2 3

4 Interview President Shigenobu Maekawa

“We strive to develop new drugs and provide good news for patients”

6 Developing the first domestic “nucleic acid medicine”

Originality, Passion and Teamwork

10 Our Product Portfolio: Focusing on Five Areas of Medical Specialty

12 P R O J E C T We take pride in our work

Delivering products with a distinctive edgeDrugs “grow” tooSales and marketing is a team effortMedicines travel across borders

22 Corporate Social Responsibility: Contributing to people’s health and prosperous lifestyles

24 A writer with the trained eye of a doctor Ryota Hosoya speaks about Nippon Shinyaku

column It starts with a healthy future

11 A state-of-the-art manufacturing plant for highly active solid formulations now completed

17 We develop dietary supplements only a pharmaceutical company can pull off

23 Turning lively, carefree ideas into picture books

26 Corporate Profile & History

From Kyoto We Aim for the Future

(cover) Tetsuya Higashikawa*(photos page) Takuma Imamura, Tetsuya Higashikawa**Photography Department

c o n t e n t s

4 55

ShigenobuMaekawaPresident

with the president

InterviewI am always thinking about ways to improve and enhance our

drug development pipeline. The ultimate goal is “to launch at least one new drug a year”. Nothing more, nothing less.

This is actually what I set out to do when I became president of Nippon Shinyaku back in 2007. The company was going through a tough time in regard to drug development. Employee morale was low, and I sensed a marked lack of energy. As the top executive I had to find a way to overcome difficulties. So I made this pledge, setting a specific target. I announced that we were going to work hard to achieve the goal. I knew our backs were against the wall and all we could do was fight gallantly.

In those days, the company lacked the willingness to meet chal-lenges, to take speedy action and investigate and analyze infor-mation. These values—challenge, speed and investigation—now serve as the company’s code of conduct. In order to realize our goal we have to strictly adhere to these three guidelines: there was no other way. I appealed to the employees again and again until I saw their eyes light up. They knew that I was committed.

Social security expenses were on the rise every year and affect-ing our business environment. We were facing higher hurdles that made new drug development even more difficult. Despite such obstacles, I decided that the way forward for Nippon Shinyaku was to pursue originality by developing our areas of specialty. We would be the first to take on the challenge and research fields that no other company has touched, develop drugs with speed in mind, while carefully investigating the situation. The strategy has served us well. So far, on average, we have managed to launch one or more new pharmaceuticals every year. Compared to existing pharmaceuticals the new drug must be superior in at least one aspect; drug effi-cacy, safety, or improvement of the patient’s quality of life (QOL). If not, we do not pursue development. This is the rule, and I make sure we stick to it.

That is why we have strong product devel-opment capabilities in the fields of intractable and rare diseases, including pulmonary arte-rial hypertension (PAH). There are patients out there who are in need, while there are no established treatments. If we could come up with high-quality pharmaceuticals, we could deliver good news for these patients with rare or intractable diseases. We want to become a company that is trusted and respected by society, prove our raison d’etre. That is what we strive for.

Specifically, in order to realize our goal, we established primary focus fields that center on urology, hematology, intractable and rare diseases. Through three avenues—in-house drug discovery, in-licensing from other com-panies and product lifecycle management (PLCM)—we continue to enhance our drug development pipeline lineup. Already, in the past decade, we have seen our revenue nearly double; we expect to achieve the financial target of the mid-term management plan to

fiscal 2018 without losing any steam. Regarding management, I support the “hands-on” management

style and push for “all hands on deck”—everyone pitching in. The job site is a treasure trove of information. It is important that I visit every location, any place around the world, and carefully lis-ten to what employees and relevant parties have to say. Sometimes I will pick up on something that I can’t let pass—which usually turns out to be an issue that requires immediate attention.

When I am faced with such pressing matters, I know I can always make a quick decision. That is because the answer is already there, in the voice of the employee. If a lot of employees get together and brainstorm, they will inevitably come up with the best solution possible. Every employee will feel that he or she “took part in the decision-making process”; and give their best when it comes to implementing the project.

The next mid-term management plan will be put together with the same “hands-on” and “all hands on deck” approach. The first year of the next mid-term management plan will be 2019, the year we celebrate the 100th anniversary of establishment of the com-pany. It will be an occasion to express our gratitude to everyone who has supported us. We will be eyeing the future, as we mark a

major milestone and renew our commitment for further development. Taking this perfect opportunity, at Nippon Shinyaku, we have just started a productivity enhancement activ-ity project called “Challenge 100”. We asked every section to come up with their own “unique challenge theme”, to challenge them-selves to take up a highly original, brand new assignment; and a “zero waste time theme” that will promote operational efficiency.

That said, these days, I often find myself with not much spare time. In the early days, even after I took on the role of president, my job rarely spilled into my non-working days, except for maybe a special company event or two. Things have changed dramatically. My work load has grown substantially along-side the expansion of our business opera-tions. These few years, I have spent most of my Saturday mornings going through piles of documents and reference material. I tell everyone at the company that I will look for a solution, and I hope you will look for solu-tions, too. That is what our “Challenge 100” project is all about. Keeping work and life separate is one way to keep people and the workplace energized.

Our company attaches paramount impor-tance to the pursuit of originality. We want people who can think on their own and act of their own volition to come and join us at Nippon Shinyaku. Versatility, to respond to changes in the environment; perseverance, to see things through to completion; ambition, to aim even higher. These are the three quali-ties that give us the strength to respond to the needs and expectations of patients who are waiting for our pharmaceuticals.

As long as there are patients in need

Find the answer in the voice of the employee

We strive to develop new drugs and provide good news for patientsTeamwork builds our identity“We will launch a new drug every year”.The announcement was made amid growing competition. It was a pledge to create pharmaceuticals that no one has created—to help patients and their families. Shigenobu Maekawa is the president of Nippon Shinyaku Co., Ltd., which will be celebrating its 100th anniversary of founding. He looks further into the future with plans to take his company to the next level of excellence.Compiled by: Toshihiko Ebata (Editorial Department) Photographs: Tetsuya Higashikawa (Photography Department)

“If they see that the top executive is committed, everyone on the frontline gets excited. Their eyes light up”

President, Nippon Shinyaku Co., Ltd.Joined the company in 1976. He became General Manager, Corporate Planning Division in 2002 after an assignment to the Japan Federation of Employers’ Associations (now Japan Business Federation), became director in 2005, managing director in 2006. He has been president since 2007. His hobbies are reading and mountain climbing. His favorite books are Tokugawa Ieyasu by Sohachi Yamaoka, Saka no Ue no Kumo (Clouds above the Hill) by Ryotaro Shiba, Shippai no Honshitsu—Nihongun no Soshikironteki Kenkyu　(Essence of Failure: Organizational Study of the Japanese Armed Forces during the World War Ⅱ) by Ikujiro Nonaka et al.

Shigenobu Maekawa

6 77

Originality, Passion and Teamwork

Bringing forth the long-anticipated “breakthrough drug” as soon as possible

Developing the first domestic “nucleic acid medicine”

A new drug is currently under development in the United States and Japan. “NS-065/NCNP-01” was discovered through a collaboration project between Nippon Shinyaku and the National Center of Neurology and Psychiatry (NCNP). The drug is being developed for the treatment of an intractable disease, Duchenne Muscular Dystrophy (DMD). It is attracting much attention around the world as the new drug that could provide a break-through for DMD treatment.

DMD is a genetic disorder with the highest incidence found in male children. It causes a severe loss of muscle power due to a deficiency of normal dystrophin, a protein that is indispensable in constructing the “framework” of muscle cells. This deficiency arises from mutation of the dystrophin gene. DMD is a serious disease that presents a dire prognosis. After onset of symptoms most patients will undergo loss of ambulation by their early teens. Cardiac and respiratory failures are the main causes of death, occuring in their twenties or thirties. It is also a rare disease, with an estimated 5,000 patients here in Japan. No effective treatment has been established, other than steroids which delay the loss of muscle power.

The new drug under development comes from the exciting new field of “nucleic acid medicine”. Nucleic acid medicines are pharmaceuticals that are synthesized from nucleic acid, the same building blocks that compose our genes. The new therapeutic technology directly targets the genetic base of the disease and pro-motes protein generation. Thus there are high hopes that nucleic acid medicines will make their mark as effective medical agents for treating hereditary disease. Here in Japan, major pharmaceuti-cal companies, universities and research institutions are involved in research and development of nucleic acid medicine. Among them, Nippon Shinyaku is considered to be the top runner, closest to receiving manufacture and marketing approval of the medi-cine. If the company succeeds in commercializing this product, it will become the very first short synthetic nucleic acid, or antisense oligonucleotide drug discovered in Japan.

