msemporda: CYNATA

Cynata's Phase 1 iPSC eMSC Trial Updates

Cynata Reports Positive 28-day Data from Cohort B of Phase 1 Trial of CYP-001 in GvHD

Melbourne, Australia: Australian stem cell and regenerative medicine company Cynata Therapeutics Limited (ASX: CYP) is pleased to announce positive safety and efficacy data from a day 28 analysis of patients in Cohort B of its Phase 1 clinical trial of CYP-001, the Company’slead Cymerus™ mesenchymal stem cell (MSC) product candidate, in steroid-resistant acute graft- versus-host disease (GvHD).

Key Highlights – Cohort B Day 28 Analysis

• Overall Response rate by Day 28 was 86% (six out of seven patients treated with CYP-001 showed an improvement in the severity of GvHD by at least one grade compared to baseline)

• Complete Response rate by Day 28 was 57% (GvHD signs/symptoms completely resolved in four out of seven patients treated with CYP-001)

• Higher dose of CYP-001 administered in Cohort B elicited a faster response than the lower dose in Cohort A. By Day 28, Cohort A had a Complete Response rate of 12.5%, compared to 57% in Cohort B

• No treatment-related serious adverse events or safety concerns have been identified

• All seven patients treated with CYP-001 survived at least until Day 28

• Data support advancement of CYP-001 into Phase 2 trial

Dr Ross Macdonald, Chief Executive Officer of Cynata said: “The 28-day results for Cohort B are highly encouraging and, together with the excellent data from Cohort A, support the advancement of CYP001 into a Phase 2 trial in GvHD. Importantly, CYP-001’s strong safety profile may enable us to advance the therapy directly into Phase 2 trials in other indications beyond GvHD where there is a high unmet medical need for a consistent and scalable source of high-quality MSCs. We are evaluating our options strategically and expect to provide more details at the appropriate time.”

Eight patients with steroid-resistant acute GvHD were enrolled in Cohort B, as originally planned. Seven out of eight patients enrolled in Cohort B received two infusions of CYP-001 at a dose level of 2 million cells per kilogram of body weight, up to a maximum of 200 million cells per infusion.

All treated patients have now reached the pre-specified Day 28 endpoint. As previously announced, the clinical investigator determined that one patient in Cohort B was no longer a suitable candidate for treatment, due to a medical complication that occurred shortly after enrolment but prior to treatment with CYP-001. This patient has been excluded from analysis, as they did not receive CYP-001 treatment.

All seven patients treated with CYP-001 in Cohort B survived until Day 28. The Overall Response and Complete Response rates were 86% and 57%, respectively. In one case, the GvHD grade remained stable up to Day 21. However, the patient withdrew from the trial on Day 22 to commence palliative care.

Dr Kilian Kelly, Cynata’s Vice President of Product Development, said, “These results build on the very encouraging data from Cohort A of this trial and are particularly impressive given that all 15 patients enrolled in the Phase 1 trial had failed to respond to corticosteroid therapy, the only approved treatment for GvHD. The response to treatment is compelling, with an even higher Complete Response rate in Cohort B than in Cohort A and no safety concerns reported in either patient cohort. Moreover, the data suggest that the higher dose level has elicited a much quicker treatment response. This is important considering the severely debilitating nature of acute GvHD symptoms in many patients.”

Next Steps:

The Primary Evaluation Period will be completed when the final patient in Cohort B reaches 100 days after the first infusion of CYP-001. Cynata will announce Day 100 Cohort B data once an analysis has been completed. In view of the very encouraging results from this trial Cynata is exploring options to evaluate its Cymerus MSCs in trial in indications beyond GvHD and will provide further information to the market when appropriate.

Source: Cynata PR

_______________________________________________________________________________

Encouraging Early Safety and Efficacy Data in Cynata’s Phase 1 Trial of CYP-001 in GvHD; DSMB Recommendation to Initiate Enrolment of Second Patient Cohort

Australian stem cell and regenerative medicine company, Cynata Therapeutics Limited (ASX: CYP) is pleased to announce that the independent Data Safety Monitoring Board (DSMB) has recommended that Cynata’s clinical trial of its lead Cymerus™ mesenchymal stem cell (MSC) product CYP-001 should progress to the next stage as planned.

Key Highlights:

• All eight participants in Cohort A (lower dose cohort) have demonstrated at least a Partial

Response (defined as an improvement in the severity of GvHD by at least one grade compared

to baseline)

• No treatment-related serious adverse events or safety concerns have been identified

• DSMB recommendation to progress clinical trial to second cohort (Cohort B)

• Patient enrolment in Cohort B (higher dose cohort) now open at seven trial sites in the U.K.

and Australia

Cynata’s clinical trial, which is the first clinical trial in which patients have been treated with an allogeneic, induced pluripotent stem cell (iPSC)-derived therapeutic MSC product, consists of a planned total of 16 patients with steroid-resistant acute graft-versus-host disease (GvHD). The recommendation to progress to the next stage (Cohort B) followed an independent review by the DSMB of the eight participants in Cohort A. Recruitment for Cohort A commenced in May 2017, and there are currently seven trial sites active and ready to enrol participants into Cohort B.

