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Nanomedicine Market

October, 2013

Maths Lundin

mailto:[email protected]


http://www.eu-japan.eu/

http://www.eubusinessinjapan.eu/

http://www.een-japan.eu/


EU-Japan Centre for Industrial Cooperation 2

TABLE OF CONTENTS

Abstract 4

1. Introduction 8

2. Global Industry Overview 9

2.1. Drivers for Market Development 9

2.2. Nanomedicine Applications 10

2.3. Global Nanomedicine Market Size 10

2.4. Global Market Trends – Novel Nanoparticle Engineering Platforms 11

2.5. Challenges 12

3. Nanomedicine Market in Japan 13

3.1. Overall State of Japan’s Pharmaceutical Industry 13

3.2. Japan Nanomedicine Market 13

3.3. Approved Nanopharmaceutical Products by Application 14

3.4. Nanopharmaceuticals in Clinical Trials in Japan 17

3.5. Market Trends 18

4. Changing Environment – Government Pushing for Change 20

5. Nanomedicine – Research and Development in Japan 22

5.1. University of Tokyo 22

5.2. Hokkaido University 22

5.3. Osaka Prefecture University 22

5.4. Osaka University 23

5.5. Tohoku University 23

5.6. National Institute of Materials Science 23



6. The Japanese Nanomedicine Industry 24

6.1. Business Model 24

6.2. Japanese Players 24

6.3. NanoCarrier Co., Ltd. 24

6.4. LTT Bio-Pharma Co., Ltd. 25

6.5. Mebiopharm Co., Ltd. 26

6.6. Nippon Kayaku Co., Ltd. 27

6.7. Kowa Company Ltd. 27

6.8. Minor Players 28

7. Pharmaceutical Regulations in Japan 29

8. Conclusions 30

Reference list 32

Tables

Table 1. Global Nanomedicine Market Size 10

Table 2. Japan Nanomedicine Market Size 13

Table 3. Lipid Microspheres 14

Table 4. Liposomes 15

Table 5. Antibody Conjugates 16

Table 6. Polymer-Conjugated Proteins 16

Table 7. Nanocrystal 17

Table 8. Polymeric Nanoparticles 17

Table 9. Nanodrugs in Clinical Trials in Japan 17



Abstract

The aim of this study is to investigate the Japanese nanomedicine market. The study involves identifying

nanopharmaceuticals that have been approved and launched on the Japanese market. The report includes

an overview of the global nanomedicine market with the main focus on market drivers and market trends.

Applications of medical nanotechnology spans over a variety of areas such as drugs and therapeutics, drug

delivery, in vivo imaging and regenerative medicine. This report focuses on nanopharmaceuticals and

systems to transport drugs in the body which is the segment that has mainly been commercialized in Japan

so far.

In addition to information about the market size in Japan including market trends, various government

initiatives to develop innovative medicine will be presented including some R&D at leading universities and

profiles of the key players.

Global industry overview: U.S. is the strong player – especially when it comes to commercialization. It is

leading in the number of nanotechnology patent applications.

Starting in 2001, many countries including U.S. and Japan have allocated national budgets to prioritize

nanotechnology and its applications in different fields. Additional drivers for the nanomedice market

development are new technologies for drug delivery, advantages of nanomedicine in various health

segments and a general need to cut expenditures for medical treatment.

According to BCC Research LLC (2012), the global market for nanomedicine was estimated at US$50.1

billion in 2011 and projected to expand to US$96.9 billion in 2016. This corresponds to approximately 5

percent of the total pharmaceutical market size (2011) constituting a small niche segment.

The first generation of nanopharmaceuticals were liposomes that were developed to increase the solubility

that was achieved through encapsulation of drugs in nanomaterials. Nanoparticles have a high surface-to-

volume ratio that increases a drug’s dissolution rate.

In recent years, multifunctional nanomedicine is being developed and some drug candidates are in clinical

trials. BIND Therapeutics is a U.S. venture start-up adopting enhanced functionalization. A nanoparticle

formulation is not only used to transport a drug. Additional functions such as putting ligands (antibodies) on

the surface of the nanoparticles will improve the accumulation of drugs at the intended location of action.

Although nanomdicine enables engineering of new nanocompounds that have advantages over existing

treatments it is still in its infancy. Some issues to consider are possible risks with nanomedicine as well as

the need to work on the classification of nanomedicine.

Japanese market: Japan’s pharmaceutical industry is the world’s second largest after U.S., valued at

US$112.1 billion in 2012 or 11.6 percent of the world market.

When it comes to nanomedicine, Japan’s share of the global segment is much smaller. A rough estimate is

1-2 percent of the Japanese pharmaceutical market or US$1 billion – US$2 billion.

Nanomedicines have not been defined in Japan and are regulated within the general framework of the

Pharmaceutical Affairs Law (PAL) on a product-by-product basis.

Sixteen approved nanodrugs have been identified. Five of these (Palux, Liple, Limethason, Ropion and

Smancs) are manufactured and launched by Japanese companies. These nanodrugs have been



developed during the 1987-1994 period and all except one are lipid emulsions belonging to the early stage

of the nanomedicine development.

Lipid emulsions have mainly been developed in Japan and are based on lipid technology developed by LTT

Bio-Pharma. The fifth approved Japanese nanodrug is a polymer-conjugated protein (Smancs) developed

by Astellas Pharma and launched in 1994.

The eleven imported nanopharmaceuticals are (1) lipid emulsion (Diprivan), (2) liposomes (AmBisome,

Doxil and Visudyne), (3) antibody conjugates (Mylotarg and Zevalin), (4) polymer-conjugated proteins

(Pegasys, Pegintron and Somavert), (5) nanocrystal (Emend) and (6) polymeric nanoparticles (Abraxane).

Seven of the imported nanodrugs are marketed by Japanese subsidiaries of the manufacturers and four

nanodrugs (AmBisome, Abraxane, Emend and Pegasys) are marketed by Japanese pharmaceutical

companies. Four drugs (Diprivan, Visudyne, Zevalin and Pegasys) are manufactured by European

companies.

In some cases, it took many years for a foreign nanodrug to be launched in Japan. For AmBisome it took

as long as 16 years. This nanodrug was approved by FDA in U.S. in 1990 and entered the Japanese

market in 2006. In case of Doxil it took 12 years.

This is a contributing factor to the slow penetration of nanomedicine in Japan. Another cause is the lack of

interest of large Japanese pharmaceutical companies in promoting investments in nanomedicine R&D.

Currently, three nano-based pharmaceuticals (NK105, NK012 and NC-6004) developed by Japanese

companies are in clinical trials in Japan. NK105 is a Paclitaxel micelle technology platform that Nippon

Kayaku has in-licensed from NanoCarrier that entered Phase III clinical trials in July, 2012. This nanodrug

candidate has potential to be approved within a couple of years.

Nippon Kayaku has developed NK012 which is a micellar anti-cancer drug (Phase II). NC-6004 is a drug

that NanoCarrier has developed applying its micellar technology to the chemotherapy Cisplatin (Phase I).

Micelles developed by NanoCarrier are primarily based on research at the University of Tokyo.

A nanopharmaceutical with the brand name Neulasta and manufactured by Amgen is presently being

reviewed by the Pharmaceutical and Medical Devices Agency (PMDA) for approval in Japan. The

application for marketing approval has been filed by Kyowa Hakko Kirin that has licensed this drug from

Amgen.

Government initiatives: The government has implemented various basic plans over the years including

nanotechnology. Under the 4th Science & Technology Basic Plan (FY2011-FY2015), nanotechnology is no

longer prioritized in favour of Life Innovation and Green Innovation.

To achieve the goals of this plan, the target level of government R&D is 1 percent of GDP with the total for

five years to be approximately 25 trillion yen.

Some of the sub-goals related to Life Innovation include the development of innovative diagnostic and

treatment methods as well as promoting transnational research.

The government is aiming at more concrete and speedy results for R&D. Issue-driven innovation based on

“exit-oriented” R&D will serve as means to shorten the time span leading to innovation. Additionally, the

integration of dissimilar fields and academic-industry collaboration are emphasized.



A report by the Japan Science & Technology Agency (2011) indicates the time span to reach selected

targets such as (1) molecular imaging (2015-2020), (2) integrated systems of drug delivery, diagnosis and

treatment (2015-2020), (3) nano-cell surgery (2020-2030) and (4) 3D-imaging in cells (2020-2030).

Through government-initiated policies the infrastructure surrounding nanomedicine is improving. One

example is the promotion by the Ministry of Health, Labour and welfare (MHLW) and EU of the

development of nano-based block copolymer micelles.

Another example is PMDA’s “Pharmaceutical Affairs Consultation on R&D Strategy” for universities,

research institutes and venture businesses related to tests needed for commercialization. PMDA has also

created a Science Board of external experts to help the agency when reviewing applications involving

cutting-edge technologies.

As the Japanese venture business landscape is immature the government will foster drug development

ventures.

Research and development: Japan’s R&D within nanodrug delivery systems is unique and competitive.

Prof. Kataoka, Faculty of Medicine at the University of Tokyo, pioneered the development of a round-

shaped carrier called polymer micelles in the late 1980s. Later, Prof. Kataoka further developed his

research focusing on practical applications that have primarily been utilized by NanoCarrier.

Prof. Kataoka and his team are at the forefront of research on nanomedicine. Other universities with front-

line research is Hokkaido University where Prof. Harashima has developed a liposomal siRNA carrier that

can deliver siRNA to target cells in tumor tissue.

Prof. Kojima, Osaka Prefecture University, has conducted research on dendritic nanoparticles that will play

critical roles in the next generation of nanomedicine. At Osaka University, Prof. Akashi and his group are

conducting research together with Takeda Pharmaceutical to develop a platform for application and

commercialization of nanoparticle vaccines.

At Tohoku University, Prof. Kasai is proposing a new concept termed “pure nanodrugs” that are delivered

into cells in a carrier-free state without use of polymer.

Key players: The key players are NanoCarrier, LTT Bio-Pharma and Mebiopharm. They all have adopted

a business model focusing primarily on off-patent drugs that are transported using own drug delivery

technology platforms.

NanoCarrier is a leader in targeted delivery technologies utilizing micellar nanoparticles. The company has

36 employees and Prof. Kataoka is one of the founding members. One strength of NanoCarrier is its strong

ties to Prof. Kataoka (scientific advisor) with continuous access to new top-level research results.

Two of its platforms are in clinical trials such as Paclitaxel Micelle NK105 and Nanoplatin NC-6004. New

pipelines include research on siRNA and sensor-incorporated micelles.

LTT Bio-Pharma is a bioventure company that has 6 employees. The company has collaborative research

with several universities. Several of its products under development are at the basic research level.

Lipid formulation is one of its core technologies. The first generation of Lipo-PGE1 preparation was

developed in 1987. Currently the third generation named LT-0101 is being developed. In recent years, it

has started research on drug repositioning (identifying new indications for discontinued drugs).



Mebiopharm, a bioventure, currently has only 2 employees which is a reduction with six since 2012. The

company is applying a liposomal approach through encapsulation of drugs.

Mebiopharm presently has no drug candidates in clinical trials in Japan. MBP-426 is an Oxaliplatin-

containing liposome that has reached Phase II in U.S. Lack of funding has stopped further trials.

Nippon Kayaku has several business lines including chemicals and pharmaceuticals focusing on anti-

cancer drugs. The company has in-licensed NK105 (Phase III) from NanoCarrier with which it is conducting

joint research to develop new formulations of micellar technologies.

Nippon Kayaku has developed NK012 (Phase II) that contains the chemo drug Irinotecan Metabolite SN38.

Kowa Company is engaged in various business fields including pharmaceuticals. The company has a co-

development agreement with NanoCarrier related to NC-6300. This drug delivery candidate is loaded with

Epirubicin which can be selectively released by sensing the intracellular pH value. NC-6300 is expected to

shortly enter Phase I clinical trials in Japan.

Minor players are Mitsubishi Tanabe Pharma (Liple and Limethason), Taisho Pharmaceutical (Palux),

Astellas Pharma (Smancs) and Kaken Pharmaceutical (Ropion). All of these companies except Astellas

Pharma have in-licensed early-developed formulations developed by LTT Bio-Pharma (1987-1992). No

new development has been identified since then.

Opportunities: The infrastructure for nanomedicine in Japan has improved in many ways that will expand

the market size. Various government initiatives have made it easier to bring foreign drugs to Japan

including approval procedures.

This is expected to increase opportunities to out-license nanodrugs to Japanese pharmaceutical companies

or to start own business in Japan. Especially, for European companies that have approved nanodrugs that

are not yet available in Japan.

The government’s stress to increase joint or contracted research with overseas universities and businesses

will create opportunities for European counterparts.

The study has identified one approved imaging agent (Resovist) manufactured by Bayer AG. The contrast

agent segment is gaining importance which could open up chances for companies specialized in this field.

There is only one approved nanocrystal (Emand). This could imply future potential in this nanodrug

segment.



1. Introduction

This study looks into the Japanese nanomedicine market. In recent years, the word nanomedicine

(medicine with new concepts and tools) is gradually getting wider attention worldwide, not only in U.S. and

Europe but also in Japan.

The report identifies approved nanopharmaceuticals launched on the market in Japan as well as promising

Japanese drug candidates that are currently in clinical trials. An overview of the global nanomedicine

industry including market drivers, market trends and the market size is presented.

Major market players in Japan are profiled together with a brief overview of research and development at

some universities and research institutions.

Nanotechnology at the nanoscale presents unique characteristics that have enabled opportunities for a

variety of medical applications. The size range that holds much interest is from 100 nm down to 1 nm. In

this range, materials can have different and enhanced properties compared with the same material at a

larger size (1). For example, a particle having a size of 30 nm has 5 percent of its atoms on the surface, at

10 nm 20 percent and at 3 nm 50 percent of the atoms are on the surface.

By converging various sciences such as chemistry, physics, engineering and biology, nanotechnology has

been able to give a new dimension to medicine (pharmaceutical/medical nanotechnology).

A whole new “nanoworld” has been created through nanotechnology. At submicron level (one nanometer is

equal to one billionth of a meter), nanoparticles are able to interact with and gain access to cells.

Nanoparticles range in size from 2 nm to 100 nm and nanoparticle materials vary depending on their

application.

A market estimate by Cientifica (2012) indicates that nano-enabled drug delivery therapeutics will represent

approximately 15 percent of the global nanotechnology market in 2021. The same market report states that

the health sector offers the greatest opportunity to add value to nanomaterials. Drug delivery with

nanomaterials is forecasted to give higher margins than other uses of nanomaterials (2).

The term nanomedicine is often applied to drugs and therapeutics, drug delivery, in vivo imaging and

regenerative medicine. In this report, the main focus is on nanopharmaceuticals and systems to transport

drugs within the body. This is also the segment that has mainly been commercialized in Japan so far.



2. Global Industry Overview

U.S. has long been a strong actor in the field of nanomedicine, especially when it comes to

commercialization. Looking at the number of nanotechnology patent applications in 2012, a study by law

firm McDermott Will & Emery shows that U.S.-based inventors accounted for 54 percent of the studied

patents, followed by South Korea with 7.8 percent and Japan with 7.1 percent (3).

As nanotechnology patents are largely related to medical applications, the study reveals that US has a

strong position in this field.

When it comes to defining nanotechnology in the context of medicine, there is no broadly accepted

definition for nanotechnology. There are slight differences between regulatory agencies how to define

nanoscale in relation to medicine.

In U.S., Food and Drug Administration (FDA) categorizes engineered materials or end products as those

having at least one dimension in the nanoscale range of 1 nm to 100 nm (4).

