Aisha Khan, PhD, MBA
University of Miami Miller School of Medicine
USA
FDA’s Approval of Ryoncil: A Milestone for MSC Therapy or Just the Beginning?
The U.S. Food and Drug Administration (FDA) has approved Ryoncil (remestemcel-L-rknd) as the first-ever mesenchymal stromal cell (MSC) therapy for the treatment of steroid-refractory acute graft-versus-host disease (SR-aGVHD) in pediatric patients. This landmark decision marks a turning point in regenerative medicine and cell-based therapies, paving the way for broader applications of MSCs in treating immune-related disorders. However, the approval also raises critical scientific, regulatory, and clinical questions about the future of MSC-based treatments.
A Long Road to Approval for MSC Therapy
Despite the vast potential of mesenchymal stromal cells (MSCs) in modulating immune responses and promoting tissue repair, FDA approval for MSC-based therapies has been notoriously difficult to obtain. Ryoncil, an allogeneic MSC product derived from donor bone marrow, is the first MSC therapy to clear regulatory hurdles in the United States.
The approval is based on data from a multicenter, single-arm study in 54 pediatric patients, where 30% achieved a complete response and 41% showed partial improvement. These results highlight the promise of MSC therapies, even in challenging, life-threatening conditions like SR-aGVHD.
Given the complexity of standardizing MSC products, particularly in ensuring potency, consistency, and reproducibility, this approval could set an important regulatory precedent for future stem cell-based therapies.
Key Milestones in Ryoncil’s Journey:
Here is the timeline of Ryoncil's development and regulatory status milestones:
- 2013-2015: Mesoblast conducted early-phase clinical trials to assess the safety and efficacy of remestemcel-L in pediatric patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD).
- April 2020: The FDA accepted Mesoblast's Biologics License Application (BLA) for Ryoncil, granting it Priority Review status.
- August 2020: The FDA's Oncologic Drugs Advisory Committee (ODAC) voted in favor of approving Ryoncil for SR-aGVHD in children.
- September 2020: The FDA issued a Complete Response Letter (CRL), requesting additional data to support the efficacy of Ryoncil.
- March 2023: The FDA accepted resubmission for pediatric GVHD, providing long-term survival data spanning at least four years on top of additional data obtained from high-risk patients
- August 2023: The FDA rejected the application and requested additional data from adult patients to support the efficacy of remestemcel-L in treating aGVHD, despite positive results seen in pediatric trials
- March 2024: FDA informed that clinical data from the phase 3 MSB-GVHD001 trial (NCT02336230) is sufficient for BLA submission for remestemcel-L in children with SR-aGVHD
- July 8, 2024: Mesoblast resubmitted the BLA for Ryoncil, addressing the FDA's previous concerns, particularly regarding Chemistry, Manufacturing, and Controls (CMC) aspects.
- December 18, 2024: The FDA approved Ryoncil (remestemcel-L-rknd) for the treatment of SR-aGVHD in pediatric patients aged 2 months and older, marking the first approval of a mesenchymal stromal cell therapy in the United States.
This timeline highlights the rigorous process, underscoring its significance in advancing regenerative medicine.
Key Concerns and Considerations
1. Manufacturing and Variability in MSC Therapies
One of the biggest challenges in the clinical translation of MSCs has been batch-to-batch variability. MSCs are highly responsive to their microenvironment, meaning that their immunomodulatory properties, viability, and functionality can vary depending on donor source, culture conditions, and expansion methods.
The FDA’s approval of Ryoncil despite its variable response rates raises an important question: Will future MSC therapies require more stringent potency assays to ensure consistent patient outcomes?
2. Safety and Long-Term Risks
While this approval is a monumental achievement, it also reinforces the importance of rigorous safety monitoring. The FDA’s guidance on infusion reactions, hypersensitivity, and ectopic tissue formation highlights the need for careful patient selection and clinical oversight.
Fortunately, advancements in GMP manufacturing, quality control, and standardization of MSC therapies continue to evolve, making the future of cell therapy more promising than ever.
Additionally, the lack of a placebo-controlled study in the approval process for Ryoncil could prompt future discussions about more rigorous clinical trial designs for MSC-based therapies.
3. Implications for Expanded Access and Future Approvals
The approval of Ryoncil for SR-aGVHD could pave the way for expanded access programs and additional clinical trials exploring MSCs for other inflammatory and autoimmune conditions, such as:
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- Acute respiratory distress syndrome (ARDS) (previously explored for COVID-19)
- Multiple sclerosis and neuroinflammatory diseases
- Cartilage and joint regeneration in osteoarthritis
- Hypoplastic Left Heart Syndrome
- Alzheimer’s Disease
- Aging Frailty
With several MSC-based therapies already in late-stage clinical trials, will the FDA’s approval process for MSCs become more streamlined, or will each therapy continue to face regulatory roadblocks?
Final Thoughts: Progress, But Not Perfection
The FDA’s approval of Ryoncil is a historic milestone for cell-based regenerative medicine, reinforcing the therapeutic potential of MSCs. However, scientific, clinical, and regulatory hurdles remain.
For researchers and clinicians in the cell and gene therapy and regenerative medicine fields, this approval is both an opportunity and a challenge, it validates MSCs as a treatment platform while also highlighting the complexities of standardizing and regulating living cell therapies.
As more MSC-based therapies enter the pipeline, continued research, rigorous clinical trials, and regulatory adaptability will be essential to fully unlock the potential of MSCs in treating complex diseases.
References:
U.S. Food and Drug Administration. FDA Approves First Mesenchymal Stromal Cell Therapy to Treat Steroid-Refractory Acute Graft-Versus-Host Disease. Published December 18, 2024. Accessed [Month Day, Year]. https://www.fda.gov/news-events/press-announcements/fda-approves-first-mesenchymal-stromal-cell-therapy-treat-steroid-refractory-acute-graft-versus-host.
U.S. Food and Drug Administration. Ryoncil (remestemcel-L-rknd). Updated 2024. Accessed on February 02, 2025. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/ryoncil.
Mesoblast Ltd. Mesoblast Investor Presentation – FDA Advisory Committee Review. Published 2024. Accessed on February 02, 2025. https://investorsmedia.mesoblast.com/static-files/1ee6fcd5-de79-4645-bc09-1f1fe8864047?utm_source=chatgpt.com.
Mesoblast Ltd. Resubmission of Biologics License Application for Ryoncil. Published 2024. Accessed on February 02, 2025. https://investorsmedia.mesoblast.com/static-files/7143e4f3-8310-44d5-9883-c68a91de85fb?utm_source=chatgpt.com.
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