MSCs rising

If you ever meet Silviu Itescu, don’t bring up “looming potential” in relation to mesenchymal stem cell therapies.

“This is a here and now therapy. Without treatment, steroid-refractory acute graft versus host disease is 70-90% fatal. Ryoncil demonstrates unquestionably that this type of off-the-shelf, allogeneic cell therapy can be delivered safely and effectively. The therapy fills a much-needed treatment gap, and we’re out there working with clinicians and hospitals to make it available,” says the Mesoblast founder and CEO.

Point taken.

For Australia-based Mesoblast, the U.S. FDA’s December 2024 approval of Ryoncil (remestemcel-L) — a mesenchymal stromal/stem cell (MSC) therapy for the treatment of steroid-refractory acute graft versus host disease (SR-aGvHD) in pediatric patients — was a testament to the company’s tenacity and scientific rigor.

“There’s no question that MSCs have had promise for a long time. This is not a brand-new technology. It took a lot of investment and effort, but the truth is that’s what you have to do if you want to commercialize new technologies that tackle big problems,” says Itescu. “And I think the message is that it has taken 20 years of great science to bring the first MSC product to the U.S. market.”

In addition to strong science and two decades, it took three BLA review cycles.

For the broader CGT community, the FDA’s recognition of an MSC therapy’s efficacy and safety was a watershed moment — and even, a taste of redemption.

“I’m happy to see it because it shows the evolution and maturity of MSCs. These cells have come a long way. They had a troubled growth period and are now finding their rightful place,” says Miguel Forte, MD, Ph.D., president of the International Society for Cell & Gene Therapy (ISCT) and CEO of Kiji Therapeutics. “And it’s a little bit of retribution. It takes away the doubt from those who said, ‘MSCs are a good attempt but they’re never going to make it.’ Well, they made it — there is a delivery, a product and a benefit being brought to patients.”

For Forte, the vindication of MSCs hits close to home. Founded by Paris-based VC firm AdBio Partners in 2023, Kiji is developing engineered cell therapies using both adipose-derived and induced pluripotent stem cell (iPSC)-derived MSCs for inflammatory diseases including SR-aGvHD — a next-generation effort that the company hopes will help continue to fulfill the long-standing promise of MSCs.

Mesoblast made history with Ryoncil, marking the first MSC therapy, as well as the first off-the-shelf allogeneic cell therapy, approved by the FDA. Globally, 12 MSC therapies have received approval — a significantly small number, given the time and attention that has been spent chasing their therapeutic promise over the course of several decades.

MSCs’ ability to home to damaged tissue and differentiate into various cell types, as well as their immunomodulatory and regenerative properties, have long made them the darling of cell therapy researchers, propelling them to become one of the most clinically studied cell types in the world. But despite the proliferation of studies, MSCs have frequently fallen short of expectations.

“MSCs were one of the first cell therapy candidates and there were huge hopes put on them — and they weren’t delivering. There was a lot of back and forth in clinical trials, trying to find the best niche way to extract their potency,” says Forte. “At the same time, the cell therapy field evolved. MSCs were the cell therapy pioneers but unfortunately, they were overtaken by other technologies.”

With MSCs back in the spotlight and a pipeline of mid- and late-stage candidates pushing toward regulatory submission, what looms now is not a question of whether MSCs can deliver, but the challenge of turning decades of insights and technology advancements into the next generation of commercialized cell therapies.

Addressing burning CMC issues

As any drug developer will attest, it’s a long road from preclinical studies to marketing approval — and some of the toughest terrain to navigate is chemistry, manufacturing and controls (CMC). A standard component of INDs and BLAs, CMC data needs to assure uniform safety, identity, quality, purity and strength of the investigational product.

For CGTs, the FDA recommends using critical quality attributes, such as potency, to help demonstrate that a product is being manufactured consistently over time. But cell product heterogeneity, aka lack of uniformity, has been a major barrier to MSC clinical use. Sourcing MSCs from donors introduces intrinsic biological variability, and the process of expanding the cells and banking them can introduce extrinsic variabilities.

Ultimately, regulators want proof that developers have control over their processes and products.

Mesoblast experienced firsthand the rigor of FDA CMC requirements. Prior to winning approval for Ryoncil, the company received two complete response letters, one in 2020 and a second in 2023, requesting clarification on outstanding CMC deficiencies, including providing proof of potency.

“The FDA was looking to make sure that we understood how to make a consistent, reproducible product and that we had the potency assays that guarantee that every batch released has the same clinical efficacy as the prior batch,” says Itescu. “It took a while to get the FDA over the line. Being the first has a lot of negatives because you don’t have any comparators.”

