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The power of partnering
GLASGOW, U.K.— A landmark, multinational, collaborative stem-cell research project led by Belgium-based biotech TiGenix recently gained a new partner in Sistemic, a provider of miRNA-based products to the drug development, cell therapy and bioprocessing markets.
The project, called REGENER-AR, aims to progress TiGenix's Cx611 stem cell therapy for rheumatoid arthritis through early clinical trials. The multidisciplinary consortium spans several countries—Belgium, Spain, France, the Netherlands and now the U.K.—and has been granted $7.8 million from the European Seventh Framework Programme (FP7) under the topic "Regenerative medicine clinical trials" within the FP7's Health theme.
TiGenix is almost as new as the consortium itself, as the company merged with Cellerix, a Spanish biotech that is also focused on cell therapies, a little more than a year ago. Since that time, the newly formed company has been working to evaluate adipose tissue-derived stem cell (eASC) therapies for autoimmune and inflammatory diseases like rheumatoid arthritis (RA).
Cx611 is an allogeneic eASC product candidate for the treatment of rheumatoid arthritis and is currently being investigated in a Phase IIa trial. The trial is based on a three-step dose-finding protocol, where each step starts with a safety review of the first three patients after 40 days of dosing. In February, the study opened the third and last cohort.
The study has three objectives. Its primary objective to determine safety, feasibility and tolerance, and to identify dose-limiting toxicity and the dose for future clinical trials on efficacy of the intravenous infusion of allogeneic eASCs for patients suffering rheumatoid arthritis under treatment with at least two non-biologic-DMARDs who have previously failed to treatment with at least two biologics. The secondary objective is to obtain information on the clinical and functional effects of the intravenous infusion of allogeneic eASCs cells in patients with rheumatoid arthritis, and the third objective is to explore pharmacodynamic parameters.
The multicenter study involves 53 patients divided into three cohorts with different dose regimens and with the same administration regimens and is being conducted in more than 20 Spanish centers. TiGenix expects to report the final results of the Phase IIa in the first half of 2013. If the results are as anticipated, TiGenix plans to take the program forward in one or several inflammatory and autoimmune orphan or niche indications.
"Our role will be the clinical coordination of clinical trials within the grant, and then we will have a series of leading roles in the preclinical evaluation of Cx611," says Wilfried Dalemans, chief technology officer and vice president of regulatory affairs at TiGenix. "The goal of this project is to progress a treatment for RA, which is a complex disease. It would be great if we have supporting clinical data which indicate that stem cells can indeed be a possible treatment option for RA patients. On the preclinical side, a more in-depth understanding of the mode of action of stem cells in controlling inflammation will be equally important."
The consortium has 10 partners to date, and the most recent addition to that group is Sistemic, which will use its miRNA-based screening platform to provide identity markers for TiGenix's product. This miRNA-based fingerprint will then be developed to fully characterize the product in line with regulatory requirements and provide a quality control (QC) tool to monitor product quality during manufacturing scale-up for subsequent clinical trials and aid in the selection of manufacturing process improvements.
"Stem cells are still in the early stages of their science," Dalemans notes, "and although we know they have great potential in inflammatory control and tissues, there are still a lot of unknowns with respect to their origin and genealogy. One aspect of miRNAs is to focus on regulatory pathways that can group types of regulatory pathways within cells. Sistemic has built a technical platform based on the scientific background of miRNAs, so they were the partner of choice."
miRNA-based characterization provides a powerful and informative way to identify and monitor the identity, purity, safety and differentiation staging of stem cells, says Vincent O'Brien, chief scientific officer at Sistemic.
"Importantly, this approach not only gives a succinct read out on the status of the cells, but also provides insight into the underlying biological effects associated with any change observed," says O'Brien. "We see miRNAs acting as molecular beacons on the molecular status of the cell system, providing a much less cumbersome, more robust and biologically informative tool to monitor cells."
miRNA-based characterization holds enormous promise for cell-therapy product development because current methodologies are time- and labor-intensive and are becoming a bottleneck in progressing cell therapies through to manufacturing, says Verna McErlane, Sistemic's director of commercial operations.
"Full characterization is the cornerstone to successful development of any cell therapy and must span from early R&D through pilot production for trials to full-scale manufacture," says McErlane. "Only in this way can a cell product be produced consistently and reproducibly. As a consequence, innovative companies such as Sistemic are working on novel methodologies, tool and products that can be used to sensitively and robustly characterize cell therapy products. In essence, sophisticated molecular characterization, and the ability to link this back to system biology, will be instrumental in delivering full characterization of the cell, the process and the product. As with any new technology it will be important that they are standardized for use in the industrial setting—something that Sistemic is developing in collaboration with its global partners."