On the other hand, for the European Medicines Agency (EMA) nanometer scale of production and

applications of structures and devices ranges from the atomic level at around 0.2 nm up to 100 nm (5).

The differences between governmental agencies sometimes lead to occasional paradoxes. One of the

most widely used nanodrugs, Abraxane, is labelled a nanopharmaceutical by governments of European

countries but is not a nanotechnology for FDA (6).

2.1. Drivers for Market Development

The application of nanotechnology in medicine is rapidly developing. Initially, many national initiatives were

started with ample funding for research and development.

In 2001, the government in U.S. launched the National Nanotechnology Initiative (NNI) to bring together

expertise needed to advance the broad and complex nanotechnology field. Totally, including the 2013 NNI

budget request, U.S. has invested US$18 billion.

Also other countries have allocated national budgets to prioritize nanotechnology (strategic initiatives).

Japan has over the years launched various basic plans. Currently, the government is running the 4th

Science and Technology Basic Plan (FY2011 – FY2015).

In addition to national initiatives to support nanotechnology R&D, the following factors can be considered as

key drivers of the global nanomedicine market:

Advantages of nanomedicine in various healthcare segments

Emerging new technologies for drug delivery (active targeting)

General need to cut costs for medical treatment

Increasing knowledge of molecular processes linked to diseases

To sum up, nanomedicine can be said to be both push- and demand-pull driven. There are also challenges

with regards to nanomedicine enabled by nanotechnology that will be discussed in section 2.5.



2.2. Nanomedicine Applications

Nanomedicine applications of nanotechnology are to a large extent related to the interaction between

nanomaterials and cells.

One important and active application area is Drug Delivery Systems (DDS) to transport drugs to the final

location of therapeutic intervention within the body. Various organic and inorganic nanomaterials have been

utilized for DDS applications (“old drugs” for more efficient delivery).

The term nanopharmaceuticals (nanodrugs) covers different nano-based DDS that can be used to

encapsulate drugs for better targeting than with conventional drugs. Some examples of different

nanocarriers are (7):

Liposomes: liposome DDS are nanoscale spheres composed of a lipid layer surrounding the drug

Polymeric miselles: consist of solid particles or capsules to which the drug is attached

Block copolymeric nanocarriers: drugs encapsulated in or conjugated to polymers

Dendrimers: repeatedly branched molecules formed by polymers that can contain drugs

The above nanocarriers are examples of organic nanomaterials. Inorganic nanomaterials such as gold or

iron oxide-based systems have also been utilized as vehicles to deliver drugs.

2.3. Global Nanomedicine Market Size

Many market reports on the global market size have been published over the years. The below table is

based upon data published by BCC Research LLC in 2012 (8). According to the study, the global market

for nanomedicine was valued at US$50.1 billion in 2011 and is projected to grow to US$96.9 billion in 2016.

Table 1. Global Nanomedicine Market Size Unit: US$ billion

Year 2010 2011 2016

Total global pharmaceutical market 879.0 953.0 1200.0

Total global nanomedicine market 43.2 50.1 96.9

Nanomedicine as % of total global market

4.9 5.3 8.1

Source: BCC Research (total global nanomedicine market size estimates).

The global nanomedicine market as a percentage of the total global pharmaceutical market has been

calculated separately in this study. In 2011, this ratio was 5.3 percent and is projected to grow to 8.1

percent in 2016. Nanomedical products still only occupy a small niche of the total market.



Originally, BCC Research’s market estimates were much higher but were later revised downward and

republished (used in this report). For various reasons, it may not yet be possible to get an accurate picture

of the current state of the market including the market potential.

Currently (2012), 18 nanopharmaceuticals and 44 nano-delivery products have been marketed (9).

Additionally, more than 120 drugs are in various stages of testing/clinical trials for cancer treatment as well

as other applications. Considering that there seems to be a dramatic drop beyond Phase II clinical trials,

this may be a contributing factor that some market research companies have revised their market figures

downward (10).

2.4. Global Market Trends – Novel Nanoparticle Engineering Platforms

Nanopharmaceuticals approved and marketed so far basically comprise first-generation technologies like

liposomes. The first generation was developed to increase the solubility that was achieved by

encapsulating drugs in nanomaterials resulting in higher tumor dose accumulation of the drug.

For example, Paclitaxel (anti-cancer chemotherapy) delivered by albumin-bound nanoparticles (trade

name: Abraxane) reduces side-effects that develop if using Paclitaxel the conventional way without a

vehicle to carry the drug. And as nanoparticles have high surface-to-volume ratios the dissolution rate of

the drug will be increased leading to better therapeutic efficacy.

The next phases of development in nanomedicine are taking advantage of combined applications as a way

of differentiation against the first-generation of commercialized products.

Multifunctional nanomedicine is the approach taken by U.S.-based BIND Therapeutics Inc. (BIND) that

develops and commercializes therapeutic targeted nanoparticles (11). BIND’s novel nanoparticle platform

utilizes targeting ligands (antibodies) put on the surface of the nanoparticle that are able to recognize and

bind to specific disease-associated cell-surface proteins or receptors. This enables nanoparticles to

accumulate at their intended site of action that will enhance the therapeutic efficacy (12).

Enhanced functionalization, i.e. not only utilizing a nanoparticle formulation to carry a drug but also to add

functions are also strategies implemented by Cerulean Pharma Inc. (pH-sensitive nanocarrier) and Calando

Pharmaceuticals (polymer nanocarrier containing gene-silencing RNA) (13).

Big pharmaceutical companies have so far showed a modest interest in nanomedicine. This year, however,

Pfizer Inc., Amgen Inc. and AstraZeneca have signed agreements to collaborate with BIND to develop

nanomedicines (14). Totally including sales milestones, these deals are worth US$590 million.

AstraZeneca is also working with CytImmune Sciences Inc. to develop gold nanoparticle-based medicines

(15).



2.5. Challenges

It has been widely predicted that in the future nanomedicine will transform clinical medicine and change the

way how to treat patients.

Progress has been made during the last decade with many nanopharmaceuticals entering the market

worldwide. At the same time, as the nanotechnology is still at its early stage, there are many issues to take

into consideration.

Some of the main issues are (16):

Long approval process

Imprecise definition of nanopharmaceuticals

Risks associated with nanomedicine (environmental impacts)

Relative scarcity of venture funds

Overlapping patent claims

Long approval processes for drug candidates can have a negative impact on commercialization plans.

Clarifications are still needed on nanomedicine classification. This was emphasized during a workshop

hosted by the European Medicines Agency in London in September 2010 by participants that included

representatives from government agencies in U.S., Europe and Japan (17).

Ambiguity over classification can cause problems and delays for decision-making agencies that need

precise language to handle patent applications as well as applications for approval.

Safety of nanoparticles is also a concern. There is a need to further study toxicity in order to assess

possible side-effects of existing nanoparticles.

Many nano-startups are focusing on life science products/technologies with nanotechnology components.

Policies to facilitate funding for new venture businesses will play an important role in strengthening the

bases for the development of new technology applications with regards to medicine.

Patent activities within the field of nanomedicine have expanded considerably during the last 10 years.

Securing patent protection will be critical for the competing players. The importance to have an adequate

patent classification system with regards to nanomedicine to avoid patent claims cannot be understated.



3. Nanomedicine Market in Japan

This section will give information on Japan’s nanomedicine market including listing of approved

nanopharmaceuticals.

3.1. Overall State of Japan’s Pharmaceutical Industry

Japan’s pharmaceutical industry is the world’s second largest market, after U.S., valued at US$112.1 billion

in 2012 or 11.6 percent of the world market.

Historically, the market has been protected from foreign competition. These days, however, deregulation

has prompted investment from abroad and increased the presence of foreign companies.

In 2011, the share of foreign companies to the total shipment value in Japan was 36.2 percent compared to

18.6 percent in 1991 (18).

The pharmaceutical industry is one of the few industrial sectors in which Japan has a trade deficit. Japan

imports more than two times what it exports. The rapid aging of the population and the weak global

competitiveness of domestic companies are contributing factors to the trade deficit.

Generics penetration rate in Japan is low. In 2011, prescription drug sales accounted for 8.8 percent and

22.8 percent by volume. According to “Drug Industry Vision 2013” by the Ministry of Health, Labour and

Welfare (MHLW), the target is to increase the percentage by volume to 60 percent by 2018 (18).

The approval process for new drugs has been slow in Japan. The “drug lag”, time from discovery of an

active ingredient in Japan to an available drug, is now getting shorter as the number of officials at the

review department of the Pharmaceuticals and Medical Devices Agency (PMDA) has increased in recent

years (19).

3.2. Japan Nanomedicine Market Size

There is no market information available on the size of Japan’s nanomedicine market published by any of

the large Japanese market research companies. Table 2 below tries to estimate the market size.

Table 2. Japan Nanomedicine Market Size Unit: US$ billion

Year 2011 2012

Total Japanese pharmaceutical market 111.6 112.1

Estimate at 1 percent of total pharmaceutical market 1.12 1.12

Estimate at 2 percent of total pharmaceutical market 2.23 2.23



The global nanomedicine market was estimated to be about 5 percent of the global pharmaceutical market

in 2010 and 2011. In case of Japan, this ratio is much lower compared to the global nanomedicine market.

A rough estimate indicates that the market size was approximately 1-2 percent of the Japanese

pharmaceutical market in 2011-2012, or roughly between US$1 billion – US$2 billion. The drug lag of

imported nanopharmaceuticals (explained in section 3.5.) is one cause of this.

Nanomedicines have not been defined in Japan and are regulated within the general framework of the

Pharmaceutical Affairs Law (PAL) on a product-by-product basis (20).

3.3. Approved Nanopharmaceutical Products by Application

As there is no specific definition for drug and device (nanocarrier) combinations, they are regulated as

drugs or medical devices according to their main function or purpose (20).

Pharmaceuticals are classified as nanomedicine by their sizes, i.e. materials in the submicron range..

Information on marketed nanopharmaceuticals in Japan comes from various sources (21) including

“Current Initiatives in Japan for Nanomedicines”, Kumiko Sakai-Kato, Toru Kawanishi, 2011, National

Institute of Health Sciences (NIHS) and Ministry of Health, Labour and Welfare (MHLW) (22).

Table 3. Lipid Microspheres

Trade name Compound Technology Company Status Indication

Palux Alprostadil Lipid emulsion Taisho (JPN) Market in JPN Vascular

(Lipo-PGE1) (200-300 nm) (1988) disorder

Liple Alprostadil Lipid emulsion Mitsubishi Market in JPN Vascular

(Lipo-PGE1) (200-300 nm) Tanabe (JPN) (1988) disorder

Limethason Dexamethasone Lipid emulsion Mitsubishi Market in JPN (1988)

Rheumatoid arthritis

palmitate

(200-300 nm)

Tanabe (JPN)

Diprivan Propofol Lipid emulsion (200-300 nm)

AstraZeneca Market (1986) In JPN (1995)

General anastesia

Ropion Flurbiprofen axetil

Lipid emulsion (200-300 nm)

Kaken (JPN) Market in JPN (1992)

Post operative and cancer pain

Table 3 shows that Palux and Liple are manufactured by Taisho Pharmaceutical Co., Inc. and Mitsubishi



Tanabe Pharma Corporation (Mitsubishi Tanabe Pharma) utilizing a Lipo-PGE1 formulation that was

developed by LTT Bio-Pharma Co. Ltd (LTT Bio-Pharma) (23).

Limethason is a Dexamethasone palmitate formulation develop by LTT Bio-Pharma for intravenous

injection to treat chronic rheumatoid arthritis and marketed by Mitsubishi Tanabe Pharma since 1988.

Diprivan, a general anesthesia drug, was marketed in 1986 and was launched in Japan by Fresenius Kabi

Japan in 1995, a company of the Fresenius Kabi Group which belongs to the AstraZeneca Group (24).

Ropion is a non-steroidal anti-inflammatory formulation developed by LTT Bio-Pharma for intravenous

injection to treat post-operative and cancer pain. Ropion is manufactured by Kaken Pharmaceutical Co.,

Ltd. (Kaken Pharmaceutical) and was launched in 1992 (25).

Three nano-based liposomes have been launched in Japan (Table 4).

Table 4. Liposomes


AmBisome Amphotericin B Liposome Gilead Market (1990) Anti-fungal

in Japan (2006)

Doxil Doxorubicin Liposome Johnson & Market (1995) Anti-cancer

Johnson & in Japan (2007)

Visudyne Verteporfin Liposome Novartis Market (2001) Age-related

in Japan (2004) macular

degeneration

AmBisome, a therapeutic agent for systemic fungal infection, was approved by FDA in 1990 and launched

in Japan in 2006 by Dainippon Sumitomo Pharma Co., Ltd (26). AmBisome is manufactured by Gilead

Sciences, Inc. located in U.S. (27).

Doxil is a specially coated form of the chemotherapy Doxorubicin for treatment of cancer that was approved

by FDA in 1995 and is marketed in Japan by Janssen Pharmaceutical K.K. since 2007 (28).

Visudyne is a liposome based on Verteporfin for treatment of macular degeneration. This drug has been

developed by Novartis and is marketed by its Japanese subsidiary Novartis Pharma K.K. since 2004 (29).

Table 5 on page 13 presents antibody-conjugated nanopharmaceuticals.

Mylotarg originally is a drug made by Wyeth. In 2009, Wyeth was acquired by Pfizer and is marketed in

Japan by Pfizer Japan Inc. (30). This drug is used to treat patients with acute myeloid leukemia. In U.S.,

however, FDA asked Pfizer to stop selling the drug in 2011 after a post-marketing trial showed the drug

was not helping patients.

Mylotarg is still sold in Japan as Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) did not



Table 5. Antibody Conjugates


Mylotarg Gemtuzumab Antibody- Wyeth Market (2000) Acute myeloid

ozogamicin conjugated in Japan (2008) leukemia

targeting

Zevalin Ibritumomab Antibody- Bayer Market (2002) Anti-cancer

tiuxetan conjugated in Japan (2008)

targeting

agree with the FDA decision (31).

In 2002, FDA approved Zevalin as treatment for patients with follicular B-cell non-Hodgkin’s lymphoma.

Zevalin has been approved in Japan and is marketed by Bayer Yakuhin Ltd since 2008 (32).

Table 6. Polymer-Conjugated Proteins


Smancs Zinostatin Polymer- Astellas (JPN) Market in Japan Anti-cancer

stimalamer conjugated (1994)

protein

Pegasys Peginterferon PEGylated Roche Market (2001) Hepatitis C

alfa2a protein in Japan (2003)

Pegintron Peginterferon PEGylated Schering-Plough Market (2000) Hepatitis C

alfa2b protein in Japan (2004)

Somavert Pegvisomant PEGylated Pfizer Market (2002) Acromegaly

protein in Japan (2007)

Smancs was approved in Japan in 1994 for the treatment of advanced and recurrent hepatocellular

carcinoma. Smancs is manufactured and marketed by Astellas Pharma Inc. (33).

Pegasys for treatment of hepatitis C was developed by F. Hoffman-La Roche AG in 2001 (34). In Japan, it

is marketed from 2003 by Chugai Pharmaceutical Co., Ltd. that entered an alliance with F. Hoffman-La

Roche in 2001 (35).

Pegintron was developed by Schering-Plough in 2001 to treat hepatitis C. In Japan, this drug is marketed

by Schering-Plough KK since 2004 and by MSD K.K. since 2009 after the merger of Merck and Schering-

Plough (36). MSD stands for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Ltd.

Somavert was developed by Pfizer and is sold in Japan by Pfizer Japan Inc. since 2007. It is used for

treatment of acromegaly which is a syndrome that results when the glands produce excess growth

hormones.



Table 7. Nanocrystal (Crystalline Nanoparticles)


Emend Aprepitant Nanocrystal Merck Market (2003) Antiemetic drug

in Japan (2009)

Table 7 presents Emend which is an antiemetic drug that is effective against vomiting and nausea. The

drug was developed by Merck in 2003 and licensed to Ono Pharmaceutical Co., Ltd. for the Japanese

market (37). Emend is marketed in Japan since 2009.

Table 8. Polymeric Nanoparticles


Abraxane Paclitaxel Albumin- Abraxis Market (2005) Anti-cancer

conjugated drug in Japan (2010)

Abraxane is an albumin-bound Paclitaxel formulation developed by Abraxis BioScience Inc. and approved

by FDA in 2005. Abraxis Bioscience Inc. is now a wholly-owned subsidiary of Celgene Corp. (38). In Japan,

Abraxane is marketed by Taiho Pharmaceutical Co., Ltd. since 2010 (39).

Additionally, Resovist which is an imaging agent for the detection and characterization of small focal liver

lesions has also been approved for use in Japan (2002). Resovist was originally developed by Schering AG

in 2001 and consists of superparamagnetic iron oxide nanoparticles coated with Carboxydxtran. In Japan,

this imaging agent is marketed by Bayer Yakuhin Ltd.

3.4. Nanopharmaceuticals in Clinical Trials in Japan

Nano-based pharmaceuticals developed by Japanese companies are listed in Table 9 showing the current

status of clinical trials.

Table 9. Nanodrugs in Clinical Trials in Japan


NK012 Irinotecan active Block copolymer Nippon Kayaku Phase II (Japan) Anti-cancer

metabolite SN38 micelle

NK105 Paclitaxel Block copolymer Nippon Kayaku Phase III (Japan) Anti-cancer

micelle

NC-6004 Nanoplatin Block copolymer NanoCarrier Phase I (Japan) Anti-cancer

micelle



Currently, there are three nanodrug candidates undergoing clinical trials. NK012 is a macromolecular

micellar anti-cancer drug developed by Nippon Kayaku Co., Ltd. (Nippon Kayaku) that has entered Phase II

(40). NK012 is a SN-38-releasing polymeric micelle (nanocarrier) that has antitumor effect.

NK105 is a Paclitaxel micelle technology platform that Nippon Kayaku has in-licensed from NanoCarrier

Co., Ltd (NanoCarrier) (41). This drug entered a Phase III clinical trial in July, 2012 (42).

NC-6004 is a polymer nanocarrier containing Cisplatin. This drug candidate is currently in Phase I for

treatment of solid cancer. NC-6004 is currently also undergoing overseas clinical trials: Phase II in Asia for

pancreatic cancer and Phase I for solid cancer in U.S.

Another drug candidate is NC-6300 which has been developed by NanoCarrier. A preclinical trial has

finished and the current status is preparation for Phase I clinical trial entry.

MBP-426 is a drug developed by Mebiopharm Co., Ltd. (Mebiopharm), a Japanese company that uses

Oxaliplatin as an active pharmaceutical agent for stomach cancer (43). This drug is currently in a Phase II

clinical trial in US.

In June 2013, Kyowa Hakko Kirin Co., Ltd. filed an application for marketing approval for Pegfilgrastim

(brand name Neulasta) developed by Amgen Inc (44). Pegfilgrastim that was approved by FDA in 2002 is

used to reduce the risk of infection while being treated with anti-cancer drugs. Pegfilgrastim has been

licensed from Amgen Inc. for marketing in Japan.

3.5. Market Trends

Totally, 16 drugs have the status as nanopharmaceuticals (having submicron size) in Japan. Five of these

drugs have been developed by Japanese companies during the 1987-1994 period. Most of these drugs are

lipid emulsions and belong to the early stage of the first-generation of nanomedicine development.

Eleven of the listed drugs have been developed by overseas companies and several of these are U.S.

entities. The time from approval until the drug was launched in Japan is very long for some drugs. For

example, in case of AmBisome that was approved by FDA in 1990, it took as long as 16 years until the

same drug was available in Japan from 2006. And for Doxil it took 12 years (from 1995 until the Japanese

launch in 2007).

A contributing factor for the delay has been the slow approval process in Japan. Additional rounds of

testing on the Japanese population have often been required. This may be mandated because of concerns

that ethnic differences might cause patients to react differently to the same drug.

This delay that in average is approximately 7 years per approved nanodrug has contributed to the slow

penetration of nanomedicine in Japan.

Large Japanese pharmaceutical companies have not actively been promoting investments in nanomedicine

research and development. This could explain the lack of new Japanese nanopharmaceuticals being

developed after 1995. The primary development so far has mainly been initiated by a few Japanese start-

up companies like NanoCarrier. NanoCarrier and other companies will be profiled in section 6.



The current pipeline (drugs in clinical trials) is to a large extent based on cutting-edge research at leading

Japanese universities. Some of the presented drug candidates seem to have a fair chance of getting final

approval for marketing launch that could give a big boost to the Japanese nanomedicine industry.

Since 2005, Japanese government-initiated actions related to the approval process have led to gradual

changes for the better. This may led to speedier launch in Japan of foreign nanopharmaceuticals in the

future.

It is interesting to note that four of the imported nanopharmaceuticals are marketed by Japanese

pharmaceutical companies:

AmBisome (Gilead Sciences, Inc., U.S.): marketed by Dainippon Sumitomo Pharma Co., Ltd.

Abraxane (Celgene Corp., U.S.): marketed by Taiho Pharmaceutical Co., Ltd.

Emend (Merck & Co., Ltd., U.S.): marketed by Ono Pharmaceutical Co., Ltd.

Pegasys (F. Hoffman-La Roche AG, Switzerland): marketed by Chugai Pharmaceutical Co., Ltd.

All of the manufacturing companies have subsidiaries in Japan. Chugai Pharmaceutical has an alliance

with F. Hoffman-La Roche which explains why it markets Pegasys in Japan.

For the other companies, licensing to Japanese companies may have been a preferable option as it is quite

costly to carry out clinical trials in Japan.

Abraxane that is marketed by Taiho Pharmaceutical Co., Ltd. (Taiho Pharmaceutical) is used to treat breast

and lung cancer. Studies in U.S. have showed that Abraxane is effective at improving overall survival

among pancreatic cancer patients when combined with chemotherapy (Gemzar).

Currently, FDA is conducting a priority review based on the supplemental New Drug Application (sNDA)

submitted by Celgene Corp. Global sales of Abraxane have grown significantly for the last three years and

reached US$486 million in 2012. The drug is expected to generate sales of about US$2.1 billion as a

treatment for pancreatic cancer if approved (45). This could become a boost in sales for Taiho

Pharmaceutical in Japan.

Four of the imported nanodrugs (Diprivan, Visudyne, Zevalin and Pegasys) are manufactured by European

companies.



4. Changing Environment – Government Pushing for Change

Through the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Ministry of

Economy, Trade and Industry (METI) the Japanese government has been allocating funding for

nanotechnology programmes (46). Basic and applied research is supported by these ministries through the

Japan Science and Technology Agency (JST) (47).

Various basic plans have been implemented over the years including nanotechnology. Under the latest

basic plan, the 4th Science & Technology Basic Plan (1 April 2011 – 31 March 2016) nanotechnology is no

longer prioritized in favour of Life Innovation and Green Innovation.

To achieve the goals of the 4th S&T Basic Plan, the target level of government R&D is 1 percent of GDP

with the total for five years to be about 25 trillion yen (48).

The positioning of Life Innovation in the new basic plan is to realize high quality of life in an aging society.

Some of the sub-goals are:

Development of innovative diagnostic and treatment methods

Promote translational research

Accelerate innovation by affirmative legal framework

Under the new basic plan, “design-based” R&D will have an important function that will shorten the time

span leading to innovation (49).

In order to reduce the time span from discovery and innovation to commercialization, the importance to

establish open user facility networks to promote the integration of dissimilar fields and academic-industry

collaboration is emphasized.

It is apparent that the government is aiming at more concrete and speedy results for R&D. Issue-driven

innovation based on “exit-oriented” R&D is targeted to impact the competitive power of related industries.

A report by the Japan Science & Technology Agency titled “Japan’s New Science and Innovation Policy –

Beyond the Boundaries for Innovation”, published in 2011 (50) lists up the time span for selected target

applications of nanomedicine, such as:

Molecular imaging (2015-2020)

Integrated system of drug delivery, diagnosis and treatment (2015-2020)

Implant devices for diagnosis and treatment (2020-2030)

Nano-cell surgery (2020-2030)

3D-imaging in cells (2020-2030)

These are quite ambitious targets showing the directions where R&D will be focused.

In addition to the latest basic plan, there are other signals that the government is increasingly prioritizing

innovative medicine. For instance, The Ministry of Health, Labour and Welfare will jointly with the European

Union (EU) promote the development of nano-based block copolymer micelles. Together with European



Medicines Agency (EMA) the ministry has released a reflection paper (February 2013) emphasizing that

such micelles are able to preferentially accumulate in solid tumors (51).

The drug candidates in clinical trials listed in section 3.4. seem to have something like the status of

“national projects” and are referred to in various documents compiled by government agencies.

Starting from July 2011, the Pharmaceuticals and Medical Devices Agency (PMDA) is offering

“Pharmaceutical Affairs Consultation on R&D Strategy” for universities, research institutes and venture

businesses (52). The purpose is to give advice on tests needed for commercialization which is not always

clear to these parties.

As a link in boosting the strength in innovative medical technologies, the government will foster drug

development ventures. Considering that the venture business landscape in Japan is characterized as

immature and according to the World Bank ranks behind Ghana in ease of starting a business, this could

bring about improvements in the venture environment (53).

As was briefly mentioned in section 3.5., deregulation of the Japanese pharmaceutical industry has

shortened the drug approval time. In 2012, PMDA created a Science Board of external experts to improve

its reviews of applications involving cutting-edge technologies.

Taken together, these improvements in the infrastructure surrounding nanomedicine in Japan are expected

to speed up the development of innovative drugs including nanopharmaceuticals.



5. Nanomedicine – Research and Development in Japan

This section presents some of the cutting-edge research and development in this field at leading Japanese

universities and research institutes.

5.1. University of Tokyo

Professor Kazunori Kataoka (Prof. Kataoka), Faculty of Medicine, University of Tokyo, Center for Disease

and Integrative Medicine, developed the first polymer drug carrier in the late 1980s (54). Prof. Kataoka

created a spherical carrier loaded with drugs and in experiments using mice could successfully target and

destroy cancer cells.

Later, Prof. Kataoka further developed his research to achieve practical application, and to date has

conducted studies using various types of anti-cancer drugs (55) based on block copolymer material.

Prof. Kataoka has also conducted research that uses photosensitizers for DDS cancer treatment. He is a

distinguished researcher in his field with connections to many of the leading universities in the world.

In recent years, Prof. Kataoka and his group has carried out research on introduction of messenger RNA

(mRNA) containing nanomicelles into the CNS (central nervous system). Messenger RNA is a promising

treatment candidate for disorders in CNS (56).

Prof. Kataoka and his group have recently showed that nano-capsule therapy is useful in treating

pancreatic cancer (57).

5.2. Hokkaido University

Professor Hideyoshi Harashima (Prof. Harashima) belongs to the Faculty of Pharmaceutical Sciences,

Hokkaido University (58).

Prof. Harashima and his group have developed a liposomal siRNA carrier, a multifunctional envelope-type

nanodevice (MEND). Studies have indicated that a small interfacing (si) RNA carrier can deliver siRNA to a

target cell in tumor tissue through improved siRNA bioavailability (59).

5.3. Osaka Prefecture University

Professor Chie Kojima (Prof. Kojima) is a researcher at the Nanoscience and Nanotechnology Research

Center, Research Organization for the 21st Century, Osaka Prefecture University (60).

Prof. Kojima has conducted research related to stimuli-responsive DDS: external stimuli and self-regulated

internal body stimuli. Temperature and light have already been clinically used as external stimuli (61).



Prof. Kojima states that the design of functional dendritic nanoparticles will be important for the next

generation of DDS. In her research, Prof. Kojima has prepared dendrimers modified with polyethylene

glycol (PEG) and found that dendrimers could encapsulate anti-cancer drugs and photosensitizers.

5.4. Osaka University

At the Graduate School of Engineering, Osaka University, Professor Mitsuru Akashi and his group have

developed a fundamental nanoparticle technology (62).

Starting in February 2012 and running until January 2015, Osaka University and Takeda Pharmaceutical

Co., Ltd. (Takeda) have established a Joint Research Chair for three years to develop a platform for the

practical application and commercialization of nano-particle vaccines (63).

The platform will utilize Takeda’s know how on vaccine antigens and drug formulation technology together

with Osaka University’s technology of nanoparticle adjuvant (a pharmacological agent added to a drug to

increase its effect).

5.5. Tohoku University

Professor Hitoshi Kasai and his group at the Institute of Multidisciplinary Research for Advanced Materials,

Tohoku University, have proposed a new concept termed “pure nanodrugs” (PNDs) which are comprised of

drug ingredients that are delivered into cells in a carrier-free state without use of polymer (64).

As the first model of PNDs, nanoparticles (50 nm size) of dimer N-38 were used. Compared to Irinotecan

(prodrug of SN-38), the SN-38 nanoparticles exhibited effective anti-cancer effect. Use of PNDs with lower

concentration level is expected to reduce side-effects commonly associated with conventional anti-cancer

agents (65).

5.6. National Institute for Materials Science

Research headed by Dr. Mitsuhiro Ebara, International Center for Materials Nanoarchitectonics, National

Institute for Materials Science (NIMS), has developed a “smart” nanofiber mesh that simultaneously

generates heat and releases chemo drugs in a controlled manner (66).

The nanofiber mesh combines a heat-responsive polymer, magnetic nanoparticles and anti-cancer drugs.

The magnetic nanoparticles, which are a self-heating substance, enable heating of the fibers by applying

an alternating magnetic field. In this process, the nanoparticles vibrate rapidly and generate heat causing

the temperature-responsive polymer to release the anti-cancer drug. This combination therapy has not yet

left the laboratory but there are lots of hope that this technology will improve tumor treatment in the future..



6. The Japanese Nanomedicine Industry

6. 1. Business Model

Nanomedicine start-ups and small-medium enterprises have driven the innovation process, not only in US

and Europe but also in Japan. The commercialization of nanopharmaceuticals have basically followed three

types of business models (67), such as:

Development of a nanotechnology platform used to add value to second-party products

Development and manufacturing of high-value materials for the pharmaceutical industry

Development of nanotechnology-improved pharmaceuticals or medical devices

The majority of start-ups has adopted the third business model utilizing nanotechnology to develop own

proprietary product pipelines. Often such companies introduce new or standard drugs that are delivered

with a drug delivery system. Then they try to team up with pharmaceutical companies that take the

products through the clinical trials.

In Japan, NanoCarrier, LTT Bio-Pharma and Mebiopharm are using this business model.

6.2. Japanese Players

The key Japanese players are briefly profiled in this chapter. The players can be classified into two groups:

start-up companies that develop nanomedicine drug delivery systems such as NanoCarrier, LTT Bio-

Pharma and Mebiopharm, and pharmaceutical companies that utilize drug delivery technology platforms.

6.3. NanoCarrier Co., Ltd.

NanoCarrier (36 employees), established in 1996, in-licenses intellectual proprietary rights and carries outs

joint research with universities and research institutes. The business model is to find existing therapeutic

drugs that are potent but lacking carriers for effective drug delivery.

NanoCarrier develops new drug components using its micellar nanoparticle technology. This technology is

based on world-class basic research made by Prof. Kataoka who is one of the founding members of

NanoCarrier. Through this connection, the company has continuously been able to get access to new

technological development from Todai TLO (Technology Licensing Organization of the University of Tokyo

(68). The University of Tokyo (Todai) commercializes discoveries made by its researchers through this

organization.

Depending on the results of the initial research, NanoCarrier may conclude a joint–research agreement

with a business partner that finds the micellar nanoparticle technology interesting. If the evaluation of the

drug formulation by the partner is favourable, then the drug is usually outsourced.



Main pipelines under development are: Paclitaxel Micelle (NK105 which is out-licensed to Nippon Kayaku),

Nanoplatin (NC-6004), DACH-Platin Guiding Micelle (NC-4016) and Epirubicin Micelle (NC-6300). Ongoing

clinical trials seem to be progressing smoothly.

New pipelines include in-house research on siRNA (small interfering RNA) and sensor-incorporated

micelles.

In 2011, NanoCarrier signed a joint research agreement with Kyoto University, aiming to create new nucleic

acid drugs to be loaded into its micellar nanocarriers. And in 2012, it concluded a collaborative research

agreement with Eisai Co., Ltd. (69). The purpose is to look at ways to adopt its nanoparticle technology with

Eisai’s pharmaceutical products.

High development costs coupled with low sales have resulted in recurring net losses during many years. In

March 2013 (FY2012), the net loss was 484 million yen. In March 2012, the net loss was 398 million yen

and 555 million yen in March 2011 (70). The sales in FY2012 amounted to 374 million yen.

The forecast for March 2014 is a net loss of 1,200 million yen (sales estimate: 416 million yen) due to many

ongoing clinical trials and several research projects.

The strengths of NanoCarrier are its micellar nanoparticle technology (many patents) and strong ties to Prof.

Kataoka (scientific advisor). High development costs and limited available capital are weaknesses that will

continue to impact the company.

6.4. LTT Bio-Pharma Co., Ltd.

LTT Bio-Pharma, a bioventure, was established in 2003 through spin-off from the LTT Research Institute

that was founded in 1988. The company is located in Tokyo and its R&D activities are focused on novel

drug delivery system technologies. The total number of employees is six.

In 2011, LTT Bio-Pharma delisted itself from the Tokyo Stock Exchange and is no longer actively traded on

any major stock exchange. In 2008, the company suffered a setback as one of its subsidiaries, Asclepius,

went bankrupt due to illicit dealings caused by a former president of the company.

The adopted business model incorporates basic research with the purpose of improving delivery of existing

drugs by applying its DDS technology. At the next step, if the outcome is satisfying, the company will file a

patent application for the relevant technology. Finally, it may out-license this technology to a

pharmaceutical company that usually will conduct clinical trials.

The company has collaborative research deals with several Japanese universities including the Faculty of

Pharmacy, Keio University (71). Several of LTT Bio-Pharma’s products under development are currently at

the basic research level.

Core technologies include lipid formulation. The first generation of Lipo-PGE1 preparation, consisting of

nanoparticles containing prostaglandin E1, was developed in 1987. The second generation named AS-013

did not show outcomes as expected. Currently, the third generation formulation of PGE1 named LT-0101 is

being developed (72).

Since 2010, the company conducts joint research and development with Asahi Kasei Pharma Corp. related

to a stealth-type nanoparticle formulation (73).



In recent years, LTT Bio-Pharma has commenced research on drug repositioning. This is a way to try to

identify new indications for drugs that have been discontinued for reasons other than safety. Compared to

US and Europe, drug repositioning has been slow to catch up speed in Japan.

Sales in March 2013 (FY2012), amounted to 67.5 million yen. LTT Bio-Pharma has a joint venture, Beijing

Tide Pharmaceutical Co., Ltd., with China-Japan Friendship Hospital (74). In FY2012, LTT Bio-Pharma

received 535.7 million yen as dividend from its share in the joint venture. The dividend income helped cover

the R&D costs (353.8 million yen) as well as other costs and contributed to the generation of a net income

of 116.3 million yen. In FY2011, the sales amount was 61.1 million yen with a net loss of 66.4 million yen.

6.5. Mebiopharm Co., Ltd.

Mebiopharm, a biotech company, was founded in 2002 and is based in Tokyo. The number of employees

was two as of March 31, 2013, and this is a reduction by six from March, 2012.

The company went public in 2011 but delisted itself from TOKYO PRO Market of Tokyo Stock Exchange in

June, 2013.

Its business model is based on development of drug formulations created through encapsulation inside

liposomes of currently used drugs. Mebiopharm’s core technology is transferrin-conjugated nanoparticle

formulations. Transferrin is a blood plasma glycoprotein (75).

Main pipelines are: MBP-426 (for stomach and pancreatic cancer), MBP-Y003 (for lymphoma), MBP-Y004

(for solid tumor) and MBP-Y005 (for solid tumor) (76).

MBP-426 is an Oxaliplatin (chemotherapy)-encapsulated transferrin-conjugated liposome. When transferrin

is exposed to a transferrin receptor on the surface of the cancer cell, it binds to the receptor and enters into

the cell (75).

MBP-426 has reached Phase II in U.S. for the indication of stomach cancer. Mebiopharm has recently been

trying to raise more capital but it did not succeed. When additional funding has been secured it is planning

to continue the clinical trials.

MBP-Y003, MBP-Y004 and MBP-Y005 are currently at pre-clinical levels.

Mebiopharm has been commissioned by a medical equipment company to develop a contrast agent

utilizing nanoparticles for ultrasound diagnosis for cancer.

In FY2012, the company achieved total sales of 31.9 million yen. R&D costs amounted to 61.2 million yen

which together with other costs resulted in a net loss of 143 million yen. Also in FY2011 it had a net loss

amounting to 203.1 million yen.



6.6. Nippon Kayaku Co., Ltd.

Nippon Kayaku is divided into three main business lines: functional chemicals, pharmaceuticals and

automotive safety parts. Its pharmaceuticals segment is focused on producing anti-cancer drugs. Total

sales in FY2012 were 128.1 billion yen and the net income was 12.3 billion yen.

Nippon Kayaku has in-licensed NK105 from NanoCarrier and for several years it has conducted joint

research with NanoCarrier to develop new formulations of micellar nanoparticles. The NK105 micelle

contains Paclitaxel for treatment of breast cancer. By encapsulating the Paclitaxel into a micelle it is

possible to reduce side-effects that usually arise when used the conventional way. In July 2012, this drug

candidate entered Phase III clinical trials in Japan.

Polymer micelles utilize polymer to contain the anti-cancer drug. The size of a polymer micelle is usually

20-100 nm in diameter, a size that easily accumulates in tumor cells (77).

NK012 is a drug candidate developed by Nippon Kayaku. It is a micellar drug that incorporates Irinotecan

Metabolite SN38 (chemotherapy). The current status is Phase II clinical trials in Japan for the indication of

colorectal cancer.

Both these drug candidates have the potential to generate large sales once approved.

6.7. Kowa Company Ltd.

Kowa Company (Kowa) started as a cotton fabric wholesaler in Japan in 1894. Today, it is engaged in

various business fields including manufacturing and sales of pharmaceuticals. It is still trading in textiles.

Total sales in FY2012 were 220.3 billion yen.

In Sept. 2011, Kowa and NanoCarrier entered into a license and co-development agreement on NC-6300

(78). Under this agreement, Kowa shall be granted a license for the worldwide right to manufacture and

sell NC-6300. NC-6300 is a micellar nanoparticle drug which incorporates Epirubicin which is widely used

as an anti-cancer drug.

In May 2013, Kowa submitted an Investigational New Drug Application to the Pharmaceuticals and Medical

Devices Agency. As soon as this application has been approved, a Phase I clinical study will start.

NC-6300 is equipped with a “pH-sensor” system developed by Prof. Kataoka and his team. This drug

candidate can selectively release Epirubicin by sensing the intracellular pH. When the drug enters into a

cancer cell, the pH level is lowered and the Epirubicin is rapidly released within the cell (79).

To expand and strengthen the collaboration and relationship between the two companies, Kowa has been

allotted 11,000 shares through a capital increase in 2012. As per March 31, 2013, it has 3.38 percent of the

outstanding shares.



6.8. Minor Players

In this section, information on minor players will be presented. With minor player means a company that

currently is not actively researching and/or developing new nanodrugs. Minor players are:

Mitsubishi Tanabe Pharma Corporation

Taisho Pharmaceutical Co., Ltd.

Astellas Pharma Inc.

Kaken Pharmaceutical Co., Ltd.

Mitsubishi Tanabe Pharma was formed in 2007 from the merger of Mitsubishi Pharma and Tanabe

Seiyaku. Net sales in FY2012 amounted to 419 billion yen and the net income was 41.9 billon yen.

Since 1988, using the Lipo-PGE1 technology developed by LTT Bio-Pharma, it has manufactured and

marketed Liple for vascular disorder and Limethason for rheumatoid arthritis. During 1988-2007 until the

patents expired, it has paid royalties for sales of these drugs under licensing agreements.

In 2004, the company entered an agreement with LTT Bio-Pharma to develop and manufacture AS-013

(second generation Lipo-PGE1). Mitsubishi Tanabe Pharma conducted a Phase III clinical trial in US but

as the data did not show results as expected, it withdraw from this project (80).

Taisho Pharmaceutical was founded in 1912 under the name Taisho Seiyaku. It is a medium-sized

pharmaceutical company that had net sales of 29.8 billion yen in FY2012.

In 1988, the company launched Palux for the indication of vascular disorder. It licensed the same Lipo-

PGE1 preparation technology that Mitsubishi Tanabe Pharma did for its Liple drug. And it paid royalties

until the patent expired.

Astellas Pharma Inc. was established in 2005 from the merger of Fujisawa Pharmaceutical and

Yamanouchi Pharmaceuticals. It ranks in the top 20 global pharmaceutical companies in sales. In FY2012,

net sales amounted to 1,005 billion yen.

In 1994, it launched Smancs which is a polymer-conjugated protein containing a chemotherapeutic agent

(Zinostatin stimalamer) for the treatment of hepatocellular carcinoma (most common type of liver cancer)

(81). Originally, this drug was developed by Yamanouchi Pharmaceuticals and was approved in 1993.

Kaken Pharmaceutical was found in 1982 from the merger of Kaken Chemicals and Kakenyaku-Kako. It is

a small to medium-sized pharmaceutical company with net sales amounting to 87 billion yen in FY2012.

The company launched Ropion in 1992 which is a non-steroidal anti-inflammatory formulation developed

by LTT-Biopharma (82). It is used for treatment of post-operative and cancer pain.



7. Pharmaceutical Regulations in Japan

Manufacturing, importation, and sales of drugs and medical devices are regulated by the Pharmaceutical

Affairs Law (PAL) of Japan.

All manufacturing and marketing applications in Japan for drugs and devices are reviewed by the

Pharmaceutical and Medical Devices Agency (PMDA) (83). All applications are thoroughly reviewed before

PMDA submits an approval recommendation to the Ministry of Health, Labour and Welfare (MHLW).

Under PAL, when importing to Japan and selling pharmaceutical products manufactured in other countries,

a license for marketing authorization is required. The Marketing Authorization Holder (MAH) will be the

owner of the license for marketing authorization.

The MAH must be based in Japan and can be the foreign company’s Japan office, the foreign company’s

distributor, or an independent third party acting as the Designated Marketing Authorization Holder (DMAH).

To import and market a new drug in Japan, an approval (marketing approval) will be necessary. And the

approval must be held by the Marketing Authorization Holder.

A foreign manufacturer intending to manufacture drugs in foreign countries and export them to Japan, is

required to be accredited by MHLW as an “Accredited Foreign Manufacturer” (84). And it is necessary to

obtain accreditation for each foreign factory location at which pharmaceuticals for export are manufactured.

The appointed MAH will be responsible for the labelling and advertising of the pharmaceuticals in Japan.

As stipulated in PAL, the manufacturer’s/seller’s address, name of product, production indication, name of

ingredients, expiration, etc., must be printed on the container of drugs.

The advertising of pharmaceuticals must not exceed the scope of the pharmaceutical product’s indications.

There are basically no tariff barriers for pharmaceutical products in Japan (85).



8. Conclusions

Nanomedicine is a promising sub-segment in medicine that took off in the 1980s with the first generation of

developed nanopharmaceuticals. With the use of nanotechnology, drugs can be delivered in ways not

experienced so far.

U.S. is a strong actor in this field with many patents having commercialized several nanopharmaceuticals.

The global nanomedicine market was valued at US$50.1 billion in 2011 and is projected to grow to

US$96.9 billion in 2016. The share of nanomedicine to the total global pharmaceutical market is estimated

at 5.3 percent in 2011 indicating its niche character presently.

In Japan, for various reasons, the nanomedicine market size in terms of the total market is much smaller. A

rough estimate shows that the share is between 1 to 2 percent corresponding to approximately US$1 to 2

billion. A limited number of approved Japanese nanodrugs together with a long time until approved foreign

products entered the Japanese market have seemingly slowed the market expansion.

Totally, sixteen drugs have the status as nanopharmaceuticals in Japan (sub-micron size). Five of these

are manufactured by Japanese companies and developed in the 1980s and early 1990s.

Currently, there are three Japanese nanodrug candidates in clinical trials. They are all related to the

University of Tokyo and top-level research by Prof. Kataoka and his team.

Three start-up bio-ventures have been identified including NanoCarrier that has in-licensed patents owned

by the University of Tokyo. The adopted business model focuses on seeking existing drugs that are potent

but lacking carriers for effective drug delivery.

The three drug candidates have attracted international attention and some of these should have a fair

chance of getting marketing approval in the short term which could give a boost to Japan’s nanomedicine

industry.

In addition to the University of Tokyo, research related to nanomedicine is conducted at Hokkaido

University, Tohoku University, Osaka University as well as research institutes such as National Institute for

Materials Science.

The Japanese government has implemented various basic plans. Initially, nanotechnology was prioritized

but under the latest plan, the 4th Science & Technology Basic Plan (FY2011-FY2015), Life Innovation has

been prioritized together with Green Innovation.

With the aim of promoting the development of innovative medicine, the government is aiming at

transforming the way research is carried out. “Exit-oriented” R&D, i.e. issue-driven innovation beyond

discipline-oriented innovation, will help in speeding up innovations.

Improvements in processing drug approval applications have reduced the drug lag. Other initiatives include

cooperation with the European Medicines Agency targeting block copolymer micelles, and enhanced

functionalities of the Pharmaceuticals and Medical Devices Agency.

When it comes to opportunities for European companies, the potential is changing for the better.

The improved nanomedicine infrastructure such as clarified approval standards and shorter approval times

are some factors that will simplify and shorten the time needed for a market launch in Japan.



Opportunities include increased out-licensing of nanodrugs to Japanese pharmaceutical companies or the

establishment of own company for a direct launch. Alternatively, if it already has a subsidiary in Japan let

the local company launch the drug. Deregulation has made it easier to start pharmaceutical operations in

Japan.

The government emphasizes the importance of increasing joint or contracted research with overseas

universities and businesses. This could create opportunities for European universities to collaborate with

Japanese universities as well as chances for European pharmaceutical companies.

As more nanodrugs enter the market in Japan including approval of Japanese-developed products, the use

of nano-scale medicine will increase and expand the market.

The need to cut healthcare expenditure in Japan will also drive the development of innovative medicine that

will give further momentum to the nanomedicine segment.

Only one approved imaging agent – Resovist - has been identified for detection of small liver lesions which

is manufactured by Bayer AG. Use of contrast agents (nano-imaging) introduced into the body to mark

diseases is gaining attention worldwide. Companies specialized in contrast agents for medical imaging

should be able to target Japan through own launch, out-licensing of the product or the related technology

platform.



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