After working closely with the FDA, Mesoblast was able to implement new potency assays and establish that it was measuring product attributes related to therapeutic effect. Ryoncil’s approval letter also includes post-marketing commitments linked to the development of additional assays to evaluate product and process comparability and stability.

Recognizing the complex CMC challenges of MSC therapies, some developers are looking to tackle these issues early by capitalizing on advanced gene editing tools to engineer MSCs with improved qualities — helping to overcome limitations that have historically held these therapies back.

Kiji’s first preclinical product, KJ01, is an adipose-derived MSC transduced with a lentiviral vector conferring stable expression of IL-10, a cytokine with potent anti-inflammatory properties and CXCR4, a surface protein involved in cell migration to inflamed sites. Building on previous industry clinical trials that have shown MSCs’ ability to modulate GvHD, Kiji is seeking to improve the anti-GvHD effect of these cells.

“MSCs were the cell therapy pioneers but unfortunately, they were overtaken by other technologies.”

— Miguel Forte

Kiji’s platform optimizes MSCs to be more potent and more targeted — and makes that quantifiable.

“Kiji and others are looking at potency using a defined measurement, which gives us the ability to show crystal clear potency. For example, measuring the amount of IL-10 being produced provides an indication of the potency of the cells. This gives us a very specific measurement connected to the product, the action and the benefit,” explains Forte. “This is now possible because the industry is more knowledgeable and has better tools for cell characterization measurement.”

Massachusetts-based Ernexa Therapeutics (formerly Eterna) is also banking on advanced technologies to optimize the therapeutic properties of MSCs. The company uses mRNA reprogramming and gene editing technologies licensed from Factor Bioscience to induce pluripotent stem cells to transform into MSCs, which are then engineered to express certain cytokines.

The company is developing its lead preclinical asset, ERNA-101, in platinum-resistant ovarian cancer. ERNA-101 secretes two potent proinflammatory cytokines: IL-7 and IL-15. These two cytokines are known to help T cells proliferate, infiltrate into tumors and prevent premature exhaustion. Not only can this method enhance the cells’ immunomodulatory capacities, but it also offers a more consistent, reproducible product.

“These iPSC-derived MSCs are very homogeneous. They are similar in many functional aspects to bone marrow MSCs, but they are very uniform. That’s a huge advantage,” says Ernexa scientific and medical advisory board member Michael Andreeff, MD, Ph.D.

Prior to teaming up with Ernexa, Andreeff, currently a professor of medicine at the University of Texas MD Anderson Cancer Center, had spent over two decades conducting MSC research, including pioneering the use of gene-modified MSCs as a potential cancer therapy. The technology used by Ernexa quickly won him over.

“I’ve spent a lot of time working in this field and when the Ernexa team approached me I realized their platform is a much better system in terms of cell of origin, MSC generation and the gene transfer technology,” says Andreeff. “The technology doesn’t even need plasmids. I have $80,000 worth of plasmid in my back pocket, paid for with my retirement account, which is useless,” he laughs.

Ernexa’s licensed technology uses mRNA to reprogram cells into iPSCs, rather than a more traditional method of using plasmids. This leads to more efficient reprogramming and purer, more uniform cells.

“Manufacturing consistency and potency remain critical hurdles in cell therapy. Our approach is designed to overcome these from the outset — not by adjusting after the fact, but by building consistency into the earliest stages of cell development,” says Sanjeev Luther, Ernexa’s president and CEO.

By confronting CMC challenges head-on — challenges brought into sharp focus by Mesoblast’s pioneering efforts with the FDA — developers are proving that it’s possible to meet regulatory expectations while also further advancing the science.

“It took a long time for Mesoblast because they were breaking ground. Now that we’ve learned from it, we can go on to the next iteration really cashing in on their efforts and knowing exactly how to address those challenges beforehand,” says Forte.

Trial by fire

According to Forte, MSCs have suffered from high — and likely, exaggerated — expectations.

Nowhere is this more evident than in regenerative medicine — a field where legitimate science is constantly up against overhyped, unsubstantiated claims. Aging populations and increasing prevalence of degenerative and chronic diseases have driven demand for regenerative treatments sky high. On the extreme end, cell therapies have suffered from bad actors eager to cash in on these unmet needs, hawking unproven stem cell ‘cures’ for everything from skin conditions to death itself.

Itescu credits the FDA with developing “fair, safe and reasonable” standards for MSC therapies.

“The FDA has laid out very clearly what they want to see from a consistent, safe and effective product. We are working closely with them, and I think all industrial organizations should do the same. This is particularly important at a time when there’s a lot of noise about cell therapies in various countries being made available for tourism,” says Itescu.

For Mesoblast, aligning with U.S. regulatory expectations hinges on robust trials and careful patient selection.

