Miguel Forte, MD, PhD
ISCT President
mC4Tx
Belgium
The year 2024 was another great year for patients with unmet medical needs as strong progress was made with cell and gene therapy products. We saw 10 new product approvals in between Europe, with EMA, and the US with the FDA. The progression of the field continues unabated despite challenges in biotech namely financing, particularly for C>, insufficient progression to clinical trials and concerns on product manufacturing options, technology and costs and, very clearly, patient access and commercial use of C> products.
The value proposition of engineered cells in hematological malignancies is now well established and led the expansion of the C> field while providing enormous value for patients with unsolvable medical needs. On the other side, the management of solid tumors remains more challenging, despite multiple attempted approaches. Indeed, we saw multiple new approaches, and cell types, being investigated to address treatment options in solid tumors. For the management of solid tumors, in 2024, the approval of two products marked a significant turning point for C>. Iovance Therapeutics received approval, in February, for their TIL (Tumor Infiltrating Lymphocyte Therapy) for the treatment of metastatic melanoma, and Adaptimune Therapeutics received approval, in August, for their TCR-T therapy for the treatment of synovial sarcoma. The meaning of these two approvals, in addition to the direct value to patients, is the opening the future to TIL, TIL-like and TIL optimized therapies. After the success of CAR-T, last year we had the first TCR-T therapy approved. This is further confirmation of the commercial recognition of lymphocyte cell therapy in oncology, now with multiple mechanisms. Also, in oncology for 2024, we witnessed several approved products progressing upwards in the therapeutic cascade, gaining commercial access to earlier lines of treatment in the previously approved indications.
Particularly in gene therapy the appearance of competing products for the same indications in the case of Hemophilia B and transfusion dependent beta-thalassemia underscorea the increasing maturity of the field and the expansion of therapeutic opportunities addressing patient needs. Very promising, realizing the potential patient benefit, has also been the preliminary clinical trial data indicating benefit in regaining sight in inherited blindness, by Editas Medicine with CRISPR gene editing, in patients with inherited blindness caused by mutations in the CEP290 gene responsible for conditions like Leber congenital amaurosis (LCA1). Similarly, Atsena Therapeutics and collaborators at Penn Medicine, have indicated potential progress with gene therapy in the same indication but targeting a different gene. Gene therapy delivered significant potential value improving hearing in children with hereditary deafness with the clinical trial preliminary data in studies from Regeneron and Akouos with Eli Lilly. The role of gene therapy in these situations is gaining ground giving strong hopes to the value it can deliver to these previously unmanageable conditions.
Regarding clinical trial activity in 2024 the shift from oncology to other indications continued, with interest in other unmet medical needs like autoimmunity and rare diseases. Namely in gene therapy about half of new clinical trials were in non-oncology indications.
On the financing front, overall the year 2024 was challenging for biotech funding. For cell and gene therapy the challenges associated with development, manufacturing and patient access and commercialization of new products led to some investor risk aversion and slow decision making. Nevertheless, while overall dealmaking remained more or less flat, start-up financing rebounded. As we come out of JPMorgan this year of 2025 we hope to see a strong and growing investor commitment.
Towards the end of the year 2024 there was an historical development and a significant piece of good news for patients and for cell therapy. The long-awaited outcome for the Mesenchymal Stromal Cell (MSC) product from Mesoblast, Ryoncil, was delivered a few weeks ahead of schedule with the approval by the FDA for use in pediatric GvHD on the 18th of December 2024 (1). This instead of January 2025, making this news still part of 2024! This culminates a long journey of product process and clinical development and makes a significant first to confirm significant, and regulatory approvable, therapeutic efficacy and patient benefit of a standard MSC based product. MSCs have been in clinical development for more than a generation, but the outcomes have fallen short of the expectations frequently raised by encouraging pre-clinical animal data in a wide array of disease models (2) and now they have achieved therapeutic recognition.
Ryoncil (remestemcel-L), the MSC product of Mesoblast, started clinical development as Prochymal with Osiris Therapeutics. Osiris was founded in 1993, taking MSCs through clinical development for more than 30 years with a major phase III clinical trial completed in 2009 precisely in GvHD. Osiris achieved approval in Canada for Prochymal in GvHD back in 2012. Subsequently, Osiris Therapeutics sold Prochymal to the Australian company Mesoblast that renamed remestemcel-L as Ryoncil.
Mesoblast has made significant efforts, and for a significant length of time, to persistently develop Ryoncil to achieve the regulatory satisfaction of the FDA. Mesoblast addressed the product and process development to demonstrate adequate product consistency and document product potency. At the same time performed clinical trial development to generate efficacy data in the overall population as well as in parts of the clinical trial population. It is key to acknowledge that MSCs have reached, as remestemcel-L, the required product and clinical evidence requirements for this approval now. Ryoncil is now available to treat steroid resistant GvHD in the pediatric population.
MSCs were one of the first cell therapies, when the field was emerging, with very high, and probably exaggerated expectations and consequently suffered, to this day from that perspective. It is important to adequately develop the product in line with the data of the mechanism of action and the pre-clinical supportive evidence, and very importantly, design adequately the clinical trials and select the appropriate target patient population. The ISCT Clinical Translation Committee recently published recommendations proposing a standardized approach regarding multiple aspects, including clinical trial design, to deal with some of the challenges of the broad heterogeneity among published clinical trials using MSCs in aGvHD (3) leading to some difficulty to interpret, across clinical trials, the true effect of MSCs in therapy, namely in GvHD.
Not minimizing the need for adequate product and clinical development and limiting the heterogeneity in clinical trial design and implementation, a main message to retain from the Mesoblast example, should be that perseverance, resilience and belief in your product are key drivers for ultimate success, as the CEO of Mesoblast, Silviu Itescu well stated. This has been a long road to success that should open a new life for therapeutic opportunities with MSCs.
Indeed, this approval will help us understand the adequate position of MSCs in the therapeutic opportunities, trusting in their documented efficacy but not overstating it. Leading to renewed enthusiasm in the adequate development of MSCs with a professionalized, resilient approach delivering MSCs as professionalized cells for targeted therapeutic opportunities. For cell therapy, and for patients, this Phoenix of MSCs may represent a significant renewed boost in MSC product development for the therapeutic benefit of patients.
References:
1. FDA Press release: FDA Approves First Mesenchymal Stromal Cell Therapy to Treat Steroid-refractory Acute Graft-versus-host Disease https://www.fda.gov/news-events/press-announcements/fda-approves-first-mesenchymal-stromal-cell-therapy-treat-steroid-refractory-acute-graft-versus-host#:~:text=Today%2C%20the%20U.S.%20Food%20and,months%20of%20age%20and%20older
2. Jacques Galipeau, Luc Sensébé; Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities; 2018, Cell Stem Cell, Vol 22, 6, 824-833
3. Abdulrahman Alsultan, et all; International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges. Cryotherapy; 2024, Cytotherapy 26, 1132 _1140
4. ISCT Press Release: ISCT Hails Landmark US FDA Approval of RYONCIL® as Major Milestone for MSC Field
https://www.isctglobal.org/isct-in-the-news/us-fda-approval-of-ryoncil
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