In January 2017 Cynata executed a license option agreement with FUJIFILM Corporation of Japan for the development and commercialisation of certain Cynata technology, including Cynata’s lead induced pluripotent stem cell(iPSC)-derived therapeutic mesenchymal stem cell (MSC) product, CYP-001, for graft-versus-host disease (GvHD). As part of the transaction, FUJIFILM acquired an equity position in Cynata through the purchase of 8,088,403 ordinary shares in Cynata, leading to Fujifilm becoming the largest shareholder in the Company with an approximate 9% stake. FUJIFILM’s option is exercisable at any time up to 90 days after the completion of the primary evaluation period of Cynata’s current phase I clinical trial in GvHD. An upfront fee of US$3 million is then payable which, together with other potential future milestones, totals over A$60 million in potential one-time payments, along with double-digit royalties on net sales of CYP-001 product. Should FUJIFILM choose to exercise this option, future CYP-001 development costs will be borne by FUJIFILM.
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The trademark Cymerus™ refers to the patented process of generating cell-based products from intermediate cells, known as mesenchymoangioblasts (MCAs), which in turn are derived from induced pluripotent stem cells (iPSCs). This technology was originally developed at the University of Wisconsin-Madison, WI, USA.
At present, Cynata is focussed on the production of mesenchymal stem cell (MSC)-based products using the Cymerus™ technology.
Mesenchymal stem cells, also known as mesenchymal stromal cells or MSCs, are a particular type of stem cell found in a wide range of human tissues, including bone marrow, adipose tissue (fat), placenta and umbilical cord blood.
There has been extensive interest in the development of MSCs as therapeutic products, in particular because of their ability to modulate the immune system. They also secrete bioactive molecules such as cytokines, chemokines and growth factors, which has resulted in these cells being dubbed “drug factories” or “medicine secreting cells”.
MSCs can be either autologous or allogeneic. Autologous means a patient is treated with their own cells, while allogeneic means that cells from a donor are used to treat other people. Allogeneic MSCs have not been shown to cause immune reactions in other people, so they can be used in an “off the shelf” manner, without any requirement for matching the donor to the recipient. This has important commercial advantages, so biotechnology companies have largely focussed on allogeneic rather than autologous MSCs.
MSCs have been shown to facilitate regeneration and effects on the immune system without relying upon engraftment – in other words, the MSCs themselves do not to become incorporated into the host, rather they exert their effects and are then eliminated within a short period of time.
There are currently over 600 ongoing, human, clinical trials, in which MSCs are being used to treat a very wide range of medical conditions, including heart disorders, diabetes, orthopaedic conditions, and autoimmune diseases, among others.
Cynata’s Cymerus™ platform stem cell technology is based upon extremely important and versatile stem cells known as mesenchymoangioblasts (MCAs). MCAs are precursors to mesenchymal stem cells (MSCs). Cynata’s proprietary technology utilises induced pluripotent stem cells (iPSCs) originating from an adult donor as the starting material for generating MCAs, and in turn for manufacturing the MSC therapeutic product.
Pluripotent stem cells are the most versatile cells of all, having the ability to reproduce themselves indefinitely, and also differentiate into any other type of cell in the body. There are two main types of pluripotent stem cell: embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).
ESCs are isolated from five to seven day-old embryos donated with consent by patients who have completed in vitro fertilisation therapy, and have surplus embryos. The first human ESCs were isolated by Professor James Thomson at the University of Wisconsin-Madison in 1998 (one of the investors of the Cymerus™ technology). The use of ESCs has been hindered to some extent by ethical concerns about the extraction of cells from human embryos.
iPSCs are a man-made version of ESCs, derived from adult cells. iPSCs have very similar characteristics to ESCs, but avoid the ethical concerns described above, since they are not derived from embryos. Professor Thomson and his team, including Professor Igor Slukvin (one of the founders of Cynata) were also pioneers in the development of iPSCs. In 2007, they were one of two independent research groups that first reported the creation of iPSCs from human cells (along with Professor Shinya Yamanaka et al, at Kyoto University, Japan).
iPSCs are typically derived from fully differentiated adult cells that have been reprogrammed back into a pluripotent state.
Cynata uses iPSCs as a starting material in its Cymerus™ process, and has secured a clinical grade human iPSC line manufactured by Cellular Dynamics International (CDI; Nasdaq: ICEL). Unlike early methods of iPSC production, the iPSCs that Cynata uses were produced without the use of viruses and without changing the cells’ DNA. Therefore, these iPSCs are well-suited to the manufacture of products for human use.
Yes, there are a number of different ways of producing iPSCs, which are often described as “reprogramming methods”. It is important to be aware of the distinction between different reprogramming methods, as studies conducted on iPSCs produced by first generation methods are generally not relevant to iPSCs produced using more recent technology.
First generation reprogramming methods involved the use of viruses that inserted particular genes into the donated cells’ DNA – a type of genetic modification. However, such reprogramming methods were never considered to be suitable for the manufacture of products for human use, because of the risk of genetic mutations (this is known as “insertional mutagenesis”). Furthermore, when reprogramming genes persist in cells, they contribute to genetic instability and aberrations. These limitations were acknowledged in the original publication of the method to produce human iPSCs by the group at the University of Wisconsin-Madison (UWM).
To address this problem, the team at UWM developed “non-integrating episomal” reprogramming methods. These methods use plasmids, which are short segments of DNA that do not integrate into the donated cells’ DNA, and consequently avoid the risks associated with insertional mutagenesis and persistence of reprogramming genes.
There is a growing body of evidence demonstrating that iPSCs produced in this way are not associated with the same problems as iPSCs produced using first generation methods. For example, scientists at Johns Hopkins University conducted a study of iPSCs generated by non-integrating episomal methods, using highly sensitive “deep whole genome sequencing” analyses, which was published in Cell Stem Cell. This study confirmed that the episomal DNA could not be detected in the iPSC lines (i.e. the plasmids did not integrate or persist in the reprogrammed cells),that it did not alter the structure of the cells’ DNA and that these reprogramming methods are not inherently mutagenic. Similarly, a recent comparison of reprogramming methods published in Nature Biotechnology by a group of scientists from Harvard University concluded that episomal reprogramming “seems particularly well-suited for clinical translation because it is integration-free, works reliably with patient fibroblasts and blood cells, and is based on a very simple reagent (plasmid DNA) that can easily be generated using current good manufacturing practice (cGMP)-compatible processes”.
Cynata’s iPSCs were manufactured by Cellular Dynamics International (CDI; Nasdaq: ICEL), using anon-integrating episomal reprogramming method based on that originally developed at UWM. Additionally, Cynata’s iPSCs were derived from a fully consented donor, in compliance with the FDA’s GMP requirements.
This ability to reprogram cells from adult donors into a pluripotentembryonic-like state has been met with great excitement, as it has significantly advanced the potential for regenerative therapy. iPSCs have similar characteristics to ESCs, without the ethical issues. The discovery is a generational advancement in processes that require repeat donor-derived materials.
iPSCs – like ESCs – are cells that can (i) be expanded without limit, (ii) can be stored over long periods and (iii) can produce tissue cells of any type. This makes iPSCs an ideal building-block for cell-based therapies.
It is important to understand that iPSCs themselves are not administered to patients. Instead, the iPSCs are used as a starting material to produce other types of cells, such as MSCs in Cynata’s case. Cynata’s Cymerus™ technology includes attributes designed to eliminate iPSCs early during the manufacturing process. Cynata’s final product contains only MSCs, which have similar characteristics to MSCs isolated from tissue donations (e.g. bone marrow).
A number of organisations around the world are currently developing iPSC-derived cellular therapies for human use. Cynata has received regulatory approval in the UK and Australia to commence a Phase 1 clinical trial in GvHD. The approval of this trial was important, as it demonstrated that regulatory authorities and ethics committees are comfortable with the concept of using iPSC-derived cells in humans.
