In January 2017 Cynata executed a license option agreement with FUJIFILMCorporation of Japan for the development and commercialisation of certainCynata technology, including Cynata’s lead induced pluripotent stem cell(iPSC)-derived therapeutic mesenchymal stem cell (MSC) product, CYP-001, forgraft-versus-host disease (GvHD). As part of the transaction, FUJIFILMacquired an equity position in Cynata through the purchase of 8,088,403ordinary shares in Cynata, leading to Fujifilm becoming the largest shareholderin the Company with an approximate 9% stake. FUJIFILM’s option isexercisable at any time up to 90 days after the completion of the primaryevaluation period of Cynata’s current phase I clinical trial in GvHD. Anupfront fee of US$3 million is then payable which, together with otherpotential future milestones, totals over A$60 million in potential one-timepayments, along with double-digit royalties on net sales of CYP-001product. Should FUJIFILM choose to exercise this option, future CYP-001development costs will be borne by FUJIFILM.
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The trademark Cymerus™ refers to the patented process of generatingcell-based products from intermediate cells, known asmesenchymoangioblasts (MCAs), which in turn are derived frominduced pluripotent stem cells (iPSCs). This technology wasoriginally developed at the University of Wisconsin-Madison, WI,USA.
At present, Cynata is focussed on the production of mesenchymal stemcell (MSC)-based products using the Cymerus™ technology.
Mesenchymal stem cells, also known as mesenchymal stromal cells orMSCs, are a particular type of stem cell found in a wide range ofhuman tissues, including bone marrow, adipose tissue (fat),placenta and umbilical cord blood.
There has been extensive interest in the development of MSCs astherapeutic products, in particular because of their ability tomodulate the immune system. They also secrete bioactive moleculessuch as cytokines, chemokines and growth factors, which hasresulted in these cells being dubbed “drug factories” or “medicinesecreting cells”.
MSCs can be either autologous or allogeneic. Autologous means apatient is treated with their own cells, while allogeneic meansthat cells from a donor are used to treat other people. AllogeneicMSCs have not been shown to cause immune reactions in other people,so they can be used in an “off the shelf” manner, without anyrequirement for matching the donor to the recipient. This hasimportant commercial advantages, so biotechnology companies havelargely focussed on allogeneic rather than autologous MSCs.
MSCs have been shown to facilitate regeneration and effects on theimmune 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 ashort period of time.
There are currently over 600 ongoing, human, clinical trials, inwhich MSCs are being used to treat a very wide range of medicalconditions, including heart disorders, diabetes, orthopaedicconditions, and autoimmune diseases, among others.
Cynata’s Cymerus™ platform stem cell technology is based uponextremely important and versatile stem cells known asmesenchymoangioblasts (MCAs). MCAs are precursors to mesenchymalstem cells (MSCs). Cynata’s proprietary technology utilises inducedpluripotent stem cells (iPSCs) originating from an adult donor asthe starting material for generating MCAs, and in turn formanufacturing the MSC therapeutic product.
Pluripotent stem cells are the most versatile cells of all, havingthe ability to reproduce themselves indefinitely, and alsodifferentiate into any other type of cell in the body. There aretwo 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 withconsent by patients who have completed in vitro fertilisationtherapy, and have surplus embryos. The first human ESCs wereisolated by Professor James Thomson at the University ofWisconsin-Madison in 1998 (one of the investors of the Cymerus™technology). The use of ESCs has been hindered to some extent byethical 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 theethical concerns described above, since they are not derived fromembryos. Professor Thomson and his team, including Professor IgorSlukvin (one of the founders of Cynata) were also pioneers in thedevelopment of iPSCs. In 2007, they were one of two independentresearch groups that first reported the creation of iPSCs fromhuman cells (along with Professor Shinya Yamanaka et al, at KyotoUniversity, Japan).
iPSCs are typically derived from fully differentiated adult cellsthat 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 ofiPSC production, the iPSCs that Cynata uses were produced withoutthe use of viruses and without changing the cells’ DNA. Therefore,these iPSCs are well-suited to the manufacture of products forhuman use.
Yes, there are a number of different ways of producing iPSCs, whichare often described as “reprogramming methods”. It is important tobe aware of the distinction between different reprogrammingmethods, as studies conducted on iPSCs produced by first generationmethods are generally not relevant to iPSCs produced using morerecent technology.
First generation reprogramming methods involved the use of virusesthat inserted particular genes into the donated cells’ DNA – a typeof genetic modification. However, such reprogramming methods werenever considered to be suitable for the manufacture of products forhuman use, because of the risk of genetic mutations (this is knownas “insertional mutagenesis”). Furthermore, when reprogramminggenes persist in cells, they contribute to genetic instability andaberrations. These limitations were acknowledged in the original publication of the method to produce human iPSCsby 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 useplasmids, which are short segments of DNA that do not integrateinto the donated cells’ DNA, and consequently avoid the risksassociated with insertional mutagenesis and persistence ofreprogramming genes.
There is a growing body of evidence demonstrating that iPSCsproduced in this way are not associated with the same problems asiPSCs 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 thatthe episomal DNA could not be detected in the iPSC lines (i.e. theplasmids did not integrate or persist in the reprogrammed cells),that it did not alter the structure of the cells’ DNA and thatthese reprogramming methods are not inherently mutagenic.Similarly, a recent comparison of reprogramming methods published inNature 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 thatoriginally developed at UWM. Additionally, Cynata’s iPSCs werederived from a fully consented donor, in compliance with the FDA’sGMP requirements.
This ability to reprogram cells from adult donors into a pluripotentembryonic-like state has been met with great excitement, as it hassignificantly advanced the potential for regenerative therapy.iPSCs have similar characteristics to ESCs, without the ethicalissues. The discovery is a generational advancement in processesthat require repeat donor-derived materials.
iPSCs – like ESCs – are cells that can (i) be expanded withoutlimit, (ii) can be stored over long periods and (iii) can producetissue cells of any type. This makes iPSCs an ideal building-blockfor cell-based therapies.
It is important to understand that iPSCs themselves are notadministered to patients. Instead, the iPSCs are used as a startingmaterial to produce other types of cells, such as MSCs in Cynata’scase. Cynata’s Cymerus™ technology includes attributes designed toeliminate iPSCs early during the manufacturing process. Cynata’sfinal product contains only MSCs, which have similarcharacteristics to MSCs isolated from tissue donations (e.g. bonemarrow).
A number of organisations around the world are currently developingiPSC-derived cellular therapies for human use. Cynata has receivedregulatory approval in the UK and Australia to commence a Phase 1clinical trial in GvHD. The approval of this trial was important,as it demonstrated that regulatory authorities and ethicscommittees are comfortable with the concept of using iPSC-derivedcells in humans.
No, Cynata uses induced pluripotent stem cells, or iPSCs, as astarting material in its manufacturing process. iPSCs are derivedfrom 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 ofscientists in particular, are widely recognised as world leaders instem cell research and have published their findings in highlyrespected scientific and medical journals.
Cynata’s Cymerus™ technology is underpinned by a series of patents(including granted patents and patent applications) licensed fromthe Wisconsin Alumni Research Foundation (WARF) – an organisationestablished to commercialise technology invented at the Universityof 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’sknowledge, this is currently the only process proven to be capableof commercially producing clinical grade MSCs from iPSCs. The keypatent rights licensed to Cynata do not expire until between 2028and 2034.
Cellular products are different from small molecule drugs. Withsmall molecule drugs, the synthesis (manufacture) of the drug isrelatively simple and easily copied – therefore, commercialisationrelies upon composition of matter intellectual property (IP). Withcellular products, it is generally recognised that “the product isthe process” – i.e. even if the starting cells were the same, it isthe in vitro “process” by which, the starting material isprocessed, which determines the output “product”. Under thisrationale, cell products generally rely upon process IP forprotection.
Process patents are very widely used in the biotechnology industry.While it is generally not possible to patent something that occursin nature, such as a type of human cell, it is possible to patent aspecific process used to obtain or produce those cells.Consequently, companies involved in the commercialisation ofcell-based therapies typically rely primarily on process patents.
It is also important to be aware that patents form just one part ofintellectual property protection for therapeutic products. Forexample, in the USA, once a biological product is approved by theFDA for therapeutic use, a period of regulatory exclusivity isgranted, which means that no other company can launch a genericversion of that product for at least an additional 12 years –regardless of when the relevant patents expire. Similar provisionsexist in other jurisdictions. In the EU, the period of exclusivityis at least 10 years, and potentially 11 years, if certainconditions are met.
Cynata Incorporated (a California registered company) was formed inOctober 2011 by two of the inventors of the Cymerus™ technology(Professor Igor Slukvin and Dr Maksym (Maxim) Vodyanik), incollaboration with Australian technology entrepreneur, Dr IanDixon.
Ian had been searching for an answer to a problem he had identified– namely how MSCs could be consistently manufactured inultra-large-scale. When he became aware of the relevance of thediscoveries at the University of Wisconsin – Madison (UWM), hecontacted Professor Slukvin. It became clear that they had a commoninterest in commercialising the technology, so they decided toestablish Cynata, with the specific objective of developingtherapeutic products using the Cymerus™ technology.
The patents underpinning Cynata’s Cymerus™ technology are owned bythe Wisconsin Alumni Research Foundation (WARF), which hasautomatic rights to all intellectual property arising from UWM.Cynata has been granted an exclusive worldwide license to therelevant patents. Further details of the agreement between WARF andCynata may be found in the 14 October 2013 prospectus.
It is common practice for WARF to license its patents to start-upcompanies, in particular those founded by the inventors. In fact,WARF actively encourages UW staff to take this approach tocommercialise 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 whichare commercialising stem cell-based technologies.
In November 2013, Cynata, Incorporated was acquired by an ASX-listedcompany called EcoQuest Limited. EcoQuest subsequently changed itsname to Cynata Therapeutics Limited. The company is nowheadquartered in Melbourne, Australia, but the majority of itsoperations 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 DrVodyanik remain closely involved with the company’s productdevelopment activities.
Yes, Cynata has been the subject of very favourable independentequities research analysis, by Stuart Roberts of Bailieu Holst, Dennis Hulme and Russell Wright of BBY, and Darren Vincent of ShawStockbroking.
No. These regulatory exemptions are only applicable to autologoustreatments, which means that a person is treated using their owncells. By definition, autologous manufacturing processes are verysmall-scale, as each donation can only be used to treat one person.
Cynata is focussed on the manufacture of allogeneic, or “off theshelf” products, at the commercial scale. Allogeneic means thatcells from a donor are used to treat other patients. MSCs,including those produced using Cynata’s Cymerus™ technology, can beused to treat unrelated patients, without any need to match therecipient to the donor. Cynata’s ultimate objective is for millionsof patients to be treated with MSCs derived from a single donation.
Allogeneic cell-based products, like Cynata’s Cymerus™ MSCs, areregulated in a similar way to drugs. This means that the productsmust undergo preclinical and clinical trials to demonstrate thatthey are safe and effective, before they will be given regulatoryapproval to be commercially supplied. Furthermore, themanufacturing process is subject to stringent regulatory oversight,to ensure the quality and consistency of the products.
The regulatory authorities that oversee Cynata’s products includethe FDA (in the USA), the EMA (in Europe) and the TGA (inAustralia). Cynata has already had successful and productiveinteractions with regulators in key jurisdictions, and willcontinue 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 donatedtissue (for example bone marrow, fat or placenta), followed by“culture expansion”. When cells are culture expanded, the totalnumber of cells increases as a result of a process called celldivision. Thus, one cell gives rise to two, then two to four, andso on.
The difficulty with this approach, using MSCs derived from donortissue, is:
This means that each tissue donation can produce only a limitednumber of MSC doses, so a continuous supply of new donors would beneeded 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 inducedpluripotent stem cells or iPSCs as a starting material. The keydifference between iPSCs and MSCs is that iPSCs have an essentiallylimitless capacity to self-renew without changing. The cornerstoneof Cynata’s intellectual property is the ability to turn iPSCs intoclinical grade MSCs in a consistent, reproducible way. This meansthat Cynata can produce an essentially limitless number of MSCsfrom the same starting material (the same iPSC bank). Furthermore,it means that Cynata does not need to excessively expand MSCs inculture in order to produce large numbers of doses.
It has been reported that certain first generation processes cangenerate 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 arevery common. For example stroke, heart attack, heart failure,osteoarthritis and diabetes each affect between 800,000 and 2million of new patients per year in the USA alone. Therefore, if anMSC product is truly successful, commercial demand worldwide couldrun to millions of doses per year. First generation methods of MSCproduction would require hundreds of new donors per year to meetthat level of demand. Moreover, the scientific literatureabounds with studies showing that even modest culture expansion ofMSCs reduces their efficacy.
In contrast, using the Cymerus™ technology, Cynata has the capacityto produce an effectively limitless supply of MSCs from a singledonation. Furthermore, this can be achieved without the need toexcessively expand the Cymerus™ MSCs in culture.
There are two problems associated with relying on a continuoussupply of new donations as starting material:
Consequently, it will be extremely expensive to manufacture MSCproducts using processes that rely on a continuous supply of tissuedonations, and there is a significant risk of supply constraint orinterruption.
In contrast, the Cymerus™ process, avoids these challenges.Therefore, the cost of manufacturing MSCs using the Cymerus™process will be significantly lower. Furthermore, continuous supplyat commercial scale with batch to batch consistency can be readilyachieved.
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 useis similar to that for drugs. It is a regulatory expectation in allmajor jurisdictions worldwide that studies in animal models areconducted before clinical trials in humans commence, in order toestablish that the product is likely to be safe and effectiveenough to warrant testing in humans.
The first stage of the research and development process is known asthe “discovery” phase, during which initial laboratory studies areconducted. This phase of the process typically takes several yearsto complete.