Collaborative research with NCNP began in 2009. The whole company—R&D Administration Department, Discovery Research Laboratories, Discovery Research Laboratories in Tsukuba, Clinical Development Division—came together to take on the challenge.

Atsushi Hashimoto works for the R&D Administration Department which overlooks the project. He said: “We believe that the product we are developing will bring good news to young DMD patients. We want to conduct a solid evaluation and make sure that we can deliver the medication to patients as swiftly as possible.”

Let us take a close look at NS-065/NCNP-01 to see what kind of medicine it is (diagram on page 8). Genetic instructions are necessary for generating proteins that play an essential role in maintaining life and growth. Genetic instructions exist in sections of DNA (deoxyribonucleic acid) called “exons”. Multiple exons are linked together, and the entire DNA code is transcribed into a temporary form, to yield mRNA (messenger ribonucleic acid). The precise code for the amino acids that make up the protein is then translated to synthesize protein.

Normally, the genetic code for making the protein dystrophin is contained in 79 exons. For a DMD patient who lacks the exons 48 to 52, exon 47 is joined to exon 53 directly. The mutation results in a disruption of the “reading frame” and hampers production of functional dystrophin.

The drug under development has “exon skipping” properties. An exon skip induces the cellular machinery to skip over an exon (to skip over exon 53, in this example) and join exon 47 directly with exon 54. Thus the amino acid code can be read, allowing for the generation of dystrophin—which may be shorter, but still functional. This is how the synthesized nucleic acid, NS-065/NCNP-01, prompts the skipping of exon 53.

“Does the technology even exist?”Taking the road untraveled

“NS-065/NCNP-01” for treating Duchenne Muscular DystrophyNippon Shinyaku has been developing agents for the treatment of rare diseases that affect few people around the world. Our long-time efforts directed towards drug discovery and development are coming to fruition. We have overcome numerous hurdles and are steadily paving the way toward commercialization.Text: Hiroyuki Nishijima (Editorial Department)Photographs: Takuma Imamura (Page 6, bottom right page 7, top page 9), Aya Kishimoto (Photography Department)

Joined Nippon Shinyaku in 2001. Worked for the Clinical Development Department before joining R&D Administration Department in April 2016. He likes to play with his children on his days off.

Atsushi Hashimoto

R&D Administration DepartmentProject Management Section

Joined Nippon Shinyaku in 2012. Tone has been involved in research and development of nucleic acid medicines at Discovery Research Laboratories in Tsukuba. He enjoys ball games.

Yuichiro Tone

Discovery Research Laboratories in Tsukuba

8 9

Ever since it was founded, Discovery Research Laboratories in Tsukuba has been advancing research on and has accumulated a large amount of knowledge and knowhow on “nucleic acid” synthesis to develop new drugs.

In developing the drug, the first step was to come up with a sequence for multiple compounds that make up this “nucleic acid”. Discovery Research Laboratories in Tsukuba was established in 1997 to serve as the major research and development center on nucleic acid drug discovery. Discovery Research Laboratories in Tsukuba became the hub that propelled the study forward.

Yuichiro Tone has been working with nucleic acid medicine at the Discovery Research Laboratories in Tsukuba, conducting basic research and testing efficacy in cells. Tone said: “With nucleic acid drugs, you only need to build a sequence that targets a specific gene. So coming up with a molecular design is relatively easier compared to working with traditional drugs. That is one advantage. However, when it comes to efficacy, that is another matter. You have to keep on testing to see if it works. Even when you deliberately choose a sequence, knowing it should work—at least theoreti-cally—unexpected things happen. Quite often”.

Researchers came up with one design after another. And every sequence was tested using human cells. Each test would take about a week before results could be confirmed. It was a slow and tedious process that had to be repeated countless times before the team managed to come up with the optimal sequence. Tone said that bringing in cutting-edge devices such as a nucleic acids synthesizing system helped speed up the development process.

An investigator-initiated clinical study by NCNP (from June 2013 to March 2015) was conducted, fol-lowed by a phase 1/ 2 clinical study in Japan which began in January 2016. A phase 2 clinical study began in the US in March 2016. At this stage of clinical trials, it is crucial to secure the quality of the drug and insure safety and protection of human subjects. Rigorous quality control protocols covering a wide range of concerns had to be developed, including establish-ing a standard procedure to evaluate drug quality, and confirm that the levels of impurities were within an acceptable range.

Takuya Hamamoto is in charge of analysis and quality control at the Discovery Research Laboratories. He said: “There had been almost nothing going on regarding development of nucleic acid medicines here in Japan. So there was limited knowhow available regarding both technology and regulations. We had to overcome numerous challenges”.

One example was how to control the level of impurities. While safety had already been confirmed through animal experiments, it was still possible for internal impurities to appear while the inves-tigational drug was in storage. And this was a drug that affects a particular gene sequence. There was the possibility of impurities

intravenous drip. We were worried whether patients who lived far away from medical institutions could make regular visits for their procedure”.

According to the clinical trial protocol, trial subjects were male patients aged 5 to 17. In reality, most of the participants who take part in the trial are young boys in the lower grades of elementary school. They are youngsters who love to play and horse around. Assessment of the clinical study involves tests that measure how much a patient can walk in 6 minutes, and how long it takes for the patient to get up from the floor. It is important to find ways to get the young patients to cooperate and concentrate on the examination. Doctors, clinical research coordinators and physical therapists are constantly discussing ways to make things easier for the patients.

The most valid approach to assess the efficacy of the inves-tigational new drug is to see if there is an increase in dystro-phin levels inside the cells after administering the drug. Initially, the testing technology did not even exist. Akagi reminisced: “Everywhere we looked, we had to start from scratch. But our clinical development project team made it possible, taking us for-ward, step by step”.

Akagi is now busy visiting medical institutions, collecting data regarding the efficacy and safety of the investigational new drug. She commented: “Every single day, I am reminded how much the young patients and their guardians need this drug”.

Once a week Akagi shares her report with NS Pharma, Inc., a US subsidiary of Nippon Shinyaku, via audio conference. The information collected in Japan is used to help the clinical study in the US.

NS Pharma, Inc., based in New Jersey is in charge of develop-ment of the drug in the US. Taishi Yamashita moved to the US in May 2014, and quickly became one of the key members of the project team. He was instrumental in setting up the US-based clinical study, seeking out medical institutions that were willing to take part in the clinical trial, and liaising with patient associations. Yamashita collaborated with headquarters in Japan, met with clinical study consultants in the US and prominent researchers, to come up with a carefully thought-out strategy for implementing the clinical study. Yamashita said: “In the US, people in research and development are highly conscious of effective time manage-ment. There is a strong demand for speed in every respect”.

And of course, Nippon Shinyaku could not lose out against the competition. This was indeed proving to be a race against time.

In Japan, NS-065/NCNP-01 received a “SAKIGAKE desig-nation” from the Ministry of Health, Labour and Welfare in

October 2015. The designation allows for a prioritized consulta-tion, shortening the review time for regulatory approval. In the US, NS-065/NCNP-01 was granted Fast Track Designation in October 2016 and Orphan Drug Designation and Rare Pediatric Disease Designation in January 2017, from the Food and Drug Administration (FDA).

Yamashita said: “It is a once-in-a-lifetime opportunity—to see a new drug that you helped develop go on the market. I am grateful to be part of this meaningful endeavor”.

Nippon Shinyaku is aiming for commercialization in Japan at the earliest time possible. The company must prepare for a phase 3 clinical study, and apply for approval. There is still a lot of work that must be completed. To “become the pioneer in nucleic acid medicine” and to “bring new drugs to patients who are waiting in hope” —these are the two goals that inspire and motivate the employees at Nippon Shinyaku. Their strong commitment and unwavering passion serve as the driving force for advancement.

affecting a different gene, which then led to another question: “In the field of nucleic acid medicine, does the technology to test for impurities even exist?” Hamamoto and his team kept on going, working closely with people in the production sector to address each difficult task.

During this time, Michiyo Akagi at the company’s Clinical Development Department was racing around trying to find patients who were willing to take part in the trial. As stated before, DMD is a rare disease. She began her search near the company headquarters, and widened the search, even reaching out to medical institutions far away in Kyushu, to collect detailed information regarding DMD patients. Akagi said: “The inves-tigational new drug needs to be administered once a week by

PROJECT:History

Collaboration between Nippon Shinyaku and National Center of Neurology and Psychiatry (NCNP) began

2009

An investigator-initiated clinical study by NCNP started

June2013

March

An investigator-initiated clinical study by NCNP completed

2015

October

Received “SAKIGAKE designation” from the Ministry of Health, Labour and Welfare

2015

January

A phase 1/2 clinical study started in Japan

2016

March

A phase 2 clinical study started in the US

2016

October

Fast Track Designation granted by the Food and Drug Administration (FDA)

2016

January

Orphan Drug Designation and Rare Pediatric Disease Designation granted by the FDA

2017

NS-065/NCNP-01 is a nucleic acid medicine with “exon skipping” properties. In this example the DMD patient is lacking exons 48 to 52, allowing exon 47 to join up with exon 53 directly, which causes a mutation in the amino acid “reading frame” and hampers production of normal dystro-phin. The new medication induces an exon skip over exon 53. Thus exon 47 joins directly with exon 54. Now the amino acid code can be translated, resulting in the generation of dystrophin that is shorter but still functional. Muscle function can thus be sustained.