No, Cynata uses induced pluripotent stem cells, or iPSCs, as a starting material in its manufacturing process. iPSCs are derived from cells obtained from an adult human donor.
The inventors of the technology underpinning Cynata’s Cymerus™ technology are Dr Maksym (Maxim) Vodyanik, Dr Junying Yu, Professor James Thomson and Professor Igor Slukvin, all of whom were at the time based at the University of Wisconsin, Madison (UWM). UWM in general, and this group of scientists in particular, are widely recognised as world leaders in stem cell research and have published their findings in highly respected scientific and medical journals.
Cynata’s Cymerus™ technology is underpinned by a series of patents (including granted patents and patent applications) licensed from the Wisconsin Alumni Research Foundation (WARF) – an organisation established to commercialise technology invented at the University of Wisconsin-Madison.
In brief, these patents describe a process to generate mesenchymalstem cells (MSCs) under serum-free conditions, using pluripotentstem cells (including iPSCs) as a starting material. To Cynata’s knowledge, this is currently the only process proven to be capable of commercially producing clinical grade MSCs from iPSCs. The key patent rights licensed to Cynata do not expire until between 2028 and 2034.
Cellular products are different from small molecule drugs. With small molecule drugs, the synthesis (manufacture) of the drug is relatively simple and easily copied – therefore, commercialisation relies upon composition of matter intellectual property (IP). With cellular products, it is generally recognised that “the product is the process” – i.e. even if the starting cells were the same, it is the in vitro “process” by which, the starting material is processed, which determines the output “product”. Under this rationale, cell products generally rely upon process IP for protection.
Process patents are very widely used in the biotechnology industry. While it is generally not possible to patent something that occurs in nature, such as a type of human cell, it is possible to patent a specific process used to obtain or produce those cells. Consequently, companies involved in the commercialisation of cell-based therapies typically rely primarily on process patents.
It is also important to be aware that patents form just one part of intellectual property protection for therapeutic products. For example, in the USA, once a biological product is approved by the FDA for therapeutic use, a period of regulatory exclusivity is granted, which means that no other company can launch a generic version of that product for at least an additional 12 years –regardless of when the relevant patents expire. Similar provisions exist in other jurisdictions. In the EU, the period of exclusivity is at least 10 years, and potentially 11 years, if certain conditions are met.
Cynata Incorporated (a California registered company) was formed in October 2011 by two of the inventors of the Cymerus™ technology (Professor Igor Slukvin and Dr Maksym (Maxim) Vodyanik), in collaboration with Australian technology entrepreneur, Dr Ian Dixon.
Ian had been searching for an answer to a problem he had identified– namely how MSCs could be consistently manufactured in ultra-large-scale. When he became aware of the relevance of the discoveries at the University of Wisconsin – Madison (UWM), he contacted Professor Slukvin. It became clear that they had a common interest in commercialising the technology, so they decided to establish Cynata, with the specific objective of developing therapeutic products using the Cymerus™ technology.
The patents underpinning Cynata’s Cymerus™ technology are owned by the Wisconsin Alumni Research Foundation (WARF), which has automatic rights to all intellectual property arising from UWM. Cynata has been granted an exclusive worldwide license to the relevant patents. Further details of the agreement between WARF and Cynata may be found in the 14 October 2013 prospectus.
It is common practice for WARF to license its patents to start-up companies, in particular those founded by the inventors. In fact, WARF actively encourages UW staff to take this approach to commercialise their inventions, and offers assistance to help such companies succeed. As of March 2015, WARF is working with approximately 60 companies that were started specifically to commercialise its technology, four of which are commercialising stem cell-based technologies.
In November 2013, Cynata, Incorporated was acquired by an ASX-listed company called EcoQuest Limited. EcoQuest subsequently changed its name to Cynata Therapeutics Limited. The company is now headquartered in Melbourne, Australia, but the majority of its operations continue to be undertaken in the USA.
The Cynata founders – Professor Slukvin, Dr Vodyanik and Dr Dixon - all still hold shares in the Company and Professor Slukvin and Dr Vodyanik remain closely involved with the company’s product development activities.
Yes, Cynata has been the subject of very favourable independent equities research analysis, by Stuart Roberts of Bailieu Holst, Dennis Hulme and Russell Wright of BBY, and Darren Vincent of Shaw Stockbroking.
No. These regulatory exemptions are only applicable to autologous treatments, which means that a person is treated using their own cells. By definition, autologous manufacturing processes are very small-scale, as each donation can only be used to treat one person.
Cynata is focussed on the manufacture of allogeneic, or “off the shelf” products, at the commercial scale. Allogeneic means that cells from a donor are used to treat other patients. MSCs, including those produced using Cynata’s Cymerus™ technology, can be used to treat unrelated patients, without any need to match the recipient to the donor. Cynata’s ultimate objective is for millions of patients to be treated with MSCs derived from a single donation.
Allogeneic cell-based products, like Cynata’s Cymerus™ MSCs, are regulated in a similar way to drugs. This means that the products must undergo preclinical and clinical trials to demonstrate that they are safe and effective, before they will be given regulatory approval to be commercially supplied. Furthermore, the manufacturing process is subject to stringent regulatory oversight, to ensure the quality and consistency of the products.
The regulatory authorities that oversee Cynata’s products include the FDA (in the USA), the EMA (in Europe) and the TGA (in Australia). Cynata has already had successful and productive interactions with regulators in key jurisdictions, and will continue to do so as development programs progress.
The fundamental difference is in the starting material:
First Generation Methods
First generation methods rely on the isolation of MSCs from donated tissue (for example bone marrow, fat or placenta), followed by “culture expansion”. When cells are culture expanded, the total number of cells increases as a result of a process called cell division. Thus, one cell gives rise to two, then two to four, and so on.
The difficulty with this approach, using MSCs derived from donor tissue, is:
This means that each tissue donation can produce only a limited number of MSC doses, so a continuous supply of new donors would be needed to facilitate manufacturing at commercial scale.
Cynata’s Cymerus™ Process
Cynata’s Cymerus™ technology uses a completely different approach, which does not involve the isolation of MSCs from tissue donations. Instead, the Cymerus™ process utilises cells known as induced pluripotent stem cells or iPSCs as a starting material. The key difference between iPSCs and MSCs is that iPSCs have an essentially limitless capacity to self-renew without changing. The cornerstone of Cynata’s intellectual property is the ability to turn iPSCs into clinical grade MSCs in a consistent, reproducible way. This means that Cynata can produce an essentially limitless number of MSCs from the same starting material (the same iPSC bank). Furthermore, it means that Cynata does not need to excessively expand MSCs in culture in order to produce large numbers of doses.
It has been reported that certain first generation processes can generate tens of thousands of MSC doses from a single donation. While that would be adequate to supply product for clinical trials, MSCs are being developed for numerous conditions, some of which are very common. For example stroke, heart attack, heart failure, osteoarthritis and diabetes each affect between 800,000 and 2 million of new patients per year in the USA alone. Therefore, if an MSC product is truly successful, commercial demand worldwide could run to millions of doses per year. First generation methods of MSC production would require hundreds of new donors per year to meet that level of demand. Moreover, the scientific literature abounds with studies showing that even modest culture expansion of MSCs reduces their efficacy.
In contrast, using the Cymerus™ technology, Cynata has the capacity to produce an effectively limitless supply of MSCs from a single donation. Furthermore, this can be achieved without the need to excessively expand the Cymerus™ MSCs in culture.
There are two problems associated with relying on a continuous supply of new donations as starting material:
Consequently, it will be extremely expensive to manufacture MSC products using processes that rely on a continuous supply of tissue donations, and there is a significant risk of supply constraint or interruption.
In contrast, the Cymerus™ process, avoids these challenges. Therefore, the cost of manufacturing MSCs using the Cymerus™ process will be significantly lower. Furthermore, continuous supply at commercial scale with batch to batch consistency can be readily achieved.
While relying on a continuous supply of new donors is currently the only option for blood transfusions and organ transplants, it is far from ideal. It is not uncommon for shortages of certain blood types to arise, which limit the ability of blood services to meet demand. The problem is even more pronounced with organs – patients requiring organ transplants are typically placed on long waiting lists, and unfortunately most of them die before a suitable organ is found. Additionally, the current approach is extremely costly. For example, in 2012/13 the Australian Red Cross spent over $550 million on its blood service, in a country with a population of just 23 million people.
In light of these challenges, there has been extensive interest in developing ways to manufacture blood and organs for transplants, without relying on new donors, much like Cynata has developed a way to manufacture MSCs without relying on new donors.
Another important distinction between blood/organs and MSCs is the way that they are regulated. MSCs are generally regulated just like drugs, which means that there is a requirement to show batch to batch consistency of the product. In contrast, blood and organs for transplant use are subject to a completely different set of regulations, and the requirement to show batch to batch consistency does not apply. This means it would be even more difficult to rely on a continuous supply of new donors to produce MSC-based products than it is with blood and organs.
With any therapeutic product that is supplied commercially, it is a fundamental requirement that the product is consistent from batch to batch. If that were not the case, then the product used in clinical trials might not be representative of the product supplied commercially. For example, batches might be less potent than the batches used in clinical trials, resulting in a treatment being less effective than expected (or even completely ineffective). Consequently, regulatory authorities worldwide – and by extension pharmaceutical companies – place great emphasis on the demonstration of batch to batch consistency.
The development pathway for MSC-based products for therapeutic use is similar to that for drugs. It is a regulatory expectation in all major jurisdictions worldwide that studies in animal models are conducted before clinical trials in humans commence, in order to establish that the product is likely to be safe and effective enough to warrant testing in humans.
The first stage of the research and development process is known as the “discovery” phase, during which initial laboratory studies are conducted. This phase of the process typically takes several years to complete.
The next phase is preclinical testing (also known as nonclinical testing). During this phase, further laboratory tests are conducted, along with studies in animal models, to generate further information on the safety and efficacy profile of the product. Avery small proportion of new therapeutic agents reach this stage of development – it has been estimated that for every 5,000-10,000 new agents that enter the discovery phase, only 250 will reach the preclinical phase. As such, the commencement of studies in animals is considered to be an important milestone in the commercial development of any therapeutic product.
Cynata has successfully completed a study in which Cymerus™ MSCs were used in an animal model of critical limb ischaemia, a condition that occurs in humans with devastating consequences. This study showed that the MSCs had a profound effect, and no safety concerns were identified. Cynata is now undertaking further preclinical testing to demonstrate the safety and efficacy of Cymerus™ MSCs in models of graft versus host disease (GvHD) and idiopathic pulmonary fibrosis (IPF), with additional proof of concept studies in the planning stage. Cynata is also working with WuXi AppTec (NYSE:WX), a leading global biopharmaceutical contract research organisation, to conduct further preclinical safety studies.
Yes. Cynata has approval to conduct a Phase 1 clinical trial with its lead Cymerus™ MSC product, CYP-001, in patients with graft-versus-host disease (GvHD). This disease often follows a bone marrow transplant procedure and occurs when the immune cells in the donor material (the graft) attack the recipient’s tissues (the host) as “foreign”. Bone marrow transplants are used in the treatment of certain cancers including leukaemia.
Steroids are currently the first line treatment for GvHD, but this treatment is often unsuccessful. Additionally, some patients are unable to tolerate side effects caused by long term steroid treatment. When steroid treatment fails, the prognosis is very poor, with as many as 80% of patients dying from “steroid-refractory” GvHD.