Because MSCs’ mechanisms of action are dependent on various factors — such as the target disease or the tissue source — developers need to choose metrics that can help identify patients who are more likely to benefit from a MSC therapy.

Mesoblast leveraged inflammatory biomarkers as one way to define the ideal patient population for Ryoncil. In a subgroup analysis of a phase 3 trial in children with aGvHD, the company used Mount Sinai Acute GvHD International Consortium algorithm probability (MAP) scores — validated biomarkers that can measure the degree of damage to the lower GI tract caused by GvHD and identify those patients at highest risk of death. The analysis demonstrated 67% survival with Ryoncil versus 10% survival with a matched group of children with similarly high MAP scores.

This focus on patient stratification reflects a broader reality in the CGT space, where the rarity of target indications often shapes trial design. Ultra rare diseases with small patient populations can make large, randomized trials unfeasible or unnecessary. Single-arm trials, in which all participants receive the same treatment being studied, have become a common model in cell therapy.

For Mesoblast, the FDA’s long-standing preference for randomized controlled trials (RCT) was an initial sticking point in the company’s first two review cycles for Ryoncil (despite the agency having initially guided the company to perform a single-arm trial in desperately ill children with severe aGvHD, says Itescu). In both CRLs, the agency recommended that Mesoblast conduct at least one additional RCT to provide further evidence of the effectiveness of Ryoncil, but then ultimately accepted Mesoblast’s multicenter, single-arm study in pediatric SR-aGvHD as sufficient for approval, following the company’s demonstration of durable treatment effect and long-term survival in five-year follow-up studies.

But as MSCs look to bridge into larger indications, they will likely require the backing that comes from RCTs.

“We are taking a leap into some big unmet needs and we’re going to tackle them the right way, with the appropriate randomized controlled trials to show we can make an impact,” says Itescu

Mesoblast has performed studies in adults with biologic-refractory Crohn’s disease, a condition that is estimated to affect up to 120,000 U.S. patients. Based on data from the adult studies and the extensive safety data it has generated in children, Mesoblast intends to pursue a label-extension study in children with biologic-refractory Crohn’s disease, where there are far fewer options.

The company is also advancing phase 3 RCTs for its second generation therapy, Revascor (rexlemestrocel-L) in chronic back pain and ischemic heart failure with reduced ejection fraction. Both have the potential to be blockbusters, targeting two conditions that affect millions of Americans.

“This is a field that has suffered from lots and lots of small studies and unsubstantiated claims. And I think this is a time to really focus on large studies that provide evidence-based outcomes,” says Itescu.

Korea-based Medipost, Co. has spent years building evidence for its flagship product, Cartistem, and is now preparing to launch U.S.-based phase 3 trials. The therapy consists of allogeneic umbilical cord blood-derived MSCs, injected into the knee through a surgical procedure. It has been marketed in Korea since 2012 for treating knee cartilage defects in patients with osteoarthritis. To date, Cartistem has been used by more than 32,000 patients.

According to Edward Ahn — who joined as CEO of Medipost, Inc., the U.S. subsidiary of Medipost, Co. in 2022 — preparing Cartistem for its U.S. debut has required careful navigation of the regulatory landscape. Medipost has worked closely with the FDA over several years to build out a regulatory framework and finalize trial protocols. Concurrently, the company has been building infrastructure with clinical sites across the U.S. and Canada.

In addition to understanding the needs of regulators, Ahn says the company also spent time understanding the requirements — and expectations — of doctors, patients and payers when it comes to MSC therapies.

Following the completion of a phase 1/2a clinical trial in the U.S., Medipost is now preparing its IND to initiate a phase 3 study, which it aims to launch by the end of 2025. In parallel, Medipost’s parent company is wrapping up patient treatment in a phase 3 trial in Japan.

“We have multiple phase 3 studies against multiple different controls in three different regions of the world — plus 10 years of real-world evidence. Coming to market with so much supportive data is such a blessing,” says Ahn.

He credits South Korea’s supportive regulatory and business environments for giving the company the time it needed to collect data and build a strong case for Cartistem’s benefit to patients.

“If we started in the U.S. there would be a lot of pressure to develop as quickly as possible and commercialize, whereas the regulatory regime and financial support in Korea has created a great environment to foster the development of this particular type of therapy and then let it incubate and grow,” says Ahn. “But now the world deserves access.”

Igniting scale

To tackle large indications, MSC developers must design manufacturing processes that scale safely and efficiently.

While scalability is known hiccup in autologous cell therapy manufacturing, many MSC therapies have the benefit of being allogeneic, relying on starting materials from healthy donors. What’s more, many of these therapies are being developed as ‘off-the shelf’ products, meaning they can be manufactured in advance, cryopreserved and administered to patients on demand.

