Rare disease expert to continue trailblazing drug development

Could you give us a brief history of your company?

We were founded in 1975 and began as an R&D-centered enterprise mainly focused on extractable biological products. However, right from the start, we were mindful of improving purification techniques and advancing towards recombinant DNA technology. With that vision in mind, we deployed our researchers and collaborated with academia, starting with Kyoto University, where our team performed viral research and began engaging in bioengineering. In the US, we reached out to the University of Alabama’s Department of Pediatrics in their virology program. At that time, we had a number of researchers being exposed to different work environments as they gained experience and broadened their knowledge. This was to become the basis upon which we grew our knowledge of recombinant technology and gene therapy.

Strengthening our research capabilities by exploring and utilizing cutting-edge technologies was our trajectory from then on. Our core focus is the research and development of proprietary recombinant technologies. It has now been more than 20 years since we started developing a follow-on of the then existing recombinant product on the market as an exercise of our glycoengineering. This endeavor allowed us to gain valuable experience in the field. However, it was challenging in terms of drug development. At that time, there were no biosimilar guidelines introduced by Japan’s Ministry of Health, Labour and Welfare (MHLW), so we had to develop our product as a new drug requiring full-scale toxicology and clinical studies. Ultimately, these efforts gave birth to our Erythropoietin (EPO) for hemodialysis treatment, the first ever “made in Japan” biosmilar approved in Japan, in 2010.

However, we didn't plan to build our company as a biosimilar company. The research into EPO was just a model we used to validate our recombinant technology. This led to the development of a more complex long-acting erythropoietin, darbepoetin, which is a biosimilar we created in response to the requirements of our partner company.

In 2009, a significant change occurred in our company when we partnered with GlaxoSmithKline (GSK) to develop multiple products for rare diseases, specifically lysosomal storage diseases (LSDs). The first program was an enzyme replacement therapy for mucopolysaccharidosis type 2 (MPS II), better known as Hunter syndrome, a rare disease. Back then, we were developing a therapeutic enzyme comparable to the commercial product on the market as a treatment for MPS II. Through our partnership with GSK and our interaction with patient advocacy groups, we realized that while traditional therapeutic enzymes could treat the somatic symptoms of the disease, they were ineffective in treating conditions related to the central nervous system (CNS), where substrates accumulated in the brain in the severe cases of MPS II. That inspired our research team to develop a new technology that would enable a drug molecule of interest to cross the blood-brain barrier (BBB). The result of our efforts became our core platform technology, the J-Brain Cargo^®. We are currently applying the J-Brain Cargo® technology to more than 16 programs in our LSD pipeline.  Notably, IZCARGO^® (pabinafusp alfa or JR-141) is the first therapeutic enzyme ever utilizing our J-Brain Cargo^® technology to cross the BBB, and it was approved in Japan in March 2021 for the treatment of MPS II.

IZCARGO® is the first-ever approved enzyme replacement treatment that penetrates the BBB via intravenous administration for the treatment MPS II. The product was approved in March 2021 in Japan.

The development of TEMCELL^® came about in a rather opportunistic fashion. When we began to understand the potential of mesenchymal stem cells (MSCs), we began developing a cell-therapy based medicine. The development of MSC-based solutions was, and remains, a challenging field due to the many uncertainties around the effectiveness of stem cells and cell therapy. In 2003, the functionality and possible uses of stem cells were totally unknown to us, so venturing into that field of research was a challenging endeavor.

TEMCELL® HS Inj. is the world’s first therapeutic product using mesenchymal stem cells for the treatment of acute graft-versus-host disease (acute GVHD), a severe complication arising from hematopoietic stem cell transplant. The product was approved in September 2015 as Japan’s first allogeneic regenerative medical product and launched in February 2016. (Source: JCR Pharma)

In a licensing agreement with Mesoblast (rights acquired from Osiris Therapeutics), we obtained the rights of a truly niche field: graft-versus-host-disease (GVHD). While many leading companies involved in cell therapy have ambitious ideas about the applicability of cell-based medicine, proving the efficacy of cell-based therapies in a clinical setting is extremely challenging.

In acute GVHD,  if the first line of treatment with steroids fail, it can become a life-threatening condition. Therefore, it was determined to be worthwhile for us to investigate whether stem cell therapy could be a beneficial treatment for this condition. It took us around 13 years to get approval for TEMCELL^®, and we are proud that we have worked diligently to address this unmet medical need.

While the current clinical successes of MSC therapies are encouraging, the predominating failures emphasize the difficulty of predicting immunomodulatory and regenerative effects within human trials.

Do you see any limitations or issues in regenerative medicine as a business model?

It was the right decision for JCR to narrow the indication of TEMCELL^® to GVHD and not target a broader market. During the manufacturing of TEMCELL^®, we follow strict specifications to grow the cells (derived from human bone marrow) on a massive scale, which has many challenging aspects. Additionally, the collection of human bone marrow for this kind of commercial purpose is not permitted in Japan. While sourcing bone marrow poses  a challenge, on the other hand, we have a different team focused on developing an allogeneic regenerative medical product  derived from dental pulp sourced in Japan. Currently, a large-scale clinical trial for acute stroke is being conducted in collaboration with Teijin Limited.

How do you think regenerative medicine will evolve in the next 10 to 15 years?

When regenerative medicine was introduced about 10+ years ago, people thought it would be a cure for everything. We know now that this was a clear overstatement. I even question whether the large-scale adoption of regenerative medicine will happen in the next 10 years. It may be possible to combine stem cells with other technologies related to gene therapy, for example, but many challenges remain. However,  JCR will continue to develop and leverage the cell technologies we have already invested in for other fields, where appropriate.

JCR Pharma is focused on the treatment of LSDs, which requires passing the BBB. As a highly selective semipermeable border, the BBB is difficult to penetrate. In recent years, a variety of techniques have been developed to penetrate the BBB, including biomechanical methods that expand the capillaries; the use of endogenous transport systems; and even the utilization of nanoparticles. What are the advantages of the J-Brain Cargo^® technology in comparison to these other methods?

There are many companies attempting to come up with barrier penetration solutions. We believe that J-Brain Cargo^® technology is the most useful and practical.

When creating J-Brain Cargo^®, we had the opportunity to conduct in-vivo experiments on mice, as opposed to the more common in-vitro approaches using petri dishes. We used a unique mouse model which we call “knock-in” mice, where the human receptor is incorporated into the mouse. By virtue of this approach, the efficacy of our solution can be evaluated much more accurately than that of our competitors.

As to how we differentiate from other companies: we know that some competitive companies focus on low affinity molecules. Our BBB-penetrating enzyme, JR-141, (pabinafusp alfa, commercial name IZCARGO^® for the treatment of MPS II (in Japan)  is a protein  enzyme fused with the J-Brain Cargo^® technology to treat MPS II. When dosed into a human, we know that the concentration in plasma is lower than that of competitors’ molecules. Additionally, there is an uptake of that enzyme into the brain, and it is distributed to other tissues and organs for a short period of time as well. So, we believe that “optimal affinity” is important, not higher or lower. Clinical studies support our findings and prove the efficacy of our technology. In March of 2021, the Ministry of Health in Japan approved JR-141. We are now conducting a Phase 3 global study in Brazil, Europe and the United States. Notably, our 2020 acquisition of ArmaGen played a strategically important role in strengthening JCR’s patent position in the US.

How are you integrating ICT technologies into your products?

We have a core product, GROWJECT^®, which is administered to mostly children on a daily basis. Enhancing patients’ quality of life is important. In partnership with PHC Corporation, we co-developed a motorized drug delivery device. The device is a smart injector, programmed to conduct dosing and automatically collect data. In the near future, a patient will be able to instantaneously share the data collected with his/her physician.

GROWJECT® is a recombinant growth hormone. Approved for production and marketing in 1993 for the treatment of short stature primarily caused by growth hormone deficiency in children, GROWJECT® is mainly used in large hospitals and specialized clinics. (Source: JCR Pharma)

Can you tell us more about the role of co-creation in your business model and its relevance to your international expansion?

Commercially expanding our LSD treatments outside of Japan is a challenging endeavor. Amongst other things, expansion depends on the local patient population. In certain regions, people affected with such diseases may be just a few hundred, a reasonable population size for JCR to undertake on its own. However, if the patient population is significantly larger, we would need to seek collaboration with a partner. This could translate into a licensing agreement with a local enterprise.

Additionally, we have had discussions with other companies about applying the J-Brain Cargo^® technology to diseases other than LSDs. For example, we are in discussion with companies that are interested in using our J-Brain Cargo^® technology to develop treatments for CNS-related conditions, including Sumitomo Dainippon Pharma, with whom we collaborate on certain cerebral and CNS conditions.

JCR has opened overseas offices and bases in Brazil, the US and Switzerland. What are the benefits of this international sales and R&D model?

Our overseas offices in the US and Brazil are intended to facilitate clinical development of JCR’s investigational products, introduce the JCR group and build its presence in those countries.

We chose Brazil as the first foreign country to develop our JR-141 for MPS II because when we made an announcement about initiating clinical studies in Japan, we were immediately contacted by a key opinion leader (KOL) in Brazil as well as the president of a patient advocacy organization, a father of a boy diagnosed with MPS II. They both visited us in Japan and urged us to conduct a clinical study in Brazil, where the environment was suitable to initiate a Phase 1/2 study expeditiously.

JCR implemented a mid- to-long term strategy entitled “Toward 2030.” Under that strategy, JCR aims to become a “research-oriented specialty pharma company with global exposure.”

In 2025, we will celebrate the 50^th anniversary of our company! Hopefully, I will have remained healthy and mentally sharp! My hope is that by 2025, our J-Brain Cargo^® technology will be adopted globally.

I see the current period as a turning point for the company. We have introduced a series of changes within our organization, including new board members. We have also made large investments to attract new talent to develop the next platform technology after J-Brain Cargo^®.

In 2020, Reuters and the New York Times reported that you would be producing the COVID-19 vaccine of AstraZeneca for the Japanese market. What investments have you made to accomplish this task?

At the moment, we are using our current facilities. As production of the COVID-19 vaccine intensifies, we plan to construct another manufacturing site. We are one of the very few biotech companies in Japan who can undertake this kind of advanced biotech manufacturing operation. Making vaccines is not a core activity of JCR, however, given the current unprecedented circumstance, we are committed to using our manufacturing capabilities to address the social needs and respond to the Japanese government.

On a personal level, what objectives would you like to achieve over the next five years?

In five years’ time, I will be 83 years old! I hope that JCR will have a clear global presence by that time. My motivation in working at JCR has always been my passion for research. While many entrepreneurs are driven by the desire to “start a business,” my main driver is to create innovative platform technologies that can pave the way for new treatment options for patients and their families affected by rare disease around the world. As such, I hope that in five years I will still be engaged in research and discussing new R&D ventures with our scientists.

The content of this report is intended to introduce the history and business of JCR pharmaceuticals and does not constitute an advertisement or recommendation for the use of pharmaceuticals.