After years of quiet maturation, new approach methodologies and emerging clinical success for cell therapies are fueling parallel momentum for induced pluripotent stem cells.
For more than a decade, induced pluripotent stem cells have generated significant interest thanks to their ability to give rise to any other cell type. Now, two trends are propelling this versatile tool toward transforming drug development.
Those trends are the rapid adoption of new approach methodologies (NAMs) and a growing body of clinical evidence in cell replacement therapeutics. These paths may seem independent, but they are in fact additive. Together, they are accelerating the maturation of induced pluripotent stem cells (iPSCs) into scalable, clinically relevant platforms.
I have long appreciated the power of iPSCs, having participated in their development for decades—including in my current role working on iPSC manufacturing and clinical translation programs at FUJIFILM Cellular Dynamics. I now have the privilege of seeing iPSCs finally land in the spotlight.
Rising prominence
In 2012, iPSCs grabbed headlines as Shinya Yamanaka and John Gurdon were awarded the Nobel Prize for their work on reprogramming mature cells for pluripotency in the mid-aughts. Parallel work by James Thomson at the University of Wisconsin–Madison identified additional reprogramming factors and leveraged iPSCs to study rare diseases such as ALS and fragile X syndrome.
Initial broad success with iPSCs was found in toxicology screening, including iPSC-derived cardiomyocytes for a standard assay and for drug-drug interaction screening. iPSCs have now moved into batch release testing as well as contributing to drug discovery efforts. NAMs based on iPSCs are also used to develop mRNA/lipid nanoparticle combinations and viral vector–based therapies, to ensure they target the right tissues.
A breakthrough in the use of iPSCs in drug development came last year, when the FDA and the National Institutes of Health spearheaded a new push away from requiring animal testing in drug development, alongside similar European regulatory efforts. Animal models have always held only limited relevance for clinical success, and significant progress in iPSCs and other technologies has brought human-relevant modeling closer to reality. Engineering cells for automated compound screening on 384-well plates yields significantly higher throughput than breeding a mouse model.
The regulatory push away from animal models is speeding up adoption of a host of new technologies including 3D spheroids, organs-on-chips, microphysiological systems and other NAMs that rely on combinations of multiple iPSC-derived cell types. We at FUJIFILM Cellular Dynamics expect that demand in this area will continue to grow as NAM developers continue to phase in new models of disease, the blood-brain barrier, neuromuscular junctions and more. Customers have described numerous instances where iPSC-based NAMs laid bare issues based on human biology that were missed in animal models, saving significant time and resources in clinical development.
iPSCs hit the clinic
In parallel with the progress iPSC technology has made in the lab, advanced cell-based therapies have generated significant interest in their ability to treat and sometimes cure diseases that otherwise lack effective therapies. Initial cell therapies, especially patient-derived autologous approaches based on T cells and CD34+ hematopoietic stem cells (HSCs), reached the market quickly—if not entirely smoothly. To date, all have downsides when it comes to patient accessibility, with demand far outstripping manufacturing capabilities and affordability.
A recent announcement from Japan’s Ministry of Health, Labor and Welfare highlighted the progress of iPSC-derived therapeutics, granting the world’s first conditional approvals for two therapies based on the technology. Sumitomo Pharma’s Amchepry is a dopaminergic neuron replacement therapy for Parkinson’s disease, and Cuorips’ ReHeart uses cardiomyocytes to treat severe heart failure.
These won’t be the last. Multiple iPSC-based programs are progressing into or through late-stage clinical testing, including numerous other Parkinson’s treatments. BlueRock Therapeutics is currently conducting a pivotal Phase 3 trial of a human embryonic stem cell (hESC)-derived therapy for Parkinson’s disease, and is, in parallel, continuing to build out its next-generation iPSC platform. Aspen Neuroscience and Kenai Therapeutics are both preparing to enter Phase 3 for their respective iPSC-based Parkinson’s therapies. Other companies are targeting therapeutics for cardiac indications, retinal diseases and diabetes.
As with NAMs, therapeutic progress in this space over the past decade has largely flown under the radar. And as with NAMs, this progress has been enabled by success in manufacturing cells with consistent quality. Unlike commercial CAR T cell and HSC therapies, iPSC-based therapies can be derived from genetically stable iPS cell banks, in some cases based on the same refined protocols used to scale up dopaminergic neuron manufacturing for NAMs. They also differ from allogeneic therapies, which are still dependent on active and recurrent donors; iPSC therapies can be truly “off-the-shelf.” With a decade or more of safety data showing genetic stability of the parent cell lines, regulators are assured these products do not harbor genetic abnormalities that put patients at risk.
Lastly, with an established approach to commercial scalability, iPSC therapies have a path to patient accessibility that other cell therapies currently lack.
Similarly, developers avoid the patient-to-patient variability and difficulties in generating a sufficient therapeutic dose that can confound other cell therapy manufacturing efforts.
As with any new therapeutic modality, the field must still demonstrate long-term safety, particularly undergoing scrutiny of their in vivo genomic stability and any tumorigenicity, as well as immune tolerability. Regulatory pathways will need to evolve to keep pace with the unique characteristics of cell-based therapies. And manufacturing, while significantly advanced, must show it can scale efficiently.
With all of this said, the overall direction is clear. After years of hidden, incremental progress, iPSCs are entering a new phase defined by convergence across research, regulation and clinical development. Together, these advances may prove transformative for drug development.
