significant challenge for both drug and drug delivery companies is to produce
existing and emerging drug technologies in a manner that improves drug
administration for the patients. Advantages of advanced drug delivery systems
over traditional systems are more convenient routes of administration, greater
efficacy and duration of drug activity, decreased dosing frequency, improved
targeting, as well as reductions in toxic metabolites. New and emerging
delivery systems - including rectal, vaginal, lymphatic implanted, or
transdermal applications - for traditional pharmaceuticals are more effective
and cause fewer side effects if delivered in forms that allow a continuous or
extended release of the drug. These factors, along with new developments in targeted
drug delivery, are aiding localized treatment of diseases with minimized harm
to healthy surrounding cells. Consequently, these developments are driving
significant growth in the global drug delivery markets.
research-based pharmaceutical companies are continuously working toward the
discovery and development of new drug delivery systems. This has led to mergers
and profitable partnerships between pharmaceutical companies. Transdermal
technologies alone have opened new doors for pharmaceutical partners seeking to
create delivery mechanisms for existing molecules with no viable delivery
system and existing drugs that could benefit from additional delivery systems,
such as compounds that were previously unable to be delivered through the skin.
in understanding human biology and diseases are opening new and exciting
possibilities in the biotechnology industry. R&D spending, along with
increasing competition, patent expiries, and new and emerging technologies will
continue to shape growth in this market for the foreseeable future. According
to BCC Research (www.bccresearch.com), the global market for advanced drug
delivery systems was valued at $151.3 billion in 2013. This market is
forecasted to reach nearly $173.8 billion in 2018, registering a 5-year
compound annual growth rate (CAGR) of 2.8%.
Monoclonal antibody (mAb)
drugs are a new generation of
pharmaceuticals created by using modern technologies, such as genetic
engineering and recombinant DNA (Deoxyribonucleic acid) technology. These protein drugs, which are produced by
living cells and organisms like Escherichia coli (E.coli), yeast, and mammalian
cells, have gained significant importance with the dramatic global rise of
chronic conditions, such as asthma, multiple sclerosis, arthritis, and fatal
diseases like cancer and cardiovascular diseases.
The mAb market has grown
rapidly in the past decade. With the development of the hybridoma method of
murine antibody production in 1975, the production of the first mAb was made possible
by Johnson & Johnson through its product, