Regenerative Medicine and Stem Cells Technologies

Drug discovery involves high cost and uncertain outcomes.  Only a few companies can take the risk of investing enormous amounts of money into research and testing, only to see undesirable side effects emerge during the final human clinical trials. In many cases, companies are spending millions of dollars to fail during clinical testing.

Now, some new medicines are being tested for safety on specialized cells developed from human pluripotent cell lines. Cell types which are frequently being using within drug discovery applications include heart (cardiomyocytes) and liver cells (hepatocytes), which are the organs where 80% of drug failures occur.

Leveraging Human iPSCs within Drug Discovery

Animal models don’t achieve perfect success in predicting the pathophysiology of many human diseases, because animals differ from humans in physiology, the immune system and individual genetic backgrounds. Animal models also differ in liver metabolism. These differences have an impact on the severity of the disease phenotype and the effectiveness of new drugs in clinical trials.

Unfortunately, these differences often contribute to the failure to identify potentially toxic side effects of new drugs in current safety pharmacology studies.

Drug attrition rates using animal models are usually high, because present preclinical assays do not reliably detect potential risk of damage to the heart, kidney, liver, and brain. The discovery of induced pluripotent stem cells (iPSCs) and achievements in producing these cells from patients and healthy individuals along with efficient gene modification has led to remarkable opportunities over the last several years to model human disease.

Researchers are now capable of routinely producing human iPSC (hiPSC) lines and inducing their efficient differentiation into different types of body cells that are affected by genetic diseases or are specific drug targets. Biotechnology companies have also optimized reagents and differentiation protocols such that they are now widely applicable across many hiPSC lines.

Repurposing of currently available drugs through patient-derived iPSCs has already resulted in some drugs entering directly clinical trials without intervening animal experiments. This has occurred for severe conditions with no available treatment options, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and Alzheimer’s disease (AD). Currently, iPSCs are most commonly being deployed for drug discovery related to oncology, diabetes, and neurological applications.

Market Competitors Using Human iPSCs within Drug Discovery

While dozens of companies offer human iPSC-derived cell types to support drug discovery and toxicology testing, there are a few clear market leaders, as described below.

Ncardia

A major market player in this area is Ncardia, which is a full-stack human iPSC technology company with headquarters in Belgium. Ncardia is built on the belief that using human induced pluripotent stem cell (hiPSC)

technology will help to improve drug screening, and therefore, get safe therapies to patients more rapidly.

With operations in both Europe and the US, Ncardia produces and commercializes high-quality, fully functional hiPSC derived cardiovascular and neuronal cell types and develops and realizes electrophysiology, biochemistry and contraction based assays for predictive safety pharmacology, toxicology testing and drug efficacy screenings.

It is one of the leading companies that is partnering with biopharmaceutical companies utilizing hiPSCs within drug discovery applications. Recently, on January 21, 2020, Ncardia and BlueRock Therapeutics announced an agreement covering process development technologies for the manufacture of induced pluripotent stem cell (iPSC)-derived cardiomyocytes, under which Bluerock gains access to Ncardia’s large-scale production processes and intellectual property for the production of iPSC-derived cardiomyocytes for therapeutic use.

FUJIFILM CDI

As the world’s larger manufacturer of human cells created from iPSCs, Fujifilm Cellular Dynamics Inc. (FCDI) also offers cells for drug discovery, basic research and regenerative medicine.

FCDI manufacturers several cell types differentiated from iPSCs, that are relevant to drug discovery, including iCell® Cardiomyocytes, iCell Neurons, and iCell Hepatocytes. The company also produces iCell Cardiac Progenitors, iCell Hematopoietic Progenitors, iCell Astrocytes, iCell Endothelial Cells, and iCell Skeletal Myoblasts, among other products.

Furthermore, FUJIFILM CDI offers MyCell® products that are created using custom iPSC reprogramming and differentiation methods, in order to provide biologically relevant human cells from patients with unique disease-associated genotypes and phenotypes. The company’s iCell and MyCell cells can also be adapted to screening platforms and are matched to function with common readout technologies.

Similar to Ncardia, FUJIFILM CDI has pursued strategic partnerships related to the use of hiPSCs within drug discovery applications. In a recent example, FUJIFILM Corporation and Axcelead Drug Discovery Partners announced a collaboration to provide customers with a hiPSC-based integrated platform for drug discovery solutions. By combining FUJIFILM CDI’s iPSC-derived products with Axcelead’s compound

evaluation and analytical services, the companies are aiming to develop new drug efficacy evaluation methods and toxicity testing protocols.

Takara Bio

Similarly, Sweden’s Takara Bio offers heart muscle cells and liver cells to drug and biotechnology companies, as well as universities. The Takara Bio Group of companies has three primary sub-brands, which are: Takara, Clontech, and Cellartis. The Cellartis brand is of particular relevance to this topic, because it is focused on stem cell-derived products and services for drug discovery, disease modeling, and regenerative medicine applications.

Historically, a key focus of the brand has been developing and distributing pluripotent stem cell lines, including both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs).

Takara Bio has developed a standardized differentiation protocol for industrial scale production of iPS-derived hepatocytes that mimics embryonic development to yield pure cells that exhibit the functionality and characteristics of mature hepatocytes. Its protocol results in pure, functional hepatocytes that are

functionally mature and give low variability from batch-to-batch. To the best of my knowledge, Takara Bio is the first company offering a a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC (iPS and ES) lines without any adaptations to individual lines.

By applying this “universal” protocol across hPSC-heps derived from different donor lines, one can mirror the metabolic diversity typically observed in human primary hepatocytes from different donors. Based on recent advances in iPSC technology, iPSC lines can now be derived from individuals with specific genotypes or phenotypes. This progress opens up new possibilities for drug discovery, toxicology studies, and regenerative medicine applications.

Evotec

Headquartered in Hamburg, Germany, Evotec is another major contender within this space. Evotec’s iPSC platform has been developed with the goal to industrialize iPSC-based drug screening as it relates to throughput, reproducibility, and robustness. Today, Evotec’s technological infrastructure represents one of the largest and most advanced iPSC platforms globally.

Evotec’s initial foray into iPSC technology was enabled by a research collaboration with the Harvard Stem Cell Institute. Since that time, Evotec has created alliances and collaborations with a diverse range of industry partners, including but not limited to: Bayer, Boehringer Ingelheim, Celgene, Center for Regenerative Therapies Dresden, Censo Biotechnologies, CHDI, Fraunhofer IME-SP, Novartis, Novo Nordisk, Pfizer, Sanofi, Takeda, UCB, and others.

Evotec is also closely aligned with the industry behemoth Bristol-Myers Squibb, an American pharmaceutical company headquartered in New York City that has a market cap of $140 billion.

Based on the depth and breath of its partnerships, Evotec is best described as a iPSC-centric drug discovery alliance and development partnership company.

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