PERTH, Australia – Melbourne-based regenerative medicine company Cynata Therapeutics Ltd. is gearing up to take its Cymerus mesenchymal stem cell (MSC) product candidate, CYP-004, into a phase III trial in osteoarthritis.

The trial is sponsored by the University of Sydney and funded by an Australian Government National Health and Medical Research Council (NHMRC) competitive project grant.

“The trial was a goldmine that dropped in our lap. Not only do we not have to pay for the trial but now it’s a phase III trial and in a very large patient population,” Cynata Therapeutics CEO Ross Macdonald told BioWorld.

Ross Macdonald, CEO, Cynata

“We’re the only company in the world that has completed a study in mesenchymal stem cells derived from induced pluripotent stem cells,” he said, adding that the phase III trial puts Cynata ahead of the pack.

“The unusual thing about this program is that it’s actually not our trial; it’s being sponsored by the University of Sydney. That’s why the NHMRC is financing it, which is the peak funding body for research and development in medicine in Australia.”

Because Cynata had compelling safety and efficacy data from a phase I study in graft-vs.-host disease (GVHD), it was prepared to launch a phase II study in osteoarthritis. The principal investigator, David Hunter, had strong evidence that a good MSC product could be effective in osteoarthritis, “and you put the two together and suddenly you have a phase III trial.”

Australia’s Therapeutic Goods Administration (TGA) has confirmed that the phase III trial of CYP-004 can be conducted under the notification-only CTN scheme, which requires submission of a notification to the TGA, as opposed to the formal review and approval process required under the CTX scheme.

Macdonald said the trial all came about through a longstanding interest of Hunter, who is an orthopedic surgeon in Sydney and who has been investigating the potential utility of mesenchymal stem cells in osteoarthritis.

“He has always been challenged by the variability of the products he gets his hands on, and this product inconsistency is the major impediment ultimately to the commercialization of MSCs,” Macdonald said.

“Because Professor Hunter had been using all sorts of different products from different sources, he was ending up with different results, because the products come from different donors.”

Other researchers have complained about variability in results due to the inconsistency of other MSC products, he said, and Hunter approached Cynata because he “believed our product was the gold standard in MSCs” and could prove whether they work in osteoarthritis.

Induced pluripotent stem cells = secret sauce

What differentiates Cynata’s stem cell product from its competitors, Macdonald said, is that its MSCs are derived from induced pluripotent stem cells (iPSCs), and most stem cell companies rely on multiple donors to donate either bone marrow or adipose tissue as their primary tissue sources.

Cynata’s Cymerus MSC therapy comes from a single donor and can be produced in limitless quantities, giving it the potential to create a new standard. The platform technology is based on versatile stem cells known as mesenchymoangioblasts (MCAs), which are a precursor of mesenchymal stem cells.

“Relying on lots of donors is not a very practical solution for an industrialized process, and MSCs, when cultured, tend to lose their potency as those cultures expand,” Macdonald said.

“Our technology uses iPSCs as starting material, and the admit of iPSCs has opened up many doors in medicine. It allows us to have an infinite quality of consistent starting material. This is impossible if you are using different donors,” the CEO said.

“There’s no effective treatment for osteoarthritis, and products just mask the pain, and patients want to delay surgery, so they often turn to opioids.”

Cynata’s product could genuinely alter the progression of the disease and even put off the need for knee or hip replacement, he said.

The phase III trial will assess the effect of Cymerus MSCs compared to placebo on clinical outcomes and knee joint structure over a two-year period, in 440 patients with osteoarthritis of the knee.

Preclinical research has shown that MSCs can exert a number of important effects that may improve outcomes in patients with osteoarthritis, including release of cytokines and growth factors that reduce inflammation and promote tissue repair, new blood vessel formation, and regeneration of compromised cartilage.

The trial will take place at study centers in Sydney and Tasmania and will be led by Hunter, the Florance and Cope Chair of Rheumatology and professor of Medicine at the University of Sydney. Cynata will supply Cymerus MSCs for the trial, but it won’t be required to contribute any cash to fund the project.

The trial will be a randomized, double-blinded placebo-controlled design. Participants will receive intra-articular injections of Cymerus MSCs or placebo three times over a period of one year, and they will be followed up two years.

The co-primary endpoints are the proportion of participants achieving patient-acceptable symptom state (PASS) for knee pain at 24 months; and central medial femorotibial cartilage loss from baseline to 24 months. Secondary outcome measures will include assessments of pain, other symptoms, physical function and quality of life.

Cynata’s lead product candidate, CYP-001, met all clinical endpoints and demonstrated positive safety and efficacy data for the treatment of steroid-resistant acute GVHD in a phase I trial.

Following the phase I trial, Fujifilm Corp. exercised its option to license CYP-001 in a $43 million global licensing deal that granted global rights to Fujifilm to develop and commercialize CYP-001 in GVHD. The product is in a phase II trial in Japan.

Cynata is also studying the utility of its Cymerus MSCs as a treatment for acute respiratory distress syndrome (ARDS) associated with COVID-19 with the Critical Care Research Group at Prince Charles Hospital in Brisbane.

The study will investigate Cymerus MSCs as a treatment for ARDS, in combination with extracorporeal membrane oxygenation (ECMO). ECMO circulates blood through an artificial lung, oxygenating the blood before putting it back into the bloodstream of a patient. ECMO has emerged as a treatment adjunct to support the vital organs in patients with severe ARDS, which can provide short- to medium-term mechanical pulmonary support.

In addition, Cynata plans to advance its Cymerus MSCs into phase II trials for critical limb ischemia (CLI). A phase II trial in CLI was to be launched earlier this year but was delayed due to the COVID-19 pandemic.

The company has MSC products in preclinical models of asthma, diabetic wounds, heart attack, sepsis and cytokine release syndrome.

Cynata has a market cap of AU$73 million (US$40.48 million), and its shares on the Australian Securities Exchange (ASX:CYP) were trading at AU63 cents as of market close on June 24.

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