In Duchenne Muscular Dystrophywith exons 48 to 52 missing

How exon skipping works

Skip exon 53 with “NS-065/NCNP-01”

45mRNA 46 47 53 54 55

DNA 46 47 53 54 55

Mutation prevents generation of functional dystrophin

Generation of shorter but functional dystrophin

DNA 45 46 47 53 54 55

mRNA 45 46 47 54 55

The “reading frame” of the amino acid is translated

Exon 47 can join up with exon 54 directly

Disruption of the “reading frame” of the amino acid

Exon 47 joins exon 53 directly

NS-065/NCNP-01 causes skip over exon 53

exon

exon

exon

exon

exon

exon

exon

exon

exon

exon

exon

exon45

We had to start from scratch, and evenestablished procedures to assess efficacy

“We can’t lose out to other companies”It is a race against time

Joined Nippon Shinyaku in 2008. He worked at Discovery Research Laboratories in Tsukuba before moving to Kyoto in 2009. His hobby is sea fishing.

Takuya Hamamoto

Discovery Research LaboratoriesCMC Research & Development DepartmentQuality Control

Joined Nippon Shinyaku in 2010. After working at Discovery Research Laboratories, he trans-ferred to NS Pharma, Inc. in April 2014. His hobby is soccer.(Photo courtesy of Taishi Yamashita)

Taishi YamashitaNS Pharma, Inc. R&D

Joined Nippon Shinyaku in 1999. She worked in drug information services before joining the Clinical Development Department in October 2015. Her hobby is yoga.

Michiyo Akagi

Clinical Development DivisionClinical Development Department

10 11

Our Product Portfolio：Focusing

on Five Areas of Medical Specialty

Nippon Shinyaku has identified five Focus Areas of Medical Specialty. They are intractable and rare diseases, urology, hematology, gynecol-

ogy and otorhinolaryngology. Using three avenues—in-house research aimed at developing original medicines, in-licensing from other com-panies, and product life cycle management (PLCM)—we are dedicated to the development of high quality, innovative medicine, spotlighting

diseases that have no established methods of treatment. We strive to deliver the good news to patients, that they can find relief from their suffering. This is our product lineup

for the five Focus Areas of Medical Specialty.Text: Toshizo Shimizu (Editorial Department)

This cutting edge “fluidized bed granulating dryer” was installed at the new plant. In the granulation process, primary particles are processed and mixed to form granules, which are later turned into tablets, using a tableting machine.

The sleek “tableting machine” manu-factured in Germany was designed by a famous sports car designer. It is the first time this type of tableting machine that compresses and seals the tablet contents has been intro-duced here in Japan.

The pharmaceutical “tablet coating machine” ensures that powder particles will not escape outside and contami-nate other products. The room environment is also decom-pressed for this purpose.

Nippon Shinyaku offers three products for treating pulmonary arterial hypertension (PAH). Uptravi®*1 is a selective IP pros-tacyclin receptor agonist, Opsumit® *2 is an endothelin recep-tor antagonist and Adcirca® is a phosphodiesterase 5 inhibitor. By offering three products with different action mechanisms we can provide a wider range of treatment options.*1 Co-promoted with Actelion Japan.*2 In-licensed from Actelion and co-promoted with Actelion Japan.

The construction of a new manufacturing plant for highly active solid formulations was completed in July 2017. The new plant, located at Nippon Shinyaku’s Odawara Central Factory compound in Kanagawa Prefecture, is equipped with state-of-the-art facilities including a tableting machine (bottom photograph). The plant has the ability to produce 400 to 500 million medicine tablets a year. For the time being, the plant will be producing Uptravi® tablets, for which the company received manufacture and marketing approval in September 2016. Uptravi® is used for the treatment of pulmonary arte-rial hypertension (PAH). In the future, the plant will continue to support the company’s endeavors to expand indications for Uptravi® from the production side, in addition to manufactur-ing the upcoming “NS-018”, a new drug now in development in the US, which is used to treat patients with myelofibrosis (MF).

The company first began considering plans for the new pro-duction facility in fall 2014. The decision became official in the summer of 2015, while Nippon Shinyaku awaited marketing authorization for Uptravi® in Europe and the US.

Mikiyo Fujiki is Department Manager, Production Planning Department at Odawara Central Factory. He reminisced: “For all of us involved in production, we had this burning desire to take care of everything at our own facilities. We wanted

to produce all pharmaceuticals, including highly active solid formulations that we couldn’t handle up until then, and every original in-house medicine that we were going to develop—on our own. We needed this new plant in order to provide a stable supply, and also, as a way to work on cost reduction”.

According to Fujiki, the plant will also be used for Nippon Shinyaku’s consignment manufacturing business, making full use of the technology and knowhow it has accumulated as an R&D-based producer of new medicine.

A state-of-the-art manufacturing plant for highly active solid formulations

now completed

A wish comes true for the manufacturing department

Text: Hiroyuki Nishijima (Editorial Department)Photographs: Akina Okada

Drugs for intractable and rare diseases

•Uptravi® •Adcirca®

•Opsumit® •Regtect®

Zalutia® is a remedy for urinary disorder caused by benign pros-tatic hyperplasia. The medication alleviates uncomfortable symp-toms such as difficulty emptying the bladder, frequent or urgent need to urinate, and weak urine stream, to improve patient QOL.**Quality of life

Drugs for urological diseases

•Zalutia® •Eviprostat®

•Bladderon® •Estracyt® •Cialis®

Lunabell® tablets LD is a female hormone agent that is widely used as a remedy for dysmenorrhea. Lunabell® tablets ULD con-tain a smaller amount of estrogen. Both medications are covered by health insurance in Japan.

Drugs for gynecology

•Lunabell® tablets LD•Lunabell® tablets ULD

Erizas® is a dry powder nasal spray for treating allergic rhinitis. The dry powder formulation contains a ste-roid as an active ingredient. The spray applicator packs a 14-day sup-ply of medication. Once daily admin-istration alleviates three symptoms of allergic rhinitis; sneezing, nasal dis-charge, and nasal congestion.

Vidaza® is used to treat myelodys-plastic syndrome (MDS). It is the only medication known to extend the survival time of patients with MDS. MDS is designated as an intractable disease. There are an estimated 12,000 patients in Japan who have been eagerly awaiting development of the new drug.

Drugs for otorhinolaryngologyDrugs for hematology

•Erizas® •Baynas®

•Azunol® Gargle liquid•Livostin®

•Vidaza®

•Cylocide®

•Cylocide® N•Trisenox®

•Amnolake®

COLUMN

It starts with a healthy future

1

12 1313

The successful launch of a new drug does not mark the completion of research and development. The nurturing process goes on—to make the drug safer and more effective, and to seek new indications for treating a wider range of diseases. Nippon Shinyaku is carefully laying the groundwork for further growth and development.Text: Toshihiko Ebata (Editorial Department)Photographs: Tetsuya Higashikawa (Photography Department, page 13), Aya Kishimoto (Photography Department, page 14, 16), Yuki Kohara (Photography Department, page 15)

Drugs “grow” tooUptravi® is headed for a “full life”

We can save more patients suffering from different ailments. We can make a difference to such a worthy cause—bringing good news to all patients. On the other hand, there were the doubters: “Are we sure we want to branch out, spreading ourselves thin?”

Employees raised their voices in a mixture of hope and concern.Uptravi® is a drug that is indicated for the treatment of pul-

monary arterial hypertension (PAH, diagram on page 14). The medication not only controls the symptoms but also delays dis-ease progression. Uptravi® will provide hope for patients suffering from PAH, a disease with a high mortality rate.

Uptravi® works only on IP receptors. IP receptors bind with a lipid called prostacyclin, or PGI2, relaxing muscles in the walls of blood vessels to dilate them. Uptravi® is the world’s first oral drug that decreases the elevated pressure in the vessels supplying blood to the lungs. As an IP prostacyclin receptor agonist, it can prove effective in many ways. Hopes are high that Uptravi® can become a therapeutic drug used to treat a wide array of illnesses.

New drug development is a long and expensive commitment. It could take as long as nine to 16 years to develop a new drug. Full research and development costs could exceed 100 billion yen. After all this work, the success rate of bringing a new drug to mar-ket is a mere one in 25,000. So once you succeed in launching a drug—against such odds—you want to keep on working on it to make sure the success story keeps on “growing”.

The goal is to enrich the “life” of a drug, to make sure the drug fulfils its promise and leads a purposeful life. Nippon Shinyaku president Shigenobu Maekawa eventually came up with an ini-tiative to promote “Product Life Cycle Management (PLCM)” (diagram on page 15), which maps the total lifecycle of a drug or compound still under development. The initiative was presented as part of the company’s medium-term management plan. One of the specific measures was to maximize a product’s value by adding

new indications to the product. In other words, to “branch out” so the drug could be used to treat other ailments.

When the scene described above took place, Uptravi® had been in development for seven years or so. It was still called by its devel-opment code, “NS-304”. Phase 2 trials were underway overseas with the cooperation of PAH patients. In order to add new indica-tions, clinical trials had to be run for each subject disease—and clinical trials were expensive and time-consuming. And of course, there was no guarantee of success at the end of the road. This was a source of nagging concern.

In order to disperse the dark clouds of doubt from the com-pany corridors, a project team comprised of numerous divisions, including Sales and Marketing, and Research & Development, was set up. The team took on the task of visiting and talking to every department.

Then the results of the phase 2 clinical trial which had been implemented in Europe came in. The drug was proven effective in humans. Shunji Funaki of the R&D Administration Department was a member of the explanatory team. He reminisced: “(When the report came in) the mood around the company changed all at once. We knew that things were going to be all right”.

Nippon Shinyaku took this opportunity to add another indi-cation. The new target was: chronic thromboembolic pulmo-nary hypertension (CTEPH, diagram on page 14). The drug was expected to benefit CTEPH patients, just like PAH patients, through dilation of blood vessels that supply blood to the lungs.

“We got the expected results!”Doubts were dispelledWe were ready for a new challenge

PROJECT 001

001U

ptravi ®PROJE

CT

Uptravi® tablets are packed into lit-tle boxes as they move along the conveyor belt to the forefront, where the packages undergo a visual check for spots and stains.

Delivering products with a distinctive edge

We take pride in our work

14 15

Reducing blood flow

Increases blood pressure in the pulmonary arteries

Chronic right ventricle pressure overload leads to right ventricular failure

Obtained Orphan Drug designation in Europe

DecemberApplied for marketing authorization in Europe (Granted in May 2016)

Phase 3 clinical study implemented in 39 countries

JanuaryApplied for manufacture and marketing approval(Granted in September)

Alongside the phase 3 clinical trial for PAH which was imple-mented overseas, Nippon Shinyaku began a phase 2 trial for CTEPH in Japan in 2010.

Chieko Yamamoto of the Clinical Development Department was in charge of two tasks. First, she gathered advice from medical specialists to draw up detailed plans for clinical trials; for the sec-ond, she monitored the process, made sure the trials conducted at medical institutions were implemented according to plan, and collected the data.

The outcome of a medical trial depends on how much relevant data can be accumulated; it is the “quality” that counts. Swift com-mercialization depends on how fast the pharmaceutical company can succeed in enrolling the required number of trial participants. That is why “solid planning makes up 80 percent” of a clinical trial. The amount of medicine to be administered, the duration of treat-ment, careful timing of tests and examinations—all need to be factored in when designing these trials in order to draw out maxi-mum efficacy of the drug while ensuring safety of the participants. Yamamoto and her team worked closely with the Pharmaceuticals and Medical Devices Agency (PMDA), an organization that con-ducts regulatory review of medical products. Finally, in June 2016, they were ready to begin phase 3 of the clinical trial here in Japan.

The team applied for Orphan Drug designation by the Ministry of Health, Labour and Welfare, proposing the need for the new treatment. Designation was granted, same as PAH, and the drug became eligible for a prioritized review for regulatory approval.

The show of such overwhelming enthusiasm from the Nippon Shinyaku team motivated the doctors and helped build mutual trust. For a clinical trial to succeed, full cooperation from the medical team is a must. It is up to the project monitor, the liaison who is in daily touch with the staff, to forge a good relationship. For one thing, the doctors have no previous experience using a drug that is still under development. During the trial there will be situations where they falter trying to make the right decision. For example, if a patient experiences side-effects, the monitor-ing team will receive information from the doctor and propose suitable measures. It takes a team effort to come up with the best treatment for a patient.

Every time she encounters a patient struggling with an ailment, Yamamoto is overcome by a strong wish “to do something to help”. This is what motivates her. She said: “I feel that my job could help patients around the world. The thought itself is quite rewarding”.

Let us turn back the clock a few years.Actually, Funaki and the project team were already working

on another indication. The next target was arteriosclerosis oblit-erans (ASO). The symptoms, called intermittent claudication, are pain and muscle cramps that occur in the legs when walk-ing for some distance. In severe cases, symptoms include pain, ulceration and necrosis. Arteriosclerosis obliterans is also caused by the hardening of the arteries which narrows the blood vessels, causing an occlusion. This is not a rare disease that affects few patients. So a clinical trial targeting ASO was going to be a huge one.

Still, Nippon Shinyaku decided to go ahead. There were no domestic drugs that treated intermittent claudication caused by ASO. And there were an estimated 1.5 million patients suffering from the condition. If the company could bring the drug to mar-ket, it would save that many people who were in pain. Based on information garnered from the phase 2 clinical trial for CTEPH,

Nippon Shinyaku initiated a phase 2 domestic clinical trial for ASO in 2013.

One of the monitors, Makiko Shibata from the Clinical Development Department Tokyo, took part in the production of a DVD which was to be shown at the medical institutions taking part in the trials. The DVD was prepared with a specific intent. One of the evaluations included an effectiveness measurement test using a treadmill. Every facility was different. And different people were going to administer the test. A slight change in test procedures or room temperature could easily affect the outcome. In order to obtain a fair evaluation of the effectiveness of NS-304, all conditions had to be standardized. That is why Shibata wanted to go over the procedures with all the technicians who were in charge of operating the devices.

Sometimes the doctors would have difficulty trying to find suit-able patients who could be enrolled in the trial. A patient could be under the care of another doctor in a different department. Sometimes a patient would be unaware of the cause of the disease. They did not think that their problem was in the blood vessels, believing “my joints hurt because of my age”. Shibata sat with the doctors to find ways to solve the problem.

Eventually the clinical trial was on its way, almost on schedule. Soon, Shibata began hearing from the patients via the medical staff. She heard encouraging words. “I want you to know that I’m doing fine”, and “I hope the medication goes on sale soon”.

Shibata said: “I am happiest when I know that the patients are happy”. She added: “I want to continue working as a monitor. I like working closely with the doctors to hear what is happening in

23

1

Pulmonary artery

Pulmonary vein

Left ventricleRight ventricle

Left lungRight lung

2004

2008

2009

2014

2016

2004,05

Microdosing study* carried out in Europe

Phase 2 clinical study implemented in Europe

How Uptravi® “Grew”

Nippon Shinyaku signed an out-licensing agreement with Actelion Pharmaceuticals Ltd., based in Switzerland. The two companies would co-develop and co-market the compound in Japan; Actelion Pharmaceuticals would develop and market it worldwide, except for Japan.

Number of patients: 2,500 in Japan

(Chronic thromboembolic pulmonary hypertension)CTEPH

(Pulmonary arterial hypertension)PAHNumber of patients: Japan 10,000 to 20,000

Overseas More than 100,000

PAH Blood vessels in the lungs become narrowerCTEPH Clots and occlusions form inside blood vessels in the lungs

Japan Overseas

Research first began around 2000

What is Pulmonary Hypertension?

PAH and CTEPH at a glance

PROFILE

Has been with the present department ever since she joined Nippon Shinyaku in 2014. An avid swimmer, she sometimes takes part in competitions.

Chieko Yamamoto

Clinical Development Department

Joined Nippon Shinyaku in 2004. He was involved in the clinical trials of NS-304, before joining the present department in 2016. He enjoys spending time with his children on weekends.

Shunji Funaki

R&D Administration Department

Has been involved in clinical development ever since joining Nippon Shinyaku in 2008. She joined the present department in 2014. On her days off, she may go for a run around the Imperial Palace in Tokyo.

Makiko Shibata

Clinical Development Department Tokyo

*An extremely low dose of medication is administered to a healthy human subject, once, to observe if the drug behaves as expected from absorption to excretion

Their passion and the effort they put into their work day after dayearned respect and trust from the medical team

We team up with doctors to find optimal treatment strategy for patients

A post-marketing surveillance study is performed by the pharmaceutical company to monitor the efficacy and safety of a new drug in actual use, after its launch.

Post-marketing surveillance studies

Studying the mechanism of the onset of a disease paves the way to developing a fundamental cure. Will this happen for PAH?

Additional new drugs

Pharmaceutical products are formulated to specific dosage forms including oral tablets, eye-drops, and injections. For easier drug taking, syrups and orally disintegrating drugs are often added to the lineup.

Developing additional formulations

CTEPHApril 2010Began phase 2 clinical studyJune 2016Began phase 3 clinical studyGranted Orphan Drug designation

ASO2013Began phase 2 clinical study

Additional indications

SeptemberGranted Orphan Drug designation in Japan

NovemberUptraviR went on sale in Japan

DecemberApplied for marketing authorization in the US (Granted in December 2015)

JanuaryUptraviR went on sale in the US

JuneUptraviR went on sale in Germany

From birth to launch

We take pride in our work

16

real-world clinical practices. It’s a great job”.

With the support of so many Nippon Shinyaku employees working hard behind the scenes, NS-304 finally went on sale here in Japan in November 2016, following launches in the US and Germany. NS-304 now became Uptravi®. In order to keep the drug “growing”, the company had implemented “attack” tactics, add-ing new indications for the drug. Now it was time to work on the “defense”—to prevent safety issues from cropping up. Information gathering became more important than ever.

Once a new drug goes on the market, it becomes accessible to a wider audience. The number of patients taking the drug grows significantly compared to the time when it was being used in closed clinical tests. Changes in the settings and circumstances become manifold. Side-effects that went undetected before could show up. This is why it is essential for pharmaceutical companies to carry out post-marketing surveillance studies.

At Nippon Shinyaku, the PMS Clinical Research Department fine-tunes the contents and duration of the post-marketing sur-veillance study. Koyuki Tajima and her team collaborated with PMDA and chose to conduct an all-patient survey in order to collect information regarding the safety and efficacy of Uptravi® at the earliest time possible. The team sent out questionnaires to the doctors and asked them to fill in information regarding treat-ment. The questionnaires were collected every six to 12 months. The team combed the data to see if there were any problem issues. The findings were reported to the PMDA. More importantly, the results were also relayed to the doctors. Tajima said: “Ultimately it all comes down to the doctors to administer the medicine prop-erly. We want to make sure they use it effectively and safely”.

Even after conducting a post-marketing surveillance study, it is not all over. The Safety Management Department then takes over to continue the monitoring process. If a red flag goes up, indicat-ing the slightest harm to the human body, cause and effect will be investigated and analyzed immediately. Even if the patient is carefully following all instructions, there is always the possibility for a serious adverse drug reaction to occur.

According to Arihiro Oyamada, this is precisely when you must be ready to step in with the correct response in order to stop the

situation from worsening. He said: “If you make the wrong deci-sion, no matter how wonderful the drug—the name gets tainted. The bad reputation may never go away. You can say the drug’s ‘life’ is over”.

Nippon Shinyaku is also looking further ahead into the future, in search of the “next generation”.

Kazuya Kuramoto at the Discovery Research Laboratories is conducting that important search. He began studying at Stanford University, in California, in July 2016, taking advantage of the company’s study abroad support program. The program was implemented in 2015, and encourages employees to go abroad for a maximum of two years to conduct research.

Kuramoto wanted to investigate the mechanism of PAH, to find out what triggers the onset of the disease. If he can unlock the mechanism the study may lead to the discovery of a drug that would truly “cure” the disease. He hopes to find a conclusion to his hypothesis during his study in this state-of-the-art environment.

Kuramoto said: “If we could define the mechanism that triggers the onset, we may be able to find a way to return the lungs to a normal condition”.

So, the journey of Uptravi® continues. Will it go on to lead a rich and fulfilling life? That is up to the commitment and good work of the Nippon Shinyaku team.

The packages will now go into cardboard boxes, ready for delivery to patients wait-ing for their medication.

Joined Nippon Shinyaku in 2009. He was investigating the pharmacology of NS-304 from 2011. He laments that he could not bring his beloved cello with him to the US.(Photo courtesy of Kazuya Kuramoto)

Kazuya Kuramoto

Discovery Research Laboratories

Joined Nippon Shinyaku in 2001 and worked at Discovery Research Laboratories, Clinical Development Department and R&D Administration Department. He works as the family chauffeur on his days off.

Arihiro Oyamada

Safety Management Department

Joined Nippon Shinyaku in 1984. She was involved in drug development at the Discovery Research Laboratories before joining the current department in 2012. She has taken up golf recently.

Koyuki Tajima

PMS Clinical Research Department

In search of the “next generation” medicationwe go after the root cause of the disease

Study abroad program in the USState-of-the-art environment for research

Information gathering is ongoing To ensure there are no safety issues

17

The goal for Nippon Shinyaku is to develop dietary supplements that contribute to “healthy longevity”.

COLUMN

It starts with a healthy future

2

April 2016—a new project was underway at the Functional Food Division in Nippon Shinyaku. The mission was to bring dietary supplements to market drawing on the com-pany’s strengths attained through development of health food ingredients.

Nippon Shinyaku had already been successful in develop-ing a wide range of ingredients and foodstuffs making use of its professional know-how as a pharmaceutical company. This included seasoning spices, preservatives, and protein powder ingredients. More recently, the company has been focusing on developing ingredients for nutritional foods—covering health foods and sports nutrition.

The enhanced effort came to fruition in October 2016 with the launch of a sports supplement that helps solve the problem of “energy drain” for athletes who take part in long workouts and endurance sports like marathons. The dietary supplement has two distinctive characteristics. First, during exercise, the supplement actively prompts the breakdown and conversion of stored fat into energy. Secondly, it promotes faster replen-ishment of glycogen supplies. The two-pronged approach enhances energy efficiency, thereby preventing energy drain. It became the first dietary supplement that focused on these two functions. The product has been well-received by athletes in track and field and other sports, in corporate and university

teams. This was followed up by

another launch in March 2017. The new dietary supplement contains polyphenols derived from mangosteens that have “glycation care” properties. Glycation is one of the causes that contribute to accelerating the aging process. About 20 to 30 percent of the human body is made of protein. Glycation occurs as a result of covalent bonding of protein with excess sugar—sugar which was consumed as food and could not be metabolized. Glycation affects collagen and other proteins, causing hardening and other changes that deteriorate inherent functions such as water retention.

Glycation progresses with age. It is thought that irregular lifestyle habits, such as lack of exercise and not getting enough sleep, as well as stress, contribute to raising the risk of glycation. Effective anti-aging care can only be made possible by imple-menting regular glycation care. Nippon Shinyaku began devel-oping this new dietary supplement to help realize this goal.

The company hopes to continue developing and expand-ing its dietary supplement product lines in the fields of sports nutrition and anti-aging.

We develop dietary supplements only a pharmaceutical company

can pull off

New initiatives for the functional food business

Text: Hiroyuki Nishijima (Editorial Department)Photographs: Aya Kishimoto (Photography Department)

18 19

Megumi Kato already knew about the profession called Medical Representative (MR) from the time she was in college. She gained a deeper understanding about the job through her internship at Nippon Shinyaku. She thought, “It is an attractive position and I like the challenge”. She decided to become one herself. Kato joined the company in 2013. She has been in charge of the National Cerebral and Cardiovascular Center (NCVC) in Suita, Osaka Prefecture, since 2016. The center is known for its team of doctors that treat pulmonary arterial hypertension (PAH), many of whom are considered opinion leaders in the field. At Nippon Shinyaku, the medical institution is considered one of its most valuable customers.

Kato spoke with great gravity: “To be honest, a newbie MR like me should not be put in charge of a major hospital like this. My predecessor was a veteran MR with a lot of experience. I am

grateful that the company was willing to take a chance on me. It is a great opportunity for a beginner”.

First and foremost, MR is translated as “person in charge of drug information”. Literally speaking, their role is to visit medi-cal institutions with the intention to ensure proper usage of the company’s pharmaceutical products. They dispense information regarding the quality, efficacy and safety of drugs and medicine. The information they gather while conducting such activities is duly assessed and analyzed, and provided as feedback to health-care personnel. MRs are tasked with connecting the company to the actual medical scene. They play a major role in increasing product awareness and promoting wider use of company prod-ucts. There are some 700 MRs at Nippon Shinyaku, breaking into 119 teams that work out of business offices and business branches throughout Japan.

Sales and marketing is a team effort

002Megumi Kato (left) explains the efficacy and features of Nippon Shinyaku prod-ucts to Yoshikazu Nakaoka, Director, Department of Vascular Physiology, at the National Cerebral and Cardiovascular Center (NCVC). Nakaoka says: “I can tell that Nippon Shinyaku medical reps know their work and have studied the diseases”.

Key requirements for MRs are strong communication skills to interact with doctors, as well as expert knowledge regarding drugs and medicine. They must be ready to provide doctors with clinical data for pharmaceutical drugs. Nippon Shinyaku pays particular attention to intractable and rare diseases. Treatment for such dis-eases sometimes calls for unprecedented approaches. MRs need to communicate the exact information to doctors; and MRs must share the doctors’ experience of administering the drug with other MRs around the nation.

Nippon Shinyaku has been putting a lot of effort in promot-ing Uptravi® which is used for the treatment of pulmonary arte-rial hypertension (PAH). Hisashi Terayama is the product leader who relays and supervises marketing strategy, market conditions, and accumulated information related to the new drug, to all MRs around the country.

Regarding the marketing strategy for Uptravi®, Terayama focused on preliminary preparations—the low-key approach of laying the groundwork. When Terayama was in sales, right at the front line, he learned from experience that every hospital had its own set of rules when it came to adopting pharmaceuticals—it was necessary to get a grasp of the different rules. Even the great-est drug would be rendered worthless if it did not reach the patients who need it.

Terayama said: “MRs who work with clinics and hospitals tend to ask for new tools like pamphlets. Actually, what is most impor-tant is that each MR knows and thoroughly understands the drug”.

Terayama reaches out to doctors, mostly those who are involved in PAH treatment, and proposes using Uptravi® in combination with two other lines of medication that are already on the market. He also hosts lectures for doctors and conducts on-line training courses for MRs around the nation. Such supportive measures are proving effective. Uptravi® sales are growing steadily.

Yuto Konaka supports Terayama’s efforts from his office at the Marketing and Planning Department. His job is to devise ways to promote and find a wider audience for Nippon Shinyaku prod-ucts, with a focus on planning marketing strategies for Uptravi®.

PAH is an intractable disease that is also little-known. Konaka makes a special effort to educate patients and their families. In addition to creating a website that helps people achieve a deeper understanding of the disease, he has developed a smartphone app called “PAH Care Notebook” for PAH patients.

Konaka explained: “In general, patients visit their doctors once a month. By using this app, the doctor can check on the patient’s condition and progress during that time period, at a glance. And of course, the app is available to all patients—even those who are not taking Uptravi®”.

In developing the app, Konaka considered various elements: What kind of functions are necessary? What could be done to make it more user-friendly? What kind of patient information does the doctor need? Through his work, Konaka offers support to patients who are battling intractable diseases. It is his work that serves as a fresh reminder of the mission of a pharmaceutical company, and brings him satisfaction and joy to be a part of it.

At home, the patient keeps a daily log of his/her condition and medicine intake. The patient can later look back on his/her personal data, using easy-to-follow graphs and charts.

002PROJE

CT

Sales Force

We make sure the drugs reach the right people and it’s not all about the tools

A smartphone app helps patients take a proactive approach to treatment

PROFILE

Joined Nippon Shinyaku in 2013. At the Osaka Business Office, she was first in charge of the Sakai area, before being appointed to the Hokusetsu area in 2016. Her hobby is travelling, domestic and international.

Megumi Kato

Osaka Business Office, Business Branch No. 1

Joined Nippon Shinyaku in 2001. He joined the Tokyo Business Office in 2014 after working at the Osaka Business Office. Terayama has been with the current department since 2016. His hobby is travelling.

Hisashi Terayama

Marketing & Development of Pulmonary Hypertension Department

Joined Nippon Shinyaku in 2004. He was at the Keiji-Hokuriku Business Office in charge of medical institutions before joining the current department in 2015. His hobby is playing with his children.

Yuto Konaka

Marketing and Planning Department, Planning Section

We help patients suffering from intractable diseases get a better understanding of the disorder

We take pride in our work

Various departments within the company including Medical Representatives (MR) and drug information services work together in collaboration to provide information about the company’s products—drug efficacy and special features—along with information regarding diseases, to healthcare professionals. We are in charge of spreading the word about our company’s pharmaceutical products.Text: Etsuko Morita, Toshizo Shimizu (Editorial Department)Photographs: Tatsuro Sekiguchi, Keitaro Horiuchi (Photography Department)

We are the key point of contact that connects doctors and the company

PROJECT

002PROJECT Planning

The PAH Care Notebook is a support service that is helpful during doctor consultations and treatment. It visu-alizes the patient’s condition and medicine intake on a daily basis.

20 21

company based in Ireland, for two drugs that were developed by the company; “NS-73” used for treatment of hepatic veno-occlu-sive disease (VOD), and “NS-87” used for treatment of secondary acute myeloid leukemia (AML). Nippon Shinyaku obtained the rights to exclusively develop and commercialize the two products in Japan. Nippon Shinyaku will now proceed with clinical devel-opment of the pharmaceuticals.

Many requests pour in from overseas seeking the latest drugs owned by Nippon Shinyaku. For example, Uptravi® is a drug used for the treatment of pulmonary arterial hypertension (PAH). It went on sale here in Japan in November 2016. The product is also sold in the US, Canada and Germany, among other countries.

The Overseas Business Section of the Business Planning Department is in charge of “export” operations, providing out-licensed products to overseas partners. According to Hiromi Miomo the work flow goes like this: “Once we receive an order from an overseas business partner, we will coordinate schedules with the production side to ensure delivery before the promised date. We take care of a wide range of things like choosing and arranging the mode of transportation—sea or air—and make sure the bill gets paid. We are also in charge of sales management”.

There are some drugs, like Nippon Shinyaku’s antibacterial agent “Prulifloxacin”, which are marketed in multiple countries. Miomo and her team set up regular meetings with each separate company the drug has been out-licensed to, to discuss marketing strategies. She said: “I work directly with overseas contacts. I find my job quite rewarding”.

Of course, there are hardships, too. Regulatory requirements

for pharmaceuticals differ with every country. And regulations are getting stricter. At times, Nippon Shinyaku has to submit additional data on top of the original data that was used to obtain approval here in Japan.

Furthermore, the signing of an in-licensing or out-licensing contract is not the “goal” here. The real goal is to deliver pharma-ceuticals to patients who need the drugs—without fail and in a consistent manner.

Masaaki Shirai of the Alliance Department said: “That is our most important mission”. After in-licensing and out-licensing contracts have been signed, this department serves as the in-house “contact point” that fields all kinds of inquiries. Shirai makes a special effort to secure a steady supply of products after in-licensing. He said: “We need to coordinate with all relevant departments. And of course, I am busy communicating with people outside the office, a lot of times”.

Every license agreement is unique. The contents differ greatly. So there is nothing routine about his job. What is required is much more than a solid academic background. He needs to have business savvy that covers global business practices in general, including an understanding of distribution systems and corporate compliance.

Shirai has to overcome time zone differences when working with overseas counterparts. He uses email and other communi-cation tools to keep in touch with contacts and share informa-tion on a daily basis. Anything could happen to delay a supply. He needs the ability to cope with an unexpected situation. It is a pretty stressful job.

That said, Shirai knows that he is on a mission to “deliver medi-cine that will treat life-threatening diseases—to all the patients around the world”. It is a goal that is shared by everyone involved in overseas operations. It is a goal that keeps them going.

If patients need a remedy that is not available in Japan, we will bring it in from abroad through in-licensing (obtaining develop-ment rights). If we have a drug here in Japan that is needed in another country, we will out-license (provide development rights for) the medicine.

Nippon Shinyaku is now expanding its cross-border operations. Mainly it is the Licensing Planning Department that coordinates such in-licensing and out-licensing operations. Takashi Homan of the Licensing Planning Section works on in-licensing. He said: “I look for promising compounds that are being developed by foreign pharmaceutical companies and biotech companies, bring them in for development in Japan at Nippon Shinyaku, and deliver the finished product to patients. That is the major part of my job”.

The company’s main focus areas include blood cancers, urology and rare diseases. For Homan, the first step is to identify drugs in these fields that are being developed abroad, well ahead of Japan. There are a number of ways to conduct this search. He could do a comprehensive search using a database that lists chemical com-pounds which are currently being developed around the world. He could also attend international meetings where personnel in charge of licensing from various pharmaceutical companies all get together and trade information. Hopefully, he will find a prom-ising “seed”, something that tells him, “This is it”. According to Homan, this is the toughest part of his job.

Homan said: “They say that the odds for a compound now under development getting launched as a commercial drug is one in 25,000. It is something like picking out a ‘rough diamond’ in a field of stones”.

The job requires specialized knowledge and experience in the field of pharmaceutical research—in essence, the qualifications of a connoisseur. The specialist needs to be aware of the marketabil-ity factor, too, and ask the question, “Will this lead us to a drug that patients really need?” Homan and his colleagues collaborate with relevant departments inside the company, meet with outside specialists including medical doctors, and listen to all opinions in making a meticulous assessment. Once the compound gets the “go ahead”, the next step is to begin negotiations with the com-pany that is actually developing the compound. Conditions are set, a contract is drawn up and signed. In-licensing to Japan is complete.