Steroid-resistant GvHD patients today have a dismal prognosis, where mortality rates are very high. At this time, seven of the eight participants in Cohort A are alive. One participant died after developing pneumonia, which is a common finding in recipients of bone marrow transplants and similar procedures.1 This death was not considered to be treatment-related. Participants enrolled in Cohort A of the dose-escalation trial received a dose of CYP-001 that was anticipated to be at the lower end of the effective dose range (one million cells per kilogram of bodyweight, up to a maximum of 100 million cells per infusion). In Cohort B, a further eight participants will receive two infusions of CYP-001 at a dose of two million cells per kilogram of bodyweight, up to a maximum of 200 million cells per infusion.

Dr Ross Macdonald, CEO of Cynata Therapeutics, said, “We are thrilled to report this encouraging early review of the Phase 1 trial of CYP-001, which marks the first time that patients have been treated with an allogeneic, induced pluripotent stem cell-derived therapeutic MSC product. The improvement in GvHD grade observed in 100% of these gravely ill people is very promising, especially given the low dose administered in Cohort A. The positive DSMB recommendation is an important milestone that enables us to begin enrolment in Cohort B, and advance toward our goal of completing the trial later this year. A successful outcome will support the application of CYP-001 in many medically and commercially significant targets where therapeutic MSCs have shown promising results.”

Next Steps:

Patient enrolment into Cohort B is now open at seven active sites across the U.K. and Australia. Cynata looks forward to providing further updates to the market as the study progresses.

Ref: Cynata PR

NEW UPDATES TO TRIAL:

Cynata Reports Positive Six-Month Data from Cohort A in Phase 1 Trial of CYP-001 in GvHD

Enrolment Completed in Cynata’s Phase 1 Clinical Trial of CYP-001 in GvHD

_________________________________________________________________

Background details and references in the below "Into the light.." article to support Cynata's recently launched the 1st iPS source based Allogeneic clinical trial using iMSCs.

UK Regulatory Authority Approves Cynata GvHD Clinical Trial

• UK regulatory authority MHRA approves Phase 1 trial with Cymerus™MSCs
• World first clinical trial with allogeneic iPSC-derived product
• Major milestone for stem cell therapeutics and regenerative medicine
• Cements Cynata’s global leadership in second generation MSC therapeutics

Australian stem cell and regenerative medicine company, Cynata Therapeutics Limited (ASX: CYP) has received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA) to proceed with its Phase 1 clinical trial of CYP-001 in patients with steroid-resistant graft-versus-host disease (GvHD). CYP-001 is Cynata’s lead Cymerus™ mesenchymal stem cell (MSC) product.

Cynata plans to conduct the Phase 1 clinical trial, which is entitled “An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease”, at a number of leading clinical centres in the UK and Australia. Additional centres in other jurisdictions are also being considered. The trial will aim to recruit approximately 16 participants who have undergone a bone marrow transplant or similar procedure, and were subsequently diagnosed with steroid-resistant Grade II-IV acute GvHD.

The Company believes that this will be the world’s first clinical trial involving a therapeutic product derived from allogeneic induced pluripotent stem cells (iPSCs). 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. iPSCs have very similar characteristics to embryonic stem cells (ESCs), but without the ethical controversies associated with ESCs, since they are derived from adult cells rather than from embryos. There has been enormous interest globally in the development of iPSC-derived therapies for a number of years. This trial represents a major milestone in the field of regenerative medicine. Results from the clinical trial will provide further insight into the use of Cynata’s proprietary technology for the potential treatment of various diseases.

“We are delighted that the MHRA has approved our clinical trial. Not only does this enable us to start providing our highly promising therapy to patients with a particularly devastating disease, it also provides clear validation of our manufacturing process and preclinical development program, from one of the most highly regarded regulatory authorities worldwide,” said Cynata Vice President of Product Development, Dr Kilian Kelly.

- Cynata Commences Manufacture of Clinical Trial Product; Files Further Patent Application

Clinical grade production has begun for the upcoming human trial with a cell batch run that will be sufficient to cover all anticipated dose requirements for the safety & efficacy studies.

The company stated "manufacture of the clinical trial batch of CYP-001 was initiated following the successful conclusion of a lengthy and intensive series of good manufacturing practice (GMP) manufacturing qualification runs. These qualification runs were conducted multiple times over the course of the past year in a rigorous program which determined that product of consistent, high quality could be derived using the Company’s unique Cymerus process."

- Sistemic and Cynata announce cooperation on in-process purity assay development for Cell Therapy (CT) product.

Manufacturing a standardized cell therapy product is of utmost importance when considering a universal off-the-shelf product like Cynata's iPS source derived MSC product. As such the recent announcement of an agreement to assist in the delivery of such with a state-of-the-art test platform with Sistemic underscores the progress to market the product management team at Cynata are making.

Jim Reid, Chairman and CEO of Sistemic said “The CT industry holds much promise in so many ways for patients who have untreatable conditions, but the need for standardisation and industrialisation are big challenges the industry has not yet overcome. The combination of the technologies from two of the industry’s leading companies in trying to solve these scalability and reproducibility problems will undoubtedly enhance the speed of clinical development and subsequent uptake into clinical practice. By combining the strength of Sistemic’s technologies and understanding of the biology of cells together with the wide range of attributes of Cynata’s Cymerus technologies we see this collaboration as potentially transformational for the industry as a whole, and would represent a step change in the industrialisation of the sector.”

- Cynata Enters License Option Agreement with apceth GmbH & Co. KG

Collaboration with apceth in Germany has developed further for Cynata with the signing of a License agreement to formalize the previously announced product research understanding. The deal terms remain sealed for the moment but the upside potential is officially noted and the gene modification of Cynata's iPS derived MSC product will potentially result in a number of bespoke derivatives with apceth taking the lead on development.

“The combined technologies of Cynata and apceth provide a powerful solution that significantly expands the range of therapeutic applications for MSCs. Through the apceth-engineered enhancements of our Cymerus MSCs we expect to see the development of new treatments that were previously not appropriate for MSCs, one of the most promising and fastest growing areas of medicine today. Outside of the arrangement with apceth Cynata remains free to develop all other applications of its technologies,” said Dr Ross Macdonald, Chief Executive Officer and Managing Director at Cynata.

Cheers

_________________________________________________________________

Into the Light with Induced Pluripotency:

Cynata & the Promise of Next Gen MSCs

Some say that the best time to be awake is when the sun rises and the brightness of the morning light powers the imagination and drives the body forward into the day. The dawn speaks to the possibilities and can do attitude of natural cycles. Fortunately this is a constant aspect of life force renewal present everywhere and in all things – even inside our own bodies.

Stem cells by their very definition are replicating entities and as we develop and age those cellular constructs we rely on to function require replacement – the efficiency of such a fundamental process is where the difference lies between defined adult cells, of the various types in our bodies, and the uniquely potent early stage pluripotent cells that have the ability to indefinitely replicate and create any tissue of the body. This is the constant never ending cell source that can be born anew every day exactly alike indefinitely and provide the light of origin renewal in an otherwise determined and limited cellular state.

This step forward in translational technology from variable adult tissue sources for cellular therapies to renewable banks of potent master cells is an empowering generational shift using state-of-the-art molecular science. A progression that was driven by lab ingenuity unlocking human biology and improving on standards of downstream process that define existing cell products.

I recently chatted on this topic with Dr. Ross Macdonald CEO of a seemingly under the radar Australian iPSC therapeutics company called Cynata, an early mover in the evolving induced pluripotent space. Ross was kind enough to walk me through the history and plans the company has on developing and launching next generation mesenchymal stem cells (MSC) products.

EcoQuest to Cynata Therapeutics

EcoQuest was the forerunner of Cynata and was created as an Australian medical hygiene company developing bioengineered health products. In 2013 it merged with the newly formed Cynata and renamed itself. The founding partners had identified the opportunity to move into pluripotent regenerative medicine and secured the exclusive license to the University of Wisconsin’s patented process via Cynata for establishing and manufacturing for therapeutic use MSCs from induced pluripotent stem cells (iPSCs) via a key intermediate cell called a mesenchymangioblasts (MCAs). They changed their original corporate strategy and have since focused on developing the business as a therapeutics company.

The method of creating MCAs from pluripotent precursors was discovered in Professor James Thomson’s lab by scientists Professor Igor Slukvin, Dr. Maksym Vodyanik and Dr. Junying Yu. This was a progressive step from the early work of Professor Thomson at the university on human embryonic stem cells. This leading edge work led to applying that knowledge to establishing proprietary techniques for creating induced pluripotent stem cells and specific cell type derivatives. The commercial result of which was the redirection of the company Professor Thomson and the university had launched, Cellular Dynamics International, as an iPSC based services facility (now a FujiFilm company). A few years after iPSC technology was established as a new pluripotent platform the team discovered MCAs and the university’s IP management division WARF patented the invention and subsequently licensed the technology to Cynata, which has since developed the strategy to productize and commercialize the platform in collaboration with the Wisconsin team’s cell line manufacturing expertise. Professor Slukvin is a co-founder of Cynata and maintains a role with the company as a member of Cynata’s Scientific Advisory Board.

Generational Step Forward Technology

Given iPSCs are a newer pluripotent source than human embryonic stem cells clinical programs based on this reprogramming technology are just now entering human trials for proof-of-concept safety studies. As with all such medical translation pre-clinical data is important to ensure the first trial efforts are solidly grounded prior to clinical trial commencement. Safety data provided the pioneering work in the field in

Japan

with the green light to commence first human application of iPSC technology in a clinical trial setting with patient results indicating safety & tolerance, albeit in only a limited context. Safety continues to be of paramount importance with the preparation for adoption of a Japanese allogeneic iPSC cell bank source moving forward. Similarly Cynata’s pre-clinical data and safety studies have been indicated as appropriate by the regulatory authorities in the UK , with additional ongoing 3rd party work due to be presented shortly, establishing the basis for final approval and commencement of a planned human clinical trial.

With regard to animal models, Ross Macdonald mentioned that large animal studies are not being required in Europe for their pre-clinical data and that animal models by nature are “not ideal indicators of method of action” for human cells.

1st Allogeneic iPSC Human Trial

If all goes according to plan Cynata’s MCA product is anticipated to be the first allogeneic iPSC cell therapy to be trialed in humans, ahead of the restart of the Japanese iPSC AMD study later this year.

Cynata’s MCA product utilizes a xeno free process produced at the clinical grade good manufacturing facility of Waisman Biomanufacturing in Madison, Wisconsin under the supervision Cynata’s US scientific colleagues. Purity, potency and stability assays are said to be proprietary and state-of-the-art. The product will be shipped worldwide from source for the trials.

A Low Hanging Fruit Strategy

The proof-of-concept treatment indication chosen to start by Cynata is Graft versus Host Disease (“GvHD”) – a target where there are already two high profile bone marrow derived adult MSC product programs, one already approved as a stem cell therapy, Prochymal/Temcell, in Canada and Japan respectively. In addition, there are also literally hundreds of other adult tissue derived MSC therapeutics in various stages of clinical development with solid safety data (see a recent review paper of GvHD data here). Cynata’s approach reflects a step forward in the product manufacturing process pioneered by these 1^st generation MSCs programs derived from adult donor tissue sources by such companies (see my recent blog review on 1^st generation MSCs here).

The planned trial will be undertaken in the

UK, and potentially in

Australia

also, as per the latest feedback from Ross. Enrollment is due to start by the end of the 2^nd quarter this year, pending finalization of site details and the necessary regulatory approvals.

Ross best describes Cynata’s current phase of their business plan as leveraging proof-of-concept by “proving iPSC-derived MSCs in a low-hanging-fruit indication” to then drive additional territorial partnership deals for the MCA platform and proceed to market through partnership driven indications.

He mentioned that the current lack of definitive success stories in the adult MSC sector has led to the risk of “throwing the babies out with the bathwater” when there is great value in the data foundation established, with safety and efficacy signals evident in a number of leading donor derived programs.

However, as the sector has appreciated, and importantly the regulators are very much aware of, the variability issues of donor sources are challenging. Ross paraphrased the FDA stating their observations to-date have suggested that “there is work to be done here” with regard to standardization. They and others, including pharma and investors, are looking to the stem cell field to address these translational issues through the adoption of greater uniform controls, quality assays and predictable process methodologies. This evolution from a cottage research business to an industrial sector speaks to overcoming this important hurdle on the road to sustainable growth for the entire stem cell field.

The point Ross and Cynata are making is clear, by switching to a replicable pluripotent source the variability weakness of batch to batch MSC donor products will be solved for therapeutic applications requiring large volumes of standard products for off-the-shelf applications. Second generational improvements in MSC therapeutics will in turn meet the strictest criteria for regulatory acceptance of uniform manufacturing and mass market adoption will follow with consistent data.

Cheers

REFS:

Cynata Current Partnerships:

TheClinical Trial Company – Clinical Research Organization (CRO) contracted tomanage Cynata’s GvHD study.

Cellular Dynamic International –iPS master cell line partner

WaismanBio – iPS MCA product manufacturing partner

Germany – Cancer usingengineered MSCs as a delivery vehicle with apceth GmbH

Japan –GvHD and other indications to be decided with Regience KK

Australia– Cardiac research with the University of Sydney

USA –Cancer using engineered MSCs as a delivery vehicle with Dr. Khalid Shah andHarvard/Mass General

WuXi AppTec CRO for pre-clinicaldata

Cynata (“CYP” on the Australian AMX exchange) - Investor Coverage: