Exploratory research for new pharmaceuticals is generally an upstream process that involves exploring compounds for possible use as new drug candidates. By contrast, new processes which seek to develop pharmaceuticals based on downstream clinical factors or patients' symptoms may offer potential to yield new treatment modalities for those afflicted.
For this interview, we sat down with Masashi Suganuma and Kinji Fuchikami, founding members of Koinobori Associate Inc., which is developing new treatment modalities for mitochondrial disease, as well as Tomoaki Shinohara, who comes from a family battling illness. We talked about the nature of their work and LUCA Science Inc., a venture spun off from their main activities.
At center: Masashi Suganuma, board director (chairman and director of Suganuma Clinic) At right: Kinji Fuchikami, director (Mitsui & Co. Global Investment, Inc. (MGI) venture partner) At left: Tomoaki Shinohara, director (comes from a patient family and head of the 7 Seas Project)
Tackling rare ailments "mitochondrial disease"
――The founding members of Koinobori were you, Mr. Suganuma, Mr. Fuchikami, and Taro Inaba (founding partner of Remiges Ventures). Could you tell us a bit more about what went into that?
Fuchikami: Yes, that's correct. We had worked together at a pharmaceutical startup that went public in 2009.
Suganuma: At the time, there was a major gap between those working in the medical sector and those producing pharmaceuticals. Mr. Fuchikami, a venture capitalist, strongly felt the same way about this issue. We felt that the prevailing context was not helping develop seeds for progress, with each camp totally separate from each other. We began talking about having a non-profit to support these two and act as a bridge between them. Patients with rare diseases have real complications associated with their condition, and there are few patients afflicted, with few doctors to treat them, so pharmaceutical companies generally do not know how to begin approaching the issue.
Fuchikami: At such time, Mr. Suganuma's nephew developed mitochondrial disease, and as we begin researching the illness, we shifted our focus to that. Critical to this process was having a real-world issue relevant to us as a problem to focus on solving.
――Tell us more about mitochondrial disease.
Suganuma: The mitochondria are organelles that reside within cells. They use nutrients broken down from food to produce ATP (adenosine triphosphate), a key source of energy for the body. Mitochondria produce over 90% of the body's energy. Mitochondrial disease is when an abnormality occurs in mitochondrial DNA or nuclear DNA. This abnormality has the greatest effect on the brain and muscles, as well as the eyes, nose, heart, liver, and digestive organs, and in the endocrine and vascular systems.
――How did you arrive at the name "Koinobori?"
Fuchikami: Mr. Suganuma came up with the name while watching carp streamers, that means "Koinobori" in Japanese, fluttering on the banks of a riverside.
Suganuma: Given that children are generally the subject of focus with genetic diseases, keywords for us were "family," "children," "health," and "growth." He happened to see these carp streamers, which represent the healthy growth of children in Japan, so we adopted this as our name. With the above keywords in mind, we began the project with a focus on mitochondrial disease.
A miraculous encounter and compassionate use
――What led to you joining the project, Mr. Shinohara?
Shinohara: My daughter, Nanami, was born in 2012. She developed mitochondrial disease within five months of birth, and was diagnosed with six months left to live. As her father, I was unable to cope with the idea of standing by as she died. I did not have a background in pharmaceuticals or science, but I discovered that a pharmaceutical startup in the US was developing a possible treatment, so I contacted them right away. They replied to me, saying that Koinobori, a Japanese organization, could probably help me. This is where I first met the team.
Fuchikami: Around that time, we were looking for an R&D team for mitochondrial disease treatments, and we had gone to meet the CEO of the American pharmaceutical venture.
We implored them to work with us, saying that we were deeply interested in their program and would like them to develop treatment drugs for Japan. This led to the subject of Mr. Shinohara, and they allowed us compassionate use (extraordinary use of unapproved drugs from a humanitarian point of view) of the drug for Nanami.
Thanks to a pharmaceutical consultant with whom we work closely, we were able to gain special authorization under the compassionate use system to import the EPI-743 mitochondrial treatment drug into Japan. Under the auspices of a doctor, we were able to gain approval for administering the drug from the IRB (Institutional Review Board), a miraculous outcome.
Shinohara: My daughter was in the ICU and in critical condition. She had only two weeks left to live. Thanks to the compassionate use approval, we were able to keep her alive. Yet she remains today bedridden and connected to a respirator.
Suganuma: After Koinobori substantively began operations in August 2009, we dedicated about 18 months to research development of treatment drugs for mitochondrial disease. In January of 2011, we resolved to support development of new compounds in the US with an American startup, and we gained authorization for compassionate use of their drug for Nanami in 2012.
The following year, clinical research began at the National Center of Neurology and Psychiatry (NCNP). Through this chance encounter, we decided to have Mr. Shinohara come on board. The organization was formally incorporated as a company in 2013.