The next phase is preclinical testing (also known as nonclinicaltesting). During this phase, further laboratory tests areconducted, along with studies in animal models, to generate furtherinformation on the safety and efficacy profile of the product. Avery small proportion of new therapeutic agents reach this stage ofdevelopment – it has been estimatedthat for every 5,000-10,000 new agents that enter the discoveryphase, only 250 will reach the preclinical phase. As such, thecommencement of studies in animals is considered to be an importantmilestone 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 withdevastating consequences. This study showed that the MSCs had aprofound effect, and no safety concerns were identified. Cynata isnow undertaking further preclinical testing to demonstrate thesafety and efficacy of Cymerus™ MSCs in models of graft versus hostdisease (GvHD) and idiopathic pulmonary fibrosis (IPF), withadditional proof of concept studies in the planning stage. Cynatais also working with WuXi AppTec (NYSE:WX), a leading global biopharmaceuticalcontract research organisation, to conduct further preclinicalsafety studies.
Yes. Cynata has approval to conduct a Phase 1 clinical trial withits lead Cymerus™ MSC product, CYP-001, in patients withgraft-versus-host disease (GvHD). This disease often follows a bonemarrow transplant procedure and occurs when the immune cells in thedonor material (the graft) attack the recipient’s tissues (thehost) as “foreign”. Bone marrow transplants are used in thetreatment of certain cancers including leukaemia.
Steroids are currently the first line treatment for GvHD, but thistreatment is often unsuccessful. Additionally, some patients areunable to tolerate side effects caused by long term steroidtreatment. When steroid treatment fails, the prognosis is verypoor, 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 resultingfrom 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 ofwhich are very common. In the long term, it is true that treatingthose more common conditions is likely to be much more commerciallyattractive than treatment of graft versus host disease (GvHD),which is a relatively rare condition.
The ultimate commercial potential of any Cymerus™ therapeuticproduct is clearly a key driver for the company. However, for aPhase 1 study, it is also important to consider factors, such asthe potential clinical outcomes, current standard-of-caretherapies, the likely duration of the study and recruitmentpotential. With this in mind, Cynata made the decision that aninitial target indication that can provide clear and speedyendpoints 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 wayfor clinical trials in more commercially attractive indications,which may be conducted by either Cynata or its partners. Inparallel to the GvHD program, Cynata is conducting preclinicalstudies in other conditions, which will also help position thecompany (and/or its partners) to move those program into clinicaltrials in due course.
No, Cynata’s current cash balance is expected to be more thanadequate to cover the costs of this trial.
Cynata’s MSCs are manufactured under contract by Waisman Biomanufacturing, Madison, WI, USA. Waisman is a GoodManufacturing Practice (GMP)-compliant facility that wasspecifically designed to manufacture cellular therapies, genetherapies and other biologicals products.
The design of the facility was reviewed by the US Food and DrugAdministration’s (FDA’s) Center for Biologics Evaluation andResearch (CBER) before construction commenced, and Waisman now hasa Facility Master File registered with CBER, which Cynata isauthorised to rely on when it submits an Investigational New Drug(IND) application (an IND is required before the commencement of aclinical trial in the US).
Waisman has developed platform manufacturing processes andanalytical methods to support clinical production of severalclasses of products including plasmid DNA, MSCs, iPSCs and viralvectors. In addition, Waisman has supported the development andclinical production of a number of novel types of biotherapeuticsfrom process development through to aseptic fill and finish.
Waisman’s core expertise lies in the transfer and scale-up ofmanufacturing processes from academic laboratories, and manufacturefor Phase 1 and 2 clinical trials. Notably, Waisman was selected toparticipate in the US-government funded PACT (Production Assistance for Cellular Therapies)Program.Awarded a five-year contract for $8.8 million from the NationalHeart, Lung and Blood Institute (part of the National Institutes ofHealth), Waisman produced clinical grade (GMP) cell-basedtherapies, including products derived from human embryonic stemcells, and MSCs or treating heart, lung and blood conditions.
The Cymerus™ manufacturing process was originally developed in anacademic laboratory at the University of Wisconsin, Madison. Ashighlighted 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 bescaled up to facilitate commercial production, a number of otherissues had to be addressed. For example, in order to manufacturecells suitable for human use, manufacture must take place in aclean room facility, using clinical-grade materials, and incompliance with Good Manufacturing Practice (GMP). Making changesof this type with a biological process is not a trivial matter, ascells are very sensitive to changes in their environment and in theway they are handled.
In February 2015, Cynata announced that the transfer and scale up of theprocess to a GMP-compliant manufacturing facility (WaismanBiomanufacturing) had been successfully completed. In addition tomanufacturing MSCs using the Cymerus™ process, Waisman and otheraccredited laboratories subjected the MSCs to an extensive range oftests, confirming that the cells have the characteristics requiredof MSCs for therapeutic use. The results of these tests will form akey part of Cynata’s dossier to support regulatory approval of itsproposed clinical trials.
The significance of reaching this milestone is that Cynata has nowovercome a major technical challenge in commercialising itsCymerus™ manufacturing process, and is now in a position tomanufacture clinical grade MSCs at scale.