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.  Subsequently Cynata has filed patent applications in its own right to further extend and protect the Cymerus technology.

The patents underpinning Cynata’s Cymerus technology are owned by the Wisconsin Alumni Research Foundation (WARF), an organisation established to commercialise technology invented at the University of Wisconsin – Madison (UWM). Cynata has been granted an exclusive worldwide licence for the life of the relevant patents. Upon expiry of those patents, Cynata will be able to continue to use the WARF technology without further payment, and Cynata’s multiple other protections will remain in place to limit competition. 

Cynata enjoys a cordial and productive relationship with WARF and the parties interact regularly on many different matters.  The rights and obligations of the parties are set out in a formal licence agreement which among other matters deals with various payments and performance obligations that Cynata has met and continues to meet (or exceed).  The parties have on several occasions reached an understanding around the dynamic nature of cell therapy product development, resulting in certain amendments to the WARF-Cynata licence, e.g. in September 2019, to accommodate changing circumstances.  Cynata is confident that the excellent relationship between the parties will continue, particularly in view of Cynata being the world's leading company in the development of iPSC-derived cell therapies, an important validation of the underlying WARF technology.

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 University of Wisconsin staff to take this approach to commercialise their inventions, and offers  assistance to help such companies succeed. As of May 2019, WARF is working with approximately 70 companies that were started specifically to commercialise its technology, seven of which are commercialising  stem cell-based technologies.

Cynata’s Cymerus technology is underpinned by several families of granted patents and patent applications exclusively licensed from the Wisconsin Alumni Research Foundation (WARF) – an organisation established to commercialise technology invented at the University of Wisconsin-Madison.  

These patents describe a process to generate mesenchymal stem cells (MSCs) under serum-free conditions, using pluripotent stem 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, and upon such expiry, Cynata will be able to continue to use this process technology without further payment. The other protections discussed below will also remain in place to limit any potential competition. 

Cynata also has licensed the iPSC technology and certain cellular material of Fujifilm-CDI.  

In addition, Cynata has filed multiple patent applications in its own right - meaning Cynata is the owner - adding further protection to the Company’s broad and extensive intellectual property.  Cynata also owns the relevant manufacturing, pre-clinical and clinical data packages upon which the development and eventual marketing approval of any Cymerus product is totally dependent.

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”. Therefore, 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 the mechanisms discussed above form just one part of protection for therapeutic products. For example, once the FDA approves a biological product, a period of regulatory exclusivity is granted, which means that no other company can launch a generic version of that product in the USA for at least an additional 12 years – regardless of when any 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.

It is not possible for another company to produce a generic version of Cymerus MSCs, or indeed any biological product (biological products include proteins, antibodies, cellular therapies and gene therapies).

The active ingredient in a generic drug must be exactly the same as the active ingredient in the equivalent branded product, but due to their complexity, it is not possible to show that a copy of a biological product is the same as the original product.

Most people will be familiar with generic versions of “small molecule” drugs, such as paracetamol or aspirin. Small molecules are relatively simple chemical compounds, so it is usually straightforward and inexpensive for a competitor to produce an exact copy. In general, other companies can seek approval to market generic drugs once the relevant patents and regulatory exclusivity periods for the branded version have expired (typically within 5-10 years of the launch of the branded product).

Because a generic drug is exactly the same as the original branded version, it is not necessary to repeat the clinical trials that were required to support the approval of the original branded version. This means that the costs associated with developing generic drugs are low, so generics can be sold at a much cheaper price than the original branded version.

As a result, generic competition poses a major threat to the continued sales of small molecule drugs, once the relevant patents and regulatory exclusivity periods end. However, the situation for biological products is completely different, as it is not possible to produce a generic version of a biological product.

To address this, legislation to facilitate approval of “biosimilar” drugs has been introduced in some countries. As the name implies, biosimilar drugs must be highly similar to the original branded drug, but due to their complexity, it cannot be shown that they are the same as the original branded drug, so they are not generics.

This distinction is very important, because a much more extensive development program is required to support the approval of a biosimilar – including clinical trials demonstrating that the safety and efficacy profile is consistent with the original branded product. The costs associated with developing a biosimilar are dramatically higher than those required to develop a generic, due to the difficulty and cost of biological manufacture and quality control, and the need for clinical trials. The level of development risk is also much higher and the timelines are much longer. Consequently, even if successful, biosimilars have to be priced much higher than generics, to recoup the development costs. Furthermore, biosimilars are not necessarily considered to be interchangeable with the original branded version, which means that uptake may remain low after launch.

Due to the costs, timelines and risks involved in their development, biosimilar products are still uncommon. As of September 2022, there are FDA-approved biosimilar versions of only 11 out of >620 approved biological products, and only three are considered to be interchangeable with the original branded product. Notably, all of the FDA-approved biosimilars are proteins/antibodies, which are the least complex type of biological products, while cellular therapies are so complex that experts in the field consider it unlikely to be possible to produce a biosimilar version of a cellular therapy product in the foreseeable future.

In September 2021 Cynata entered into a strategic partnership  agreement with FUJIFILM Corporation of Japan.  This agreement included core terms for Fujifilm to provide clinical and commercial manufacturing services for Cynata’s Cymerus™ MSC products and Cynata regaining all development and commercialisation rights to CYP-001 for graft-versus-host disease with US$5m fee payable by Fujifilm.   This new partnership followed a now terminated 2019 licence agreement in respect of the GvHD indication. Fujifilm remains a significant shareholder in Cynata with around 5.8% of the Company's shares and also is highly committed to ensuring the long term success of Cynata, especially given the original iPS cell line was derived from Cellular Dynamics International, now part of Fujifilm.   

Cynata has an active and vigorous business development program intended to attract additional commercial partners to participate in the development and commercialisation of the Cymerus technology across multiple indications and multiple geographies.  Commercial discussions are often very lengthy and complex, frequently involving the negotiation and execution of multiple contracts (such as confidential disclosure agreements, due diligence agreements and term sheets) before definitive, binding and announceable agreements are signed.  The release of the data from the clinical trial in graft-versus-host disease (GvHD), completed in 2018, has provided very important validation of the Cymerus technology for the Company’s business development activities. The advancement of aditional clinical trials, for example the Phase 3 trial in osteoarthritis, also opens new opportunities for potential partnerships.

Cynata has an active and vigorous business development program intended to attract additional commercial partners to participate in the development and commercialisation of the Cymerus technology across multiple indications and multiple geographies.  Commercial discussions are often very lengthy and complex, frequently involving the negotiation and execution of multiple contracts (such as confidential disclosure agreements, due diligence agreements and term sheets) before definitive, binding and announceable agreements are signed.  The release of the data from the clinical trial in graft-versus-host disease (GvHD), completed in 2018, has provided very important validation of the Cymerus technology for the Company’s business development activities. 

Cynata’s business strategy is widely practiced in the pharmaceutical and biotech industry. Big pharmaceutical companies spend vast sums on drug product R&D, typically around 20% of revenues, making them among the biggest investors in R&D.  Nevertheless, the industry consistently turns to small, nimble innovation-based biotech companies as a rich source of new products, technologies and intellectual property.  With cell therapies and regenerative medicine now very much at the forefront of new pharmaceutical product endeavours and with Cynata being one of the most advanced companies in iPSC-based technologies, the Company is ideally placed to execute on its partnering strategy. In order to build on its existing successes such as the license with Fujifilm, Cynata has to be prepared to invest in its technology assets to generate data that supports a compelling and cogent valuation thesis. Cynata Board and management will consider all opportunities to optimise value in the best interest of all shareholders.

Each country has its own regulatory process for governing the conduct of clinical trials and the granting of marketing authorisations for medical products.  In selecting the jurisdictions in which Cynata has pursued clinical development it has given careful consideration to the quality of the relevant regulatory jurisdiction, the time and costs to satisfy the regulatory requirements, the ultimate pathway to market and the value thereof, the availability of patients and the particular standards of care of the relevant disease.  The USA is the most commercially attractive market for pharmaceutical products and Cynata has engaged with the relevant regulatory agency, the US Food and Drug Administration (FDA) and in 2022 succesfully obtained clearance of an Investigational New Drug (IND) in respect of a propsed Phase 2 clinical trial in acute graft-versus-host disease (aGvHD).   Clearance of Cynata's IND application confirms that the FDA is satisfied with both the clinical and preclinical data as well as the manufacturing and quality control data on our product that we submitted in support of this application.  This was a transformative event for Cynata as it provides a gateway in the USA to potential further clinical targets and is a critical validation step for Cynata’s ongoing commercial partnering activities.  

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 800 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 inventors 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 (then an independent, Nasdaq listed company, but now known as Fujifilm CDI following Fujifilm’s acquisition of CDI in 2015). 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.

Cynata's Cymerus Technology

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.

This ability to reprogram cells from adult donors into a pluripotent embryonic-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.  In fact many researchers and companies worldwide are now using iPSCs to develop specific cell therapy products.

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 (now called Fujifilm CDI), using a non-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.

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. In 2016 Cynata 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. The trial was successfully completed in 2018, meeting all safety and efficacy endpoints.  Cynata has also engaged with other regulatory agencies including the U.S. FDA with very clear outcomes indicating a general acceptability of the Cymerus technology.

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:

• In practice, MSCs start to change as culture expansion progresses. This can result in the cells losing potency, and ultimately they stop dividing altogether (this is known as “senescence”).
• Only a relatively small number of cells can be isolated from each donation – for example a bone marrow donation typically yields fewer than 20,000 MSCs, while a clinical dose is typically more than 100 million  MSCs.

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.

Cynata’s proprietary Cymerus technology provides multiple clear advantages over conventional methods of producing MSC-based products that rely on securing multiple donors of tissue sources of MSCs such as bone marrow, purifying the MSCs and then causing them to expand (divide) excessively in culture to produce sufficient quantities for even small scale applications.  These advantages are summarised below:

When referring to conventional drug products the concept of substitutability relies on one product having essentially identical properties as the substituting product.  More particularly, this pertains to “generic” pharmaceutical products which are copies of brand-name drugs that have exactly the same dosage, intended use, effects, side effects, route of administration, risks, safety, and strength as the original drug.  Cell therapy products are much more complex than conventional drugs and current generic drug legislation around the world does not accommodate this type of medicine.  As such, the typical “generic drug” rules do not currently apply to cell therapy products. 

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 multiple problems associated with relying on a continuous supply of new donations as starting material:

• There are significant logistical challenges and costs associated with collecting tissue donations:
  • It is likely to be difficult to find sufficient numbers of suitable donors to meet large scale commercial demand, particularly with donation procedures that are potentially risky, painful and invasive such as bone marrow harvesting.
  • The process of screening and testing multiple donors, followed by collecting and testing the donated material, is both time consuming and expensive.
• Changing the starting material is likely to change the characteristics of the end product:
  • It has been shown that the number and quality of MSCs that can be isolated from different donations varies substantially.
  • With biological products, when the starting material is changed, regulatory authorities require evidence that the final product does not change. This is known as comparability testing.
  • Comparability testing with this type of product is a very complex, time consuming and costly process.
  • There is also a risk of failing to demonstrate comparability, in which case, the MSCs manufactured from the new donation would be classified as a different product. Commercial supply of a non-comparable product would not be permitted under the regulatory approval for the original product.

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 2017/18 the Australian Red Cross spent  over $620 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.

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.

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.

Clinical Development

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. A very 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 multiple preclinical studies in a diverse range of disease models including asthma, heart attack, diabetic ulcers, sepsis, acute respiratory distress syndrome (ARDS), cytokine release syndrome, graft-versus-host disease and critical limb ischemia.  In the latter study, 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. 

Yes. In 2018 Cynata successfully completed a Phase 1 clinical trial with its lead Cymerus MSC product, CYP-001, in patients with acute graft-versus-host disease (GvHD). It was the first time in the world that a clinical trial had been completed using an iPSC-derived allogeneic therapeutic product.  This garnered much attention for the Company and was a very important achievement, especially since the trial began just a few short years after Cynata Therapeutics was established.

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.

In Cynata’s Phase 1 trial:

• The Overall Response rate by Day 100 was 87%  (13 out of 15 patients showed an improvement in GvHD severity by at least one grade compared to baseline)
• The Complete Response rate by Day 100 was 53% GvHD (signs and symptoms completely resolved in 8 out of 15 patients)
• Overall survival at 2 years was 60%, which compares very favourably to outcomes with other therapies in this population.

No treatment-related serious adverse events or safety concerns were identified.

Cynata is currently conducting a Phase 1 clinical trial in diabetic foot ulcers (DFU) and a Phase 2 clinical trial in GvHD, which builds on the highly successful Phase 1 trial described above. Additionally, the University of Sydney is conducting a Phase 3 clinical trial using Cymerus MSCs in osteoarthritis (recruitment is expected to complete in November 2023), while in 2024, Leiden University Medical Center is expected to commence a trial using Cymerus MSCs in patients who have received a kidney transplant.

Yes. The highly successful Phase 1 clinical trial of CYP-001  in patients with graft-versus-host disease (GvHD) together with compelling preclinical data in a range of models, has facilitated planning for further clinical studies. Current clinical studies are a Phase 3 trial in osteoarthritis and a Phase 1 in diabetic foot ulcers (DFU).  A Phase 3 clinical trial in aGvHD is expected to commence in 2023.  Cynata continually assesses its broader clinical pipeline in the context of available resources, commercial opportunity and partnering activities.

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.

The result was that the GvHD clinical program has paved the way for clinical trials in more commercially attractive indications.

Yes, Cynata has collaborated with many different academic researchers around the world, for example Professor Khalid Shah at Harvard University, and Associate Professor Chrishan Samuel at Monash University.  These collaborations have produced compelling data which has furthered our understanding of the biology of Cymerus MSCs and provided guidance on the eventual conduct of clinical trials.  For example, the collaboration between Cynata and Professor John Fraser at The Prince Charles Hospital in Brisbane, Australia (and others) provided a solid foundation for advancing a clinical trial in COVID-19 patients with severe respiratory distress.  Cynata will continue to undertake collaborations with parties where there is a shared mutual interest in progressing the development of MSC-based therapies.

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. 

More recently, Cynata entered into a Manufacturing Services Agreement (MSA) with FUJIFILM Cellular Dynamics, Inc (“FCDI”) for the manufacture and supply of Cynata’s Cymerus™ therapeutic MSC products for clinical trials and commercial applications. This new agreement was foreshadowed in the Strategic Partnership Agreement between FUJIFILM Corporation (FCDI’s parent company) and Cynata, as announced on 30 September 2021. Further details regarding the terms of the MSA are provided in the 30 September 2021 announcement.  Cynata’s existing manufacturing relationship with Waisman Biomanufacturing will continue in order to manufacture product for Cynata’s current clinical trials.