――So things began in earnest in 2013, then.
Suganuma: That's right. We then partnered with the United Mitochondrial Disease Foundation (UMDF), based in the US, and obtained a range of information. To tell the truth, though, we came to realize that outside of the compound we had gained compassionate youth authorization for, there were no other useful drugs on the horizon. We held meetings at three sites nationwide to exchange information with patients and their families and share data on global development of new treatment drugs, as well as get feedback and insights about patients' daily lives with these ailments. These meetings proved exceedingly beneficial, allowing us to pinpoint key issues of concern in specific ailments.
Mitochondrial diseases affect the eyes, so ophthalmologists check those symptoms. By contrast, neurologists handle other aspects of the disease, so these two domains are compartmentalized, we found. We wanted to bridge this gap, so we had medical scientists from an American firm conducting R&D into treatment drugs for LHON (Leber's hereditary optic neuropathy) give talks at ophthalmology seminars and research groups, which was a way of fostering debate and discussion around how to treat these ailments and what key points to focus on in terms of drug discovery.
――Does Koinobori work with patient associations directly?
Suganuma: No, as we feel that we need to keep some distance when it comes to drug discovery in terms of taking a rationalized approach. If we take into account that these drugs may be used for treatment in the future, our position must remain neutral. Therefore, when holding sessions to exchange information, we approached a wide range of stakeholders, not just patient associations.
Fuchikami: Patient associations have a different outlook and goal in mind. After meeting with groups in the West, we came to find that the thrust of Koinobori as an organization is somewhat different. Patient associations in the West are very systematized as organizations and play a public role, with chairpersons and CEOs, and deliberation each year at annual meetings as to which projects to support. Projects on which a resolution passes are then eligible for charitable donations and public funding. By contrast, Koinobori functions in a pro bono capacity.
Suganuma: Through our work, we have elucidated the fact that projects for research and drug discovery for mitochondrial diseases are lacking around the world, so we want to spearhead change and make this a reality. We created an ethics board in 2015 and launched the 7 SEAS PROJECT as a means of conducting observational research.
The drug discovery process as a linear approach
――The project seems to get its name from the Kanji meaning of 七海's name, which means "seven seas." Could you tell us more about this project?
Shinohara: The 7 SEAS PROJECT (7SP) is designed to support drug discovery research. Between 2015 to about 2016, we approached a range of researchers and made the rounds at conferences, read up on the latest papers, and met with various doctors. This led to some collegial relationships with doctors and specialists and enabled us to launch 7SP as a venue for joint research.
After internal deliberation and discussion, we began to develop a hypothesis for what treatment modalities we were looking for. We then reached out to specialists with whom we wanted to pursue that research, and we built out a network, with Koinobori acting as a hub that links various researchers and doctors.
――So how do you go about linking the researcher community with the community at large in society?
Suganuma: This is something Mr. Shinohara is hard at work on for us. We periodically hold meetings with contributors, among them researchers and members of the lay public, creating a community with whom we share information.
Shinohara: We refer to philanthropists as Honorary Fellows, with our research-oriented community meetings as "Fellows Meetings." These are held once annually. We have scientists take the podium to speak and we make this an opportunity to exchange information and findings on the latest research.
――Where do you procure funding for research?
Fuchikami: We have two avenues. The first is charitable donations from members and philanthropists, and the second is donations made against the future value of research outcomes.
Suganuma: Funding is instrumental to the process of drug discovery, which is different from just "supporting" research. In order to delineate our objectives more clearly and raise funding, we focused on creating discrete projects. We explored various organizational approaches, such as creating a separate framework for funding. Ultimately, we arrived at the idea of launching 7SP as a group internal to Koinobori.
Mr. Shinohara then agreed to act as project leader. Nanami is like a symbol of the issues we face with Leigh syndrome and mitochondrial diseases, so we took inspiration from her name to christen this as a project seeking to cure those diseases.
We made the rounds with various corporate investors and philanthropists to raise funding, but as an organization conducting exploratory research, we did not have a proven body of data to show, so we were unable to raise a vast amount of funding all at once. Therefore, we rely on donations from members or the families of patients, as well as the use of the READY FOR crowdfunding platform.
――Ordinarily, when you have the seeds for drug discovery, you can turn to public research grants or several stages for funding tailored to VC milestones. But in your case, you were starting further upstream, before that process.
Suganuma: We had our hypothesis, but no one actively pursuing research in that area. So we began by approaching researchers doing similar work and asking them if they could share some research findings on mitochondrial disease. In terms of creating a startup and raising funding, you generally need the minimum patents to demonstrate your technology and solid data to back it up. To obtain public research monies from AMED (the Japan Agency for Medical Research and Development), you need to have some demonstrable track record in the target domain.
