Btobioinnovation.com 

Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com 

SPECIAL REPORT #21.26

Human Induced Pluripotent Stem Cells as Innovative Therapies

When, in 2007, Professor Shinya Yamanaka disclosed its discovery that mature human cells could be transformed into stem cells, better known now as human induced Pluripotent Stem Cells (hiPSC), the biopharmaceutical community immediately recognised that this new biological technology could become a breakthrough innovation with an enormous scientific, medical and economical potential. Many small and large organisations went to visit or invite Professor Yamanaka to discuss feasible collaborations and subsequently launched “Regenerative Medicine” initiatives. The scientific community was also very keen to rapidly recognise the major impact of this discovery with the awarding of the Nobel Prize in Medicine and Physiology in 2012 to Shinya Yamanaka and John Gurdon. Less than five years later several “Regenerative Medicine” initiatives were stopped and ten years later the many expected outcomes in some of the most interesting therapeutic domains are still far out of reach.

Why so?

Like always with a new technology, several hurdles were underestimated, and in this case, the one with the most impact was high quality and reproducibility of mass production of millions and even billions of hiPSC. The industry already mastered technologies where cells were not the product themselves and their modifications were at the core of the bioproduction of new products (recombinant proteins, monoclonal antibodies). In the case of hiPSC, the final products of the bioprocess are the pluripotent stem cells themselves, and their modifications may induce variabilities and worrisome ethical issues. Counterintuitively, the almost simultaneous emergence of the CAR-T cell technology would become a support to the hiPSC technology. In both approaches cells are the final products, complexity of high-quality mass production is similar, dedicated facilities have to be acquired, the issue of autologous versus allogenic has to be considered and, last but not least, genomic integrity has to be fully mastered.  In spite of all the mentioned hurdles, in a November issue of the New York Times, an article stated there are currently fifty ongoing clinical trials using stem cells in various therapeutic indications. To the best of our knowledge all of them are using progenitor stem cells with the potential risk of inducing undesired cell proliferation.

Within this very fastmoving environment, TreeFrog, a start-up company founded by Kevin Alessandri and Maxime Feyeux, in 2018, in Bordeaux, France, has made considerable progress and has already raised $82 million with the completion of a $75 million series B in September 2021. Their motto is “making cell therapies safer, more efficient, more accessible and more affordable for millions of patients”. The originality of TreeFrog relies in their C-Stem® technology which is disruptive because it allows 3D culture in classical bioreactors rather than 2D culture on Petri dishes. In April 2021, TreeFrog announced a world-first, with the production of a single batch of 15 billion allogenic stem cells in a 10-liter bioreactor within 6.59 days, starting with only 50 million cells, resulting in an precedented 276-fold expansion. This raw material would be sufficient to deliver 10,000 doses for the treatment of Parkinson’s disease.

Why did the C-Stem® technology allow this leapfrog increase?

Stem cells are very fragile, highly sensitive to shear stress and cannot be produced as such in mass quantities in bioreactors. The C-Stem® technology consists in an automated cell alginate encapsulation which allows to protect an in vivo-like biomimetic cell culture environment in large bioreactors.  This in sharp contrast with the usual cell culture in Petri dishes where hundreds of plates need to be maintained over weeks requiring labour intensive and costly manipulations.

During the interview, on December 3^rd, Maxime Feyeux made very clear that from the inception of the company, the Treefrog founders had in mind “that to be successful, they had to be able to mass produce, safe, efficient, highly reproducible and affordable products to patients” he said.

Three years after the launch of the company the current results are already remarkable:

• tens of billions of therapeutic stem cells can be produced in a single batch within one week at drastically reduced costs.
• hiPSC quality produced with C-Stem® will be assessed by an international Quality Control-Stem consortium uniting world class experts from the Harvard Stem Cell Institute (HSCI) in Boston (USA), the Foundation for Biomedical Research and Innovation (FBRI) in Kobe (Japan) and the Imagine Institute in Paris (France).
• Furthermore, preliminary results suggest that the C-Stem® technology is capable of maintaining genomic integrity through large-scale hiPSC expansion. In fact, the current process is of sufficient high yield to only require a maximum of six passages per batch and thus avoid issues with accrueing passages.
• The company has ongoing contracts with two Fortune 500 companies and an in-licensing agreement with the les Etablissement Français du Sang (EFS), the French Blood Agency.
• TreeFrog Therapeutics has already incorporated a subsidiary in Boston and will do so in a short future in Kobe to set up hubs with the aim of driving the adoption of the C-Stem® technology in the USA and Japan, through an open innovation strategy, blending co-development, in and out licensing deals with local major actors.

What is next?

• Construct and consolidate a pipeline of products for small volume (millions of cells) therapeutics for Parkinson’s disease, blood and immune disorders, up to large ones (several billions of cells per dose) for heart failure and liver disorders.
• Validate the entire C-Stem® GMP process.
• Start a clinical trial for Parkinson’s disease with C-Stem® labelled hiPSC in 2024.

The current ten ongoing cell therapy clinical programs for Parkinson’s disease rely on the transplantation of stem cell-derived progenitors, which are expected to differentiate in the host brain into dopaminergic neurons without an undesired risky differentiation. Treefrog has already demonstrated that C-Stem®-produced hIPCS could be differentiated into 3D microtissues of mature neurons and performed the world’s first transplantation of mature neurons into an animal model of Parkinson’s disease. Treefrog reported full motor function recovery in eight weeks versus sixteen weeks with progenitors in three separate in vivo studies. The mechanical resistance of the 3D microtissue facilitated surgery and allowed better integration with eight times more engrafted dopaminergic neurons according to the study reported at ISSCR 2021. The human clinical trial protocol of the C-Stem® labelled hiPSC is already under discussion with EU and US health authorities as well as with patient associations.

 It has always been a rocky road for pioneers, and it will undoubtedly be true for those who will engage in the hiPSC field.  Players on the pitch are not numerous but highly determined ones such as: 

Center for iPS cell and Application (CiRA) and the Institute for Integrated Cell-Materials (ICeMS) in Kobe, Heartseed in Tokyo partnered with Novo Nordisk, Astellas Pharma in Tokyo, Fujifilm in Tokyo, Sana Biotechnology in Seattle, Bluerock Therapeutics in Cambridge acquired by Bayer, Clade Therapeutics in Cambridge, Vertex Pharmaceuticals in Boston, Fate Therapeutics in La Jolla, IStem in Evry¸ Roche in Basle and Johnson and Johnson in the US.

“Our ultimate goal is to provide cell therapy for all at an affordable cost. To succeed in this race, we know we have to jump through a fire circle. We are preparing for it” Maxime Feyeux said while concluding the interview.

Paris, December 14, 2021.

The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.