ISCT 2024 took place in Vancouver, Canada, (author’s image).
Last month, the U.S. Food and Drug Administration (FDA) agreed to formally review a revised Biologics License Application (BLA) from Mesoblast for their mesenchymal stromal cell (MSC) product, remestemcel-L. The submission represents the third attempt by the company to receive FDA approval for their MSC product aimed at treating the deadly condition known as graft-versus-host disease (GvHD). Notably, this year also marks two decades since Dr. Katarina Le Blanc’s seminal case report documenting the remarkable recovery of a pediatric GvHD patient after receiving two MSC injections.
As mentioned in my last MSC-themed blog post for Signals (check this out for more background information on MSCs), twenty years of clinical research have produced only a handful of MSC products with regulatory and market endorsement. On this subject, a panel discussion was held at the 2024 International Society for Cell & Gene Therapy (ISCT) Annual Meeting to draw on the expertise of individuals involved in the successful development of market-approved MSC products. The panel featured Dr. Pawan Gupta, representing Stempeutics (India), and Dr. Eleuterio Lombardo, representing Takeda (Spain).
Stempeucel for treatment of critical limb ischemia and knee osteoarthritis
Stempeucel is an allogeneic bone marrow-derived MSC product developed by Stempeutics. It has received market authorization in India for the treatment of critical limb ischemia and knee osteoarthritis. The company’s unconventional manufacturing strategy involves the pooling of MSCs derived from multiple cell donors. According to Dr. Gupta, this unique pooling strategy has conferred multiple advantages, including: i) minimizing batch-to-batch variability for the final cell product; ii) enabling the creation of larger cell banks that can be used to treat many patients from a single product batch; and, iii) increasing the functionality of the final cell product relative to the MSCs derived from individual donors. Thus, the pooling method has been key to the success of Stempeucel.
In the context of knee osteoarthritis, Dr. Gupta discussed the clinical trials that led to eventual market approval for Stempeucel. He highlighted results from the company’s Phase II clinical trial that was performed as a dose-finding study in which knee osteoarthritis patients were injected with MSCs and hyaluronic acid. Based on results from the trial, the company selected the cell dose showing the most positive trend in the improvement of patient-reported outcome measures. In a subsequent Phase III randomized controlled trial, the company showed that MSC treatment could prevent further cartilage loss and significantly improve patient-reported outcome measures at six- and 12-months follow-up relative to the placebo group (hyaluronic acid alone). These positive findings led to market authorization for Stempeucel for the treatment of knee osteoarthritis in India.
According to Dr. Gupta, patient selection must be carefully considered so that only patients likely to benefit receive treatment. For example, patients with mid- to late-stages of knee osteoarthritis (as defined by Grades 2 and 3 on the Kellgren-Lawrence scale) were selected as a population who may achieve therapeutic benefit from MSC injection. He further commented that patients with severe meniscus or anterior cruciate ligament tears do not respond to the therapy and are therefore excluded from treatment with Stempeucel.
In terms of study endpoints, Dr. Gupta highlighted that appropriate readouts should be selected to capture the effects of the MSC injection. For example, in knee osteoarthritis, he commented that patient-reported outcome measures are sufficient to detect patient improvements, while detecting changes in cartilage via imaging modalities would require longer periods of follow-up. Importantly, the selected study endpoints should also align with the expected timeline for detecting measurable changes because of the treatment.
Darvadstrocel for treatment of complex perianal fistulas in Crohn’s disease
Dr. Lombardo discussed darvadstrocel (commercialized under the brand name, Alofisel), an allogeneic adipose-derived MSC product produced by Takeda. The product has been approved in the European Union, Israel, Switzerland, Serbia, Japan and the United Kingdom for treating complex perianal fistulas, a common and painfully debilitating complication of Crohn’s disease.
Drawing insights from two successful Phase III randomized controlled trials to commercialize the cell product (reference one and two), Dr. Lombardo discussed several key points for developing a successful MSC product. First, he highlighted that the target disease should be carefully selected, as MSCs will not be suitable to treat every disease. He cited that due to the strong anti-inflammatory/immunomodulatory properties of MSCs, complex perianal fistulas represent a condition that may be treatable with darvadstrocel.
In addition, Dr. Lombardo emphasized the importance of developing an economically sustainable manufacturing process. Cell therapy manufacturing can be extremely costly, and it is challenging to alter a manufacturing process after the product has received regulatory approval; therefore, economic factors should be considered during process development.
MSC potency assays are being heavily studied as surrogate in vitro readouts that correlate to clinical efficacy. These assays are intended to help ensure the consistent quality of the MSC product, but the complexity of MSC therapies has made potency assay development vital. In parallel, researchers are working to identify biomarkers that may be used to stratify patients more likely to benefit from an MSC treatment.
While these approaches may help optimize treatment outcomes, Dr. Lombardo emphasized that it is difficult to demonstrate the robustness of these tools until a large sample of individuals has been treated with the cell product (e.g. over 500 patients). Given that many cell therapy trials enroll small numbers of patients, Dr. Lombardo called for harmonized protocols for clinical trial designs and analysis of trial samples. This would enable the pooling of data across multiple studies and could accelerate potency assay development and patient stratification efforts in MSC clinical trials.
Unfortunately, in the complex world of cell therapy, there is no silver bullet. Despite the successes of darvadstrocel in other regions, a recent Phase III clinical trial aimed at gaining regulatory approval from the FDA and Health Canada failed to achieve its primary endpoint in Crohn’s disease patients. Dr. Lombardo shared that while the expected safety and efficacy results were observed after darvadstrocel treatment, the response rate within the placebo group was higher than expected. As a result, no significant differences were observed between the treatment and control groups. Takeda is performing an investigation to identify the cause of these unexpected findings.
Despite these challenges, Dr. Lombardo reminded the audience that the goal in developing a cell therapy should not be focused solely on gaining regulatory approval. Rather, the cell therapy needs to be designed to work in the “real world” where its primary purpose is to benefit patients. Whether MSC products can be demonstrated to achieve this goal in North America remains to be seen, but efforts toward this objective continue.
Kevin Robb
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