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Nanomedicine Market
October, 2013
Maths Lundin
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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
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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
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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
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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.
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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).
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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.
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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.
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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.
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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.
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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).
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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.
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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
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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
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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
Trade name Compound Technology Company Status Indication
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
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Table 5. Antibody Conjugates
Trade name Compound Technology Company Status Indication
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
Trade name Compound Technology Company Status Indication
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.
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Table 7. Nanocrystal (Crystalline Nanoparticles)
Trade name Compound Technology Company Status Indication
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
Trade name Compound Technology Company Status Indication
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
Trade name Compound Technology Company Status Indication
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
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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.
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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.
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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
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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.
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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).
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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..
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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.
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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).
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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.
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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.
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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.
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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).
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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.
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EU-Japan Centre for Industrial Cooperation 31
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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EU-Japan Centre for Industrial Cooperation 32
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