Inside the Rapid Rise of iPSC Based Therapies

iPSC derived therapies are rapidly gaining traction in the advanced therapeutics space. Induced pluripotent stem cells (iPSCs) are adult cells, such as skin or blood cells, that are reprogramed back into an embryonic-like pluripotent state using specific genes.  

The goal of iPSCs is to provide a renewable, standardized source of cells for allogeneic therapies and to provide an opportunity as a scalable solution for complex indications from regenerative medicine to oncology. However, their use presents challenges, including optimizing genetic engineering strategies for pluripotent cells, meeting GMP-grade production requirements, and ensuring consistency across large-scale manufacturing platforms. 

With the iPSC market expected to further expand, Nina Bauer, Executive Vice President of Strategy and Commercial, FUJIFILM Cellular Dynamics, shares hands-on experience manufacturing iPSCs, their increasing importance, as well as the technical bottlenecks standing in their way. 

Contract Pharma: What development tools/technologies are being used to advance iPSCs-based therapies?

Nina Bauer: More and more, gene editing technologies are being applied to support therapeutic specificity and efficacy, as well as post-transplant persistence. The most commonly used technologies are various CRISPR approaches, Zink Finger Nucleases and Talens, to mention but a few.

From a manufacturing efficiency perspective, like other types of cell therapy, there are benefits to leveraging closed, automated cell culture systems for iPSC therapy manufacturing. Improvements in cryopreservation and assay miniaturization similarly benefit multiple areas.

However, there is also significant divergence. One key distinction is that iPSC therapies can be based on cell banks, including those developed for other technologies. In fact, iPSC lines developed for uses including new approach methodologies (NAMs) in drug discovery and development have generated therapeutic candidates for Parkinson’s disease and primary photoreceptor diseases that are already in clinical testing.

New Approach Methodologies (NAMs) are testing methods and strategies used to assess the safety, efficacy, and quality of drugs, biologics, and other FDA-regulated products.

As a result, analytical technologies including single-cell RNA sequencing and whole-genome sequencing are critical, ensuring batch-to-batch consistency and monitoring off-target population analysis. Unique protocols are needed to progress iPSCs to the right phase of development for each specific therapy, aided by advanced analytics based on in-process monitoring.

Contract Pharma: What are the manufacturing challenges associated with iPSC derived therapies and how can they be overcome?

Nina Bauer: For therapies dependent on cell banking, selecting and validating high-quality iPSC lines for long-term expansion and consistent differentiation is a critical early hurdle. It is essential to establish robust master and working cell banks with high post-thaw viability and reproducibility to avoid variability that can cause manufacturing inconsistency.

Whole-genome sequencing is now a regulatory expectation to demonstrate continued genomic stability. Fit-for-purpose assays are needed to monitor parameters and control residual undifferentiated iPSCs. iPSC therapy manufacturing may be more complex than CAR-T cell therapies, with multiple steps from initial expansion to differentiation into the target cell types. Many of these steps are difficult to scale as they are often still performed manually. Manufacturing can take several weeks, which makes maintaining sterility and process control a significant challenge. Automation, especially in process analytics, will be a critical component of future scalability. Conversely, in contrast to autologous, patient-specific CAR-T, iPSC approaches are less exposed to on-time manufacturing and supply chain complexities.

Contract Pharma: What are some commercial products that leverage iPSCs?

Nina Bauer: There are quite a few approved therapeutics in the small molecule and biologics space that leverage iPSC-based NAMs to ensure quality as they are used in release and potency testing.  Outside of the therapeutic space, the vast majority of commercial iPSC products are applications like NAMs that can be used to model the blood-brain barrier, heart or liver tissue. These platforms are used for drug discovery, potency assays, toxicology, drug-drug interactions, and more, and sold commercially as tools and technologies.

In March, Japan’s regulatory agency granted conditional approval for two iPSC-based therapies – one for Parkinson’s disease, the other for heart failure. These are the only commercial iPSC therapies to date.  There are multiple Phase 3 trials for Parkinson’s anticipated soon, and a growing pipeline in retinal, cardiac and diabetes therapies.

Contract Pharma: Where do the greatest opportunities lie for these therapies?

Nina Bauer: iPSC-derived cell replacement approaches are particularly relevant for degenerative conditions, ranging from the neurodegeneration seen in Parkinson’s and  to primary photoreceptor diseases, or to replace dysfunctional cells like islets to treat diabetes. The term we use is “functional cure” where new cells are transplanted to take on functions that have been lost over the course of degeneration. Unlike CAR-T cell therapies that have faced commercial challenges in scaling to meet patient demand, iPSC-based therapies have structural advantages, including the ability to be manufactured at scale consistently. This makes them a promising option for diseases that impact large populations of patients.

Nina Bauer, PhD MBA, is EVP Strategy and Commercial at FUJIFILM Cellular Dynamics, Inc. She is an expert on biomanufacturing and novel modality therapies, focused on commercialization. At FUJIFILM CDI, she works on iPSC manufacturing and clinical translation programs, collaborating with therapy developers to move iPSC-derived products from research-grade processes to GMP manufacturing, and enabling NAMs through an extensive catalogue of off-the-shelf cell types for screening and testing.