In reality, very few cases reach the final signing stage. The Licensing Planning Department assesses dozens of compounds every year. But in the end, only a few compounds get licensed in. Sometimes the parties fail to agree on the license fee. You could also lose out to a competitor that is seeking the same compound. Homan said: “A lot of times people compare our work to building a stone tower. You choose a stone, and carefully place one atop another. But the tower keeps on tumbling down. You repeat the process, again and again. It is all about trial and error”. When he actually does manage to finish building a “tower”, there is a won-derful sense of accomplishment.

Here is one success story. In March 2017 Nippon Shinyaku entered a license agreement with Jazz Pharmaceuticals plc, a

Medicines travel across borders

There are patients all over the world who need and await new therapeutics. Sometimes we bring in promising medicines from overseas. Sometimes we “export” our own. In-house development of original medicine and our overseas operations are the “two wheels” that work smoothly together so that we can respond to every request.Text: Hiroyuki Nishijima (Editorial Department)Photographs: Aya Kishimoto (Photography Department)

We try to fulfill all requests through in-licensing and out-licensing

PROJECT 003

When out-licensing original in-house developed medicines such as Uptravi®, the other parties often ask for a detailed explanation of the data. Nippon Shinyaku employees need to be prepared. Here, they are rehearsing their presentations in English.

Joined Nippon Shinyaku in 1991. She worked in quality control of medical products before joining the current department in 2009. Her hobby is aerial yoga.

Hiromi Miomo

Business Planning Department, OverseasBusiness Section

Joined Nippon Shinyaku in 1999. He was involved in exploratory research to identify new compounds before joining the current department in 2016. He likes to play with his children when he is off work.

Masaaki ShiraiAlliance Department

PROFILE

Joined Nippon Shinyaku in 2009. He conducted research into urologic diseases before joining the current department in 2015. He enjoys outdoor activities.

Takashi Homan

Licensing Planning Department, LicensingPlanning Section

It is like building a stone towerA lead rarely ends in a contract

Every country has different regulationsThey get stricter all the time

We train to become discerning connoisseurs to pick out the “rough diamond” out there

003Global

PROJE

CT

We take pride in our work

22

Baseball clinics for children

Contributing to people’s health and prosperous lifestyles

Corporate Social Responsibility:

In addition to supplying high-quality products, Nippon Shinyaku actively engages in a variety of social contribution activities.

Photographs: Courtesy of Nippon Shinyaku

For Communitiesand Society

The Nippon Shinyaku Baseball Team, which competes in the Intercity Baseball Tournament and the Amateur Baseball Japan Championship, offers baseball clinics for high school baseball players and children’s baseball teams in order to raise the level of local baseball and pro-mote interpersonal exchanges.

The Nippon Shinyaku Children’s Literary Awards contest was started in 2009. The con-test solicits entries in two categories: stories and artwork (Column 3 on page 23).

Nippon Shinyaku Children’s

Literary Awards

Nippon Shinyaku’s headquarters is located in Kyoto, ancient capital city of Japan. In order to support the city’s rich cultural heritage, Nippon Shinyaku produces tenugui (functional and decorative cloths) and calendars using tradi-tional craftsmanship, and also publishes a newsletter titled “Kyo”, providing various information about Kyoto.

Preservation of traditional Kyoto culture

Yamashina Botanical Research Institute pre-serves and cultivates more than 3000 species of medicinal and useful plants from around the world, including rare species threatened with extinction. The institute contributes to the preservation of biodiversity through plant breeding and cultivation research.

Yamashina Botanical Research

Institute

Nippon Shinyaku engages in various educa-tional activities related to disease, such as Yellow Ribbon drive to provide accurate infor-mation about menstrual pain and endometrio-sis, and a civic public lecture to spread correct, up-to-date information on illnesses and medicine.

The Yellow Ribbon drive

CulturalActivities

Baseball clinic

Yamashina Botanical Research Institute

Nippon Shinyaku’s newsletter “Kyo” and calendar

For People Livingwith Disease

23

The Nippon Shinyaku Children’s Literary Awards is an annual contest with two divisions, for stories and artwork. The first-prize winners from these two divisions collaborate to pro-duce a picture book.

Turning lively, carefree ideas into picture books

Nippon Shinyaku Children’s Literary Awards

Text: Toshizo Shimizu (Editorial Department)Photographs: Akina Okada

COLUMN

It starts with a healthy future

3

Hana Tomikawa (right) and her mother at an editorial meeting that was held at Nippon Shinyaku’s Tokyo Office. Tomikawa was all smiles as she checked out pictures that were laid out for reference.

Our future lies in the hands of our children. The Nippon Shinyaku Children’s Literary Awards was created in 2009 with the support of the Japan Juvenile Writers Association. The award was created with the hopes of giving wings to young children’s dreams and to nurture their minds and spirits through picture books.

For the 9th Nippon Shinyaku Children’s Literary Awards which was held in 2016, we received a total of 1,965 submissions; 1,538 stories and 427 pieces of artwork from all over the nation. The panel of judges included Dr. Ryota Hosoya, a pediatrician at St. Luke’s International Hospital in Tokyo. The first prize for the story division went to Kotoba Ninpo Onomatopoeia (Onomatopoeia is word magic), which was penned by Hana Tomikawa who is in the fifth grade at elementary school. The first prize for the artwork division was awarded to Yukari Igeta’s Yoru no Ashioto (Footsteps by night).

Tomikawa, the budding young author, said: “I was really surprised. This prize is going to be my first step to realizing my dream”. Igeta commented: “(Tomikawa’s) story is full of move-ment. It is very different from my style”.

One of the judges, Shozo Yamamoto, creator of children’s picture books, praised Tomikawa’s story-telling: “It is a unique piece of work full of speed and rhythm”.

Igeta, the first prize winner for artwork, added pictures to

this story. Nippon Shinyaku produced 30,000 picture books and distributed copies to children nationwide through medi-cal institutions and public facilities. In addition to the literary award, the company established the “Kira Kira Mirai Kodomo Bokin” children’s fund in 2009. When supporters give to the fund they receive a picture book in return. All donations are used for activities to support children.

“I wrote a story that would get readers all excited!”

Ryota Hosoya

Pediatrician at St. Luke’s

International Hospital

Haiku Poet

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Nippon Shinyaku is a pharmaceutical company also known for its unique CSR initiatives.So how does the company measure up in the medical scene? Ryota Hosoya, a pediatrician and poet, shared his thoughts about Nippon Shinyaku.Compiled by: Hiroyuki Nishijima (Editorial Department)Photographs: Yuki Kohara (Photography Department)

“The company has a deep, mature corporate culture”

My take on Nippon Shinyaku

A writer With the trained eye of a doctor

“I want to treat cancer relapse”My wish brought me to Nippon Shinyaku

“I eventually became close friends with the MR”

“The company is really dedicated to their cultural activities”

cancer treatment”. I took his advice. In the late 1970s I began working at the University of Texas MD Anderson Cancer Center. To be honest, I was flabbergasted when I saw former patients who had overcome leukemia, now all grown up, walk-ing in to the hospital with their own children in tow. It made me ponder, “What is the medical care that would help us in Japan?” I kept my eyes peeled and my ears open. I wanted to pick up every-thing. I studied really hard.

In those days, the biggest challenge for doctors in Japan was finding a way to prevent childhood cancer from recurring. Especially worrisome were central nervous system relapses of childhood leukemia. In the US, treatments such as administering drugs into the bone marrow cavity, or administering large dosages of drugs intra-venously were proving effective. After returning to Japan, I decided that I wanted to use one such drug, “Cylocide”. I found out that the drug was manufactured by Nippon Shinyaku, a company based in Kyoto. So I got in touch with the company’s medical representative (MR) to talk about my request. That was the beginning of my friendship with Nippon Shinyaku.

During the years, I continued to meet with and trade infor-mation with many Nippon Shinyaku MRs. I came to realize that there was a “distinctive feel” to the company that was quite different from other pharmaceutical companies. First of all, Nippon Shinyaku puts out a unique public relations magazine. Normally, pharmaceutical companies put together PR magazines brimming with medical information. But Kyo, Nippon Shinyaku’s PR magazine which first came out in 1967, takes a novel approach. The cover art depicts seasonal scenes of Kyoto. Inside, there are many articles that spotlight local cultural assets and discuss traditional crafts. You don’t have to be a doctor to enjoy the magazine.

When the MRs from Nippon Shinyaku came over with new information regard-ing pharmaceuticals, without fail, they would leave me with a new copy of Kyo. Some MRs were assigned to St. Luke’s for many years and we ended up becoming good friends. Mind you, I have been practicing medicine for more than 40 years but I have rarely made friends with MRs. I heard that in the olden times, during the Edo period, avid sumo wrestling fans would look out for a favorite sumo wrestler, cheering him on as he rose in ranks. In Kyoto, I heard that there is a similar hobby involving young monks. People would make note of a “promising” young monk and be tickled pink when he became a top priest at a renowned temple. It was the same with me. I just loved watching a young MR from Nippon Shinyaku make his way, get promoted, and climb the corporate ladder.

It is not only their PR magazine that stands out. The com-pany produces a beautiful calendar every year using Kyoto’s traditional “kataezome” stencil-dyed prints. In 2009, the company created the “Nippon Shinyaku Children’s Literary Awards” for which I am a member of the selection committee. Furthermore, the company has its own baseball club. The team

was still considered “incurable”, doctors at Boston Children’s Hospital were treating children using chemotherapy, open-ing doors to new possibilities in the battle against childhood cancer.

After returning to Japan, based on his experience at Boston Children’s Hospital, Dr. Nishimura introduced a new approach to treating cancer. Total care is a coordinated approach that employs every type of treatment available, including chemo-therapy and radiation. Team care was brought to St. Luke’s. It

was Dr. Nishimura who made the suggestion that I should “go see the progress being made in childhood

I seem to have an intriguing connection with Kyoto. After graduating from university I began working as a pediatrician at St. Luke’s International Hospital in Tokyo. That is where I met Dr. Kozo Nishimura, who was pediatrician-in-chief at that time. It was this encounter that led me to specialize in childhood cancer. Dr. Nishimura was originally from Kyoto. He graduated from Kyoto Prefectural University of Medicine, and soon after World War II, went overseas to train as a cli-nician at Boston Children’s Hospital in Massachusetts. The hospital was already offering inno-vative children’s cancer treatment. At a time when childhood cancer

is a regular contender at the Intercity Baseball Tournament and other nation-wide tournaments.

Amateur baseball is a sport that is rooted deep in the psyche of the Japanese people. And the Intercity Baseball Tournament is the pinnacle of authentic amateur baseball. Apparently, Nippon Shinyaku is a company that takes its cultural activities and pursuits seriously. There is nothing half-committed about this business. It shows that they have an extremely mature cor-porate culture.

Lately there has been a surge of mergers and acquisi-tions (M&A) taking place in the pharmaceuticals industries. Pharmaceutical firms are getting bigger, scaling up. Maybe that is why corporate images seem to blur and their colors blend into one another. Nippon Shinyaku may not be one of

the pharmaceutical giants, but manages to stand distinctly independent. The company actively pursues development of pharmaceuticals to treat intractable and rare diseases that big-name compa-nies rarely go after. We are also seeing a

new crop of drug companies with special features emerge in the field of generic medicine.

It is important that we have a contingent of such compa-nies—with distinct strengths and features—when we consider Japan’s medical scene. And I feel that Nippon Shinyaku is at the forefront, the leader of the pack. I hope the company will remain rooted in Kyoto, where they started their business, and continue to grow without ever losing their inherent goodness.

Was born in 1948 in Yamagata Prefecture. He gradu-ated from Tohoku University School of Medicine in 1972. After graduation he joined the Pediatric Department at St. Luke’s International Hospital in Tokyo. He was with the University of Texas MD Anderson Cancer Center in Texas, USA, from 1977 to 1980. After returning to St. Luke’s, he became deputy director, head of ambulatory care center for children, and now serves as advisor. His field of specialty is child-hood cancer. He is also a haiku poet who uses the pseudonym Hosoya Ryoryo.

Ryota Hosoya:

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Corporate Profile History&

Nippon Shinyaku has steadily paved its way supported by creative ideas and solid technology. It is proud of its long history as a unique developer of new pharmaceuticals. The company is based in Kyoto, where it was founded. And from this vantage point, it continues to look out into the world and aim for the future.Photographs: Ryo Kusumoto (left, page 26), Tetsuya Higashikawa (Photography Department, page 27), Nippon Shinyaku

From Kyoto We Aim for the Future

Corporate Profile

Corporate Name Nippon Shinyaku Co., Ltd.

Founded November 20, 1911

Date of Incorporation October 1, 1919

Representative Shigenobu Maekawa, President and Representative Director

Capital 5.2 billion￥Net Sales 98.7 billion (for the year ended March 31, 2017)￥Ordinary Income 16.2 billion (for the year ended March 31, 2017)￥Employees 2,011 (as of end of March, 2017)

Head Office 14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan

Phone +81-75-321-1111

Major Offices, Plants and LaboratoriesTokyo Office

Business Offices

Sapporo, Tohoku, Kitakanto-Koshinetsu, Tokyo, Saitama, Chiba, Yokohama, Nagoya, Osaka, Keiji-Hokuriku, Kobe, Chushikoku, Kyushu

Business Branches

Asahikawa, Koriyama, Kitatohoku, Utsunomiya, Ibaraki, Niigata, Nagano-Yamanashi, Tokyo, Tama, Yokohama, Shizuoka, Hokuriku, Himeji, Okayama, Shikoku, Fukuoka, Nagasaki-Saga, Kumamoto, Miyazaki, Kagoshima, Okinawa

Discovery Research Laboratories, Discovery Research Laboratories in Tsukuba, Yamashina Botanical Research Institute, Food Development Laboratories, Odawara Central Factory, East Logistic Center, West Logistic Center

Domestic subsidiaries and affiliated companiesSioe Pharmaceutical Co., Ltd.Tajima Food Industry Co., Ltd.NS Shared Service Co., Ltd.

Overseas offices and subsidiariesNS Pharma, Inc.Beijing Representative OfficeLondon Office

Business PhilosophyHelping People Lead Healthier, Happier Lives

Company History

1911 Founded “Kyoto Shinyakudo”

1919 Founded Nippon Shinyaku Co., Ltd. taking over operations of Kyoto Shinyakudo

1940 Launched Japan's first domestically produced anthelmintic, Santonin

1953 Opened Yamashina Plant Materials Laboratory (now Yamashina Botanical Research Institute)

1954 Completed construction of Nishioji Plant

1957 Relocated headquarters to current location in Minami-ku, Kyoto City

1960 Concluded business alliance agreement with Kuroishi Pharmaceutical Co., Ltd. (now Nippon Shinyaku subsidiary, Sioe Pharmaceutical Co., Ltd.)

1961 Established Food Division (now Functional Food Division) and entered the food business

1962 Completed construction of Research Laboratory (now Discovery Research Laboratories, Building 3) at company headquarters

Established Nippon Shinyaku subsidiary, Royal Motors Co., Ltd. (now NS Shared Service Co., Ltd.)

Was listed on Tokyo Stock Exchange

1964 Completed construction of Odawara Factory (now Odawara Central Factory)

1969 Concluded business alliance agreement with Tajima Starch Manufacturing Co., Ltd. (now Nippon Shinyaku subsidiary, Tajima Food Industry Co., Ltd.)

1970 Completed construction of Food Development Laboratories

1991 Opened Düsseldorf Office in Germany

1997 Completed construction of the Discovery Research Laboratories in Tsukuba

1999 Established US subsidiary, NS Pharma, Inc. (formerly Nippon Shinyaku New York Office)

2001 Completed construction of new plant for pharmaceuticalsformulation production in Odawara Central Factory

2004 Completed construction of new Tokyo Office/Tokyo Business Office building, “Nihonbashi Sakuradori Building”

2009 Created “Nippon Shinyaku Children's Literary Awards” to mark the 90th anniversary of foundation

2011 Opened Beijing Representative Office in China

2012 Relocated Düsseldorf Office to London, UK

2016 Completed construction of Active Pharmaceutical Ingredient Manufacturing Building at Kyoto headquarters

Launched Pulmonary Arterial Hypertension agent Uptravi® in the US, which was followed by successive launches in Europe, Japan, and other countries

2017 Completed construction of manufacturing facility for highly active solid formulations in Odawara Central Factory

Corporate Slogan

Our goal is for people to live “longer, healthier lives”. Nippon Shinyaku is an R&D-based company that produces medical products and functional food to help people enjoy “fruitful”, “healthy” and “energetic” lives.

To build a healthier future

86.4%

Drugs for urology 16.2%

14.9%

5.2%

37%

13.6%

5.1%8%

Net Sales

98,781million ￥Nippon Shinyaku

Departmental profits(for the year ended March 31, 2017)

Pharmaceuticals

Functional Food

Drugs for hematology

Drugs for intractable and rare diseases

Drugs for gynecology

Drugs for otorhinolaryngology

Others

Company laboratory, circa 1917

Nishioji Plant, circa 1955

Panoramic view of Odawara Central Factory

London Office