The Pipeline for iPSC-Derived Cell Therapeutics in 2021

Despite progress involving the use of induced pluripotent stem cells (iPSCs) within disease modeling and drug discovery applications, it will be a long path to achieve the broad-scale use of iPSC-derived cell types in human patients.

Within a preclinical context, cell types differentiated from iPSCs are tested for their therapeutic response. Then, clinical trials are conducted to assure that essential parameters, such as tumorigenicity, dose toxicity, and immunogenicity, are assessed before authorizing the product for use in human patients. iPSC-derived cells have the potential to be used as therapies for treating cardiovascular, neurological and metabolic diseases and repairing damaged cartilage, spinal, motor neuron and eye tissues resulting from genetic defects or injuries.

In general, the targets for iPSC-derived therapies include any diseases or disorders for which there are no other viable treatments and where there is a need to repair or replace dysfunctional tissue.

Pipeline for iPSC-Derived Cell Therapeutics

Today, the following companies and organizations are forging the path toward iPSC-derived cell therapeutics.

These market leaders include:

• BlueRock Therapeutics, which was acquired by Bayer in August 2019, uses pluripotent stem cells to target Parkinson’s disease and heart failure.
• Century Therapeutics was created in July 2019 by Versant Ventures and Fujifilm to develop iPSC-derived adaptive and innate immune effector cell therapies.
• Cynata Therapeutics manufacturers iPSC-derived MSCs using its proprietary Cymerus™ technology. It is testing these cells in the treatment of graft-versus-host disease (GvHD), critical limb ischemia (CLI) and osteoarthritis (OA).
• Fate Therapeutics is developing iPSC-derived NK and CAR-T cells for the treatment of cancer and immune disorders.
• Healios K.K., in collaboration with Sumitomo Dainippon Pharma, is undertaking a clinical trial using allogeneic iPSC-derived retinal cells to treat age-related macular degeneration.
• Keio University won approval from the the Japanese government in February 2018 for an iPSC trial that involves the treatment of patients with spinal cord injuries (led by Professor Hideyuki Okano).
• Kyoto University Hospital, in partnership with the Center for iPS Cell Research and Application (CiRA), is performing a physician-led study of iPSC-derived dopaminergic progenitors in patients with Parkinson’s disease.
• Osaka University grafted a sheet of iPS-derived corneal cells into the cornea of a patient with limbal stem cell deficiency, a condition in which corneal stem cells are lost.
• RIKEN administered the world’s first iPSC-derived cell therapeutic into a human patient in 2014 when it transplanted an autologous iPSC-RPE cell sheet into a patient with AMD.
• Semma Therapeutics, which was acquired by Vertex Pharmaceuticals for $950 million in late 2019, is developing a treatment for Type 1 diabetes. This treatment consists of cells derived from iPSCs that behave like pancreatic cells.
• Stemson Therapeutics has been developing a therapy for hair loss involving generation of de novo hair follicles.
• TreeFrog Therapeutics has a 13,000 sq ft facility in France for the development and scale-up of its cell therapy manufacturing process that leverages human iPSCs. It plans to develop its own iPSC-derived therapies and support co-development programs.
• The U.S. NIH is undertaking the first U.S. clinical trial of an iPSC-derived therapeutic. Its Phase I/IIa clinical trial will involve 12 patients with advanced-stage geographic atrophy of the eye.

iPSC-Derived Cell Therapeutics in Clinical Trials

While the groups above are involved with the development of iPSC-based cell therapeutics, not all of them have reached clinical-stage. Companies and organizations developing clinical-stage iPSC-derived therapeutics are described below.

In 2016, Cynata Therapeutics received a landmark approval to launch the world’s first formal clinical trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. In collaboration with Fujifilm, Cynata Therapeutics completed this Phase I trial in December 2018, reporting positive results.

Cynata Therapeutics is now testing its product candidate CYP-004 in a Phase 3 clinical trial enrolling up to 440 patients. CYP-004 is an allogeneic, iPSC-derived mesenchymal stem cell (MSC) product derived using Cynata’s proprietary Cymerus™ technology. Led by the University of Sydney and funded by the Australian Government National Health and Medical Research Council (NHMRC), the trial will assess whether the cells can improve patient outcomes in osteoarthritis (OA).

It will be the world’s first clinical trial involving an iPSC-derived cell therapeutic to enter Phase 3 and the largest one ever completed.

In December 2019, the National Institutes of Health (NIH) announced it would be undertaking the first U.S. clinical trial of an iPSC-derived therapeutic. The goal of this trial is to restore dying cells of the retina. The Phase I/IIa clinical trial involves 12 patients with advanced-stage geographic atrophy who received an iPSC-derived retinal pigment epithelial (RPE) implant into a single eye. This trial is supported by the Ocular and Stem Cell Translational Research Section of the National Eye Institute (NEI). The NEI is part of the NIH.

In February 2019, allogeneic iPSC-derived NK cells produced by scientists from the University of Minnesota in collaboration with Fate Therapeutics were granted approval by FDA for a clinical trial. Specifically, Fate Therapeutics is exploring the clinical use of FT516 and FT500, which are its off-the-shelf, iPSC-derived natural killer (NK) cell product candidates. In December 2019, the company released promising clinical data from its Phase 1 studies.

In July 2020, Fate Therapeutics subsequently announced FDA clearance of its IND application for the world’s first iPSC-derived CAR T-cell therapy, FT819.  FT819 is an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. Notably, the use of a clonal master iPSC line as the starting cell source will position Fate to mass produce CAR T-cells to be delivered “off-the-shelf” to patients.

The Japanese company Healios K.K. is preparing, in collaboration with Sumitomo Dainippon Pharma, for a clinical trial using allogeneic iPSC-derived retinal cells to treat age-related macular degeneration (AMD).  

Of course, there are also numerous physician-led studies underway in Japan investigating the use of iPSC-derived cellular products inhuman patients. These clinical trials are for diseases such as macular degeneration, ischemic cardiomyopathy, Parkinson’s disease, solid tumors, spinal cord injury (SCI) and platelet production.

Physician-Led Studies of iPSC-Derived Cell Therapeutics

Details on each of these Japanese trials are provided below:

Clinical Trials for AMD

Significant progress has been made for retinal degeneration diseases, particularly for age-related macular degeneration (AMD). In 2009, preclinical data showed for the first time the recovery of visual function in patients injected with retinal pigment epithelium (RPE) differentiated from iPSCs in a rat model’s retina. A major breakthrough was made when the group led by Masayo Takahashi at the Riken Centre for Developmental Biology in Japan produced iPSC-RPE cell sheets in 2014.

Autologous iPSC-RPE for AMD

The above-mentioned successes led to the initiation of the first iPSCs clinical trial in 2014 itself. Scientists at the RIKEN Centre in Japan transplanted an autologous iPSC-RPE cell sheet just below the affected retina, without immunosuppression, in a 77-year-old woman with AMD. One year after the transplantation, the progression of the degeneration simply halted, an area with photoreceptors recovery was observed, and the patient’s vision remained stable. There were no symptoms of immune rejection or tumor development.

Allogeneic iPSC-RPE for AMD

In March 2017, Japanese scientists announced that a 60-year-old man was the first patient to receive iPSC-RPE cells derived from another person (an allogeneic source). A clinical-grade iPSC bank for collecting and storing healthy HLA homozygous donors is now being established at the Centre for iPS Cell Research and Application (CiRA) in Kyoto (Japan).

iPSC-derived Cardiomyocytes for Ischemic Cardiomyopathy

Also in 2017, iPSC-derived cardiomyocytes were grafted on to a porcine model of ischemic cardiomyopathy by Kawamura, et al., using a cell-sheet technique. Cardiac function was significantly improved, and neovasculogenesis was observed. Recently, scientists from Osaka University were granted approval for a clinical trial to transplant allogeneic sheets of tissue derived from iPSCs onto the diseased hearts of three human patients.

iPSC-derived Cells for Spinal Cord Injury

Several preclinical studies in spinal cord injuries using iPSC-derived neural progenitor cells in animal models have provided evidence for remyelination and locomotor function recovery. In February 2018, the Japanese government gave an approval to Professor Hideyuki Okano for a clinical trial that will involve the treatment of patients with spinal cord injuries at Keio University.

iPSC-derived Platelets

In September 2018, group of scientists from Kyoto University were granted approval to begin a transfusion trial using platelets derived from iPSCs into an individual with aplastic anemia. The hope is that iPSC-derived platelets could replace transfusions of donated blood.

iPSC-Derived Dopaminergic Neurons for Parkinson’s disease

As early as 2008, it was confirmed that iPSC-derived dopaminergic neurons improved the symptoms and dopaminergic function of a rat model of Parkinson’s disease. Approximately a decade later, in October 2018, dopamine precursor cells were created from allogeneic iPSCs produced by Jun Takahashi’s research group at Kyoto University. Physicians at Kyoto University Hospital then transplanted these cells into subjects with Parkinson’s disease. A total of seven patients were involved.

iPSC-derived Corneal Cells for Limbal Stem Cell Deficiency

In July 2019, scientists at Osaka University started a clinical trial for limbal stem cell deficiency, a condition in which corneal stem cells are lost. The scientists grafted a sheet of iPS-derived corneal cells onto the cornea of a patient. Within one month, her vision seemed to have improved.

To learn more about the surging market for iPSCs, view the “Global Induced Pluripotent Stem Cell (iPS Cell) Industry Report 2021.”

What questions do you have about the development of iPSC-derived cell therapeutics? Ask them in the comments below.