP-001 in adults with steroid-resistant GvHD.
Using Professor Yamanka’s Nobel Prize winning achievement of ethically uncontentious iPSCs and CDI’s high quality iPSCs as source material, Cynata has achieved two world firsts:
- Mass production of iPSC-derived Allogeneic MSC’s for therapeutic use using limitless starting material of high quality iPSC’s (no more ethical issues)
- Human trial to treat GvHD using Cynata’s Cymerus™ iPSC derived Allogeneic MSC’s.
There are four key advantages of Cynata’s proprietary Cymerus™ MSC manufacturing platform. Because the proprietary Cymerus™ technology allows nearly unlimited production of MSCs from a single iPSC donor, there is batch-to-batch uniformity. Utilizing a consistent starting material allows for a standardized cell manufacturing process and a consistent cell therapy product. Unlike other companies involved with MSC manufacturing, Cynata does not require a constant stream of new donors in order to source fresh stem cells for its cell manufacturing process, nor does it require the massive expansion of MSCs necessitated by reliance on freshly isolated donations.
Finally, Cynata has achieved a cost-savings advantage through its unique approach to MSC manufacturing. Its proprietary Cymerus technology addresses a critical shortcoming in existing methods of production of MSCs for therapeutic use, which is the ability to achieve economic manufacture at commercial scale.
On June 22, 2016, RIKEN announced that it is resuming its retinal induced pluripotent stem cell (iPSC) study in partnership with Kyoto University.
2013 was the first time in which clinical research involving transplant of iPSCs into humans was initiated, led by Masayo Takahashi of the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan. Dr. Takahashi and her team were investigating the safety of iPSC-derived cell sheets in patients with wet-type age-related macular degeneration. Although the trial was initiated in 2013 and production of iPSCs from patients began at that time, it was not until August of 2014 that the first patient, a Japanese woman, was implanted with retinal tissue generated using iPSCs derived from her own skin cells.
A team of three eye specialists, led by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, implanted a 1.3 by 3.0mm sheet of iPSC-derived retinal pigment epithelium cells into the patient’s retina. Unfortunately, the study was suspended in 2015 due to safety concerns. As the lab prepared to treat the second trial participant, Yamanaka’s team identified two small genetic changes in the patient’s iPSCs and the retinal pigment epithelium (RPE) cells derived from them. Therefore, it is major news that the RIKEN Institute will now be resuming the world’s first clinical study involving the use of iPSC-derived cells in humans.
According to the Japan Times, this attempt at the clinical study will involve allogeneic rather than autologous iPSC-derived cells for purposes of cost and time efficiency. Specifically, the researchers will be developing “retinal tissues from iPS cells supplied by Kyoto University’s Center for iPS Cell Research and Application,” an institution headed by Nobel prize winner Shinya Yamanaka. To learn about this announcement, view this article from Asahi Shimbun, a Tokyo- based newspaper.
4) Astellas, Previously Ocata Therapeutics
In November 2015 Astellas Pharma announced it was acquiring Ocata Therapeutics for $379M. Ocata Therapeutics is a biotechnology company that specializes in the development of cellular therapies, using both adult and human embryonic stem cells to develop patient-specific therapies. The company’s main laboratory and GMP facility is in Marlborough, Massachusetts, and its corporate offices are in Santa Monica, California.
When a number of private companies began to explore the possibility of using artificially re-manufactured iPSCs for therapeutic purposes, one such company that was ready to capitalize on the breakthrough technology was Ocata Therapeutics, at the time called Advanced Cell Technology. In 2010, the company announced that it had discovered several problematic issues while conducting experiments for the purpose of applying for U.S. Food and Drug Administration approval to use iPSCs in therapeutic applications. Concerns such as premature cell death, mutation into cancer cells, and low proliferation rates were some of the problems that surfaced. 
As a result, the company shifted its induced pluripotent stem cell approach to producing iPS cell-derived human platelets, as one of the benefits of a platelet-based product is that platelets do not contain nuclei, and therefore, cannot divide or carry genetic information. While the company’s “Induced Pluripotent Stem Cell-Derived Human Platelet Program” received a great deal of media coverage in late 2012, including being awarded the December 2012 honor of being named one of the “10 Ideas that Will Shape the Year” by New Scientist Magazine, unfortunately the company did not succeed in moving the concept through to clinical testing in 2013.
Nonetheless, Astellas is clearly continuing to develop Ocata’s pluripotent stem cell technologies involving embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells). In a November 2015 presentation by Astellas’ President and CEO, Yoshihiko Hatanaka, he indicated that the company will aim to develop an “Ophthalmic Disease Cell Therapy Franchise” based around its embryonic stem cell (ESC) and induced pluripotent stem cell (iPS cell) technology. 
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