MSCs have the ability to modulate a recipient’s immune response: consequently, MSCs may be useful treatments for diseases resulting from an immune response, such as GvHD. Numerous clinical trials of MSCs as a GvHD treatment have been conducted, most with very positive results.
MSCs have shown promise for a wide range of conditions, some of which are very common. In the long term, it is true that treating those more common conditions is likely to be much more commercially attractive than treatment of graft versus host disease (GvHD), which is a relatively rare condition.
The ultimate commercial potential of any Cymerus™ therapeutic product is clearly a key driver for the company. However, for a Phase 1 study, it is also important to consider factors, such as the potential clinical outcomes, current standard-of-care therapies, the likely duration of the study and recruitment potential. With this in mind, Cynata made the decision that an initial target indication that can provide clear and speedy endpoints is ideal, even if it has a modest commercial potential. GvHD is such an indication.
Ultimately, Cynata expects the GvHD clinical program to pave the way for clinical trials in more commercially attractive indications, which may be conducted by either Cynata or its partners. In parallel to the GvHD program, Cynata is conducting preclinical studies in other conditions, which will also help position the company (and/or its partners) to move those program into clinical trials in due course.
No, Cynata’s current cash balance is expected to be more than adequate to cover the costs of this trial.
Cynata’s MSCs are manufactured under contract by Waisman Biomanufacturing, Madison, WI, USA. Waisman is a Good Manufacturing Practice (GMP) - compliant facility that was specifically designed to manufacture cellular therapies, gene therapies and other biologicals products.
The design of the facility was reviewed by the US Food and Drug Administration’s (FDA’s) Center for Biologics Evaluation and Research (CBER) before construction commenced, and Waisman now has a Facility Master File registered with CBER, which Cynata is authorised to rely on when it submits an Investigational New Drug (IND) application (an IND is required before the commencement of a clinical trial in the US).
Waisman has developed platform manufacturing processes and analytical methods to support clinical production of several classes of products including plasmid DNA, MSCs, iPSCs and viral vectors. In addition, Waisman has supported the development and clinical production of a number of novel types of biotherapeutics from process development through to aseptic fill and finish.
Waisman’s core expertise lies in the transfer and scale-up of manufacturing processes from academic laboratories, and manufacture for Phase 1 and 2 clinical trials. Notably, Waisman was selected to participate in the US-government funded PACT (Production Assistance for Cellular Therapies)Program. Awarded a five-year contract for $8.8 million from the National Heart, Lung and Blood Institute (part of the National Institutes of Health), Waisman produced clinical grade (GMP) cell-based therapies, including products derived from human embryonic stem cells, and MSCs or treating heart, lung and blood conditions.
The Cymerus™ manufacturing process was originally developed in an academic laboratory at the University of Wisconsin, Madison. As highlighted in Cynata’s Prospectus to investors in October 2013, “ The process of manufacturing stem cell products based on the Cynata Technology has only been conducted at laboratory scale and there are risks inherent in scale-up to a commercial manufacturing environment, including that it is not economically feasible”.
In addition to the fact that the academic process needed to be scaled up to facilitate commercial production, a number of other issues had to be addressed. For example, in order to manufacture cells suitable for human use, manufacture must take place in a clean room facility, using clinical-grade materials, and in compliance with Good Manufacturing Practice (GMP). Making changes of this type with a biological process is not a trivial matter, as cells are very sensitive to changes in their environment and in the way they are handled.
In February 2015, Cynata announced that the transfer and scale up of the process to a GMP-compliant manufacturing facility (Waisman Biomanufacturing) had been successfully completed. In addition to manufacturing MSCs using the Cymerus™ process, Waisman and other accredited laboratories subjected the MSCs to an extensive range of tests, confirming that the cells have the characteristics required of MSCs for therapeutic use. The results of these tests will form a key part of Cynata’s dossier to support regulatory approval of its proposed clinical trials.
The significance of reaching this milestone is that Cynata has now overcome a major technical challenge in commercialising its Cymerus™ manufacturing process, and is now in a position to manufacture clinical grade MSCs at scale.