“A big advantage of allogeneic MSCs is that we’re able to do everything in a scaled up, consistent way that is very difficult to do with autologous products that involve patient-to-patient changes,” says Itescu.

But still, predicting biological activity in MSCs remains an ongoing challenge — one that can be amplified as cells are scaled for manufacturing. MSCs in culture cannot expand indefinitely, which means developers must regularly create new donor cell banks. Deriving batches from different donors or expanding cells using different tissue culture conditions or durations can affect the quality of MSCs.

These broad concerns about the scalability of donor-derived, culture-expanded MSCs were brought up during Mesoblast’s initial Oncologic Drugs Advisory Committee meeting, with the committee emphasizing the need for proof that Mesoblast’s product would not become less effective as it was scaled.

“The FDA has laid out very clearly what they want to see from a consistent, safe and effective product. We are working closely with them, and I think all industrial organizations should do the same.”

— Silviu Itescu

According to Itescu, over the course of Ryoncil’s development, Mesoblast made considerable efforts to improve its cell manufacturing process, and these advancements significantly reduced product potency variability between production lots. In a recent ISCT North American Town Hall, Itescu said that following optimization of the manufacturing process, 100% of Ryoncil product lots meet the FDA-required potency standards for commercial release. In contrast, the predecessor product to Ryoncil (called Prochymal) had substantially lower potency, with more than 30% of lots failing the rigorous potency assays.

Another option to produce a more controlled, reproducible scaled-up product is to start with MSCs derived from iPSC lines. In this scenario, the engineered MSCs have a single source (the iPSC line) that can be well-characterized.

“We believe the future of MSC therapies lies in starting with a consistent foundation. By deriving our MSCs from iPSCs and applying an allogeneic, synthetic platform to program their function, we’re able to achieve high purity and reproducibility — two qualities that have historically challenged this field,” says Ernexa’s Luther.

This approach can also lead to cost reductions.

“MSCs are usually grown in hypoxia because they originate from bone marrow, which is naturally low oxygen. iPSC-derived products don’t require hypoxia because they come from very primitive cells. So it’s easier — and cheaper — to manufacture,” says Andreeff.

Ernexa’s ERNA-101 aims to address a critical unmet need: Ovarian cancer lacks targeted treatments and has a high recurrence rate, with advanced disease resulting in 13,000 deaths per year in the U.S. Ernexa is proactively planning for scale, with preparations underway for an upcoming FDA meeting to get feedback on its manufacturing process.

Eyeing manufacturing efficiencies, Kiji is developing its second-gen allogeneic assets on an iPSC platform as well, with the company initially targeting inflammatory bowel disease, psoriasis and CNS disorders.

“iPSC sourcing allows us to differentiate the MSCs from a cell line that expands indefinitely. It will make the cost of goods significantly lower, which will make the products — which are already easy to use because they’re off-the-shelf — even more competitive in terms of cost,” says Forte.

Next-gen on the rise

The innovation and refinement in MSC development is ongoing, reflecting the quick pace of technology growth in the industry.

While Ryoncil is built on the Mesoblast’s first-generation platform, Revascor utilizes the company’s next-gen technology. The allogeneic therapy uses monoclonal antibodies to isolate mesenchymal precursor cells (MPCs), the earliest precursors of the mesenchymal cell lineage in adult tissues, which are then expanded in culture without differentiation — meaning their multipotent potential is preserved for future therapeutic use.

According to Itescu, Revascor is an extension of the foundation established with Ryoncil.

“We’ve adapted all of our learnings from Ryoncil to present to the FDA our intended approaches for commercial manufacturing, which focus on ensuring batch-to-batch consistency and maintaining product potency,” says Itescu.

Mesoblast recently announced that it has aligned with the FDA on key items for Revascor’s BLA filing in ischemic heart failure, including CMC, potency assays for commercial product release, and proposed design for a confirmatory trial if accelerated approval is obtained.

In Korea, Medipost has a second-gen cord blood-derived MSC platform under development for an injectable treatment for osteoarthritis and an infused treatment for diabetic nephropathy, a progressive kidney disease. The tech combines advanced cell selection with a proprietary culture method for retaining and enhancing optimum stem cell characteristics, facilitating ultra-potent, large-scale culture expansion, with the end product being cord blood-derived MSCs with higher efficiency and lower cost.

The adaptability of MSCs means that once companies have proven their technology, the door is open for exploration in a wide array of disease indications.

“Because these cells are easy to work with, we’ve documented their safety, and we now know how to gene engineer them for a specific function, they’ve become a significant platform to use for quite a few large indications,” says Forte.

While the first U.S. approval of an MSC therapy may have quieted talk of looming potential, it appears we are only at the start of the field’s ascent.

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