Going forward, we will be conducting joint research with universities in order to build up a demonstrable background in drug discovery. In terms of patents, Mr. Inaba, one of our directors, looked up some of the major lawyers in the US and found a law firm willing to take on our project on a pro bono basis. Furthermore, we have Japanese lawyers on board on a pro bono basis.
Fuchikami: Only one in ten drug discovery projects get off the ground and reach the clinical phase. And only one in ten of those are ultimately approved as new drugs. You may have an outstanding idea but be unable to yield persuasive data to back it up. I previously worked in drug discovery research at a pharmaceutical firm. Sometimes, I would get an idea from a paper and put it into practice, but was unable to reproduce the data described. This kind of thing happens many times. In that sense, we are moving ever forward through trial and error.
――What are some key points for 7SP?
Fuchikami: We believe having a clear objective and purpose that people can relate to is important. For example, pharmaceutical firms tend to take an upstream approach without necessarily knowing the fundamentals of the patient's reality. They want researchers to find new molecules or mechanisms that can be turned into drugs consumed once daily. But 7SP is patient-centric and begins with considering the patient's condition and how to treat it. In other words, our awareness of the issues starts from the bottom up, rather than vice versa. Traditionally, you set goals and milestones in a linear progression, and if these do not go to plan, the drug discovery process comes to a halt. For many engaged in basic research, the process of pursing research while engaging with real patients is eye-opening. As we spearhead the 7SP project, we think this will become even more refined going forward and lead to a paradigm shift.
LUCA Science, a drug discovery venture spun off from 7SP
――Tell us more about your plans for joint research and the future.
Suganuma: We have spent about two years entering into agreements with eight universities. We have tooled the 7SP package to allow us to bring research outcomes as more tangible outcomes to patients. The project is designed such that patients are at the forefront. We have a core foundation that allows us to engage research institutes. Around summer of 2018, we had new patents, the result of three projects, subject to provisional filing in the US. In December of 2018, we established LUCA Science.
――So LUCA Science was spun off from Koinobori?
Fuchikami: We had three core projects in progress, and LUCA Science was the result of those. Koinobori periodically shifts focus to a specific project and then drives a specific one forward. Next time we get a breakthrough with Koinobori, we may turn to spinning it off again in the future.
Suganuma: We definitely want to make LUCA Science a success in its own right as a company. It takes time to treat intractable diseases. We need time, funding, and lots of people's help. One concrete treatment modality we are considering is transplanting healthy mitochondria in patients. We are hastening to obtain a patent for a mitochondria (a type of organelle) that looks like it would prove useful for organelle transplantation.
――Could you tell us more about your future outlook, and share any pointers with LINK-J?
Fuchikami: The question is what outcomes you can bring to patients on the ground. Our mission is creating new pharmaceuticals for the next generation. Yet maybe one in one thousand researchers is lucky enough to achieve this. To that end, we want to create a new structure for drug discovery that can be passed down for the future. It is not merely a black box process of shaking test tubes and peering at the contents. We need to bring together philanthropists and determine precisely what needs real patients have. I consider this my life mission.
We are truly grateful to LINK-J for everything you are doing for the field. Above all, we are grateful for your providing this venue. We also think it is essential that we gain the understanding of those involved with LINK-J, the pharmaceutical industry, and academia about our project, so we greatly appreciate the showing of support.
Shinohara: The networking night held in December last year was an outstanding opportunity. Ultimately, patients fervently want to find a cure. Our goal is sharing that zeal to live with pharmaceutical manufacturers and helping make that a reality. So having LINK-J, for instance, provide a venue for a patient-centric approach to sharing our work is ideal. Our foremost goal is bringing patients' real feedback to a wider audience, so we hope to continue doing just that.
Suganuma: As we move through the initial stages of growth, having people with entrepreneurial experience, those who understand the sciences, capitalists who want to help remedy rare diseases, and patients' families to drive us forward -- having this total combination - will create a winning team.
If anyone reading this would be interested in creating a new working group within Koinobori or partnering with us through LINK-J, we would love to have them. Having patients involved makes the process more tangible, real-world, and drives it forward. Having the backing of corporations, VC, and scientists enables us to go forward. Moreover, pro bono support is extremely meaningful, so creating a context for lawyers to want to offer their services is important. It's about enabling various players to enter the field and create that new wave of change. The scope we can focus on is perforce limited, so we welcome everyone's continued support and encouragement.
――The efforts being made by Koinobori may give a hint of the future of the Japanese medical industry and serve as a useful role model. We encourage you to continue with delivering useful treatments to patients. LINK-J is hopeful for the outcomes and will continue supporting you going forward.
Making charitable donations
Charitable donations to and support of the 7 Seas Project from readers are welcomed through Shinrai Shihon Zaidan. As with the Hometown Tax system, these contributions are tax exempt.
For details, please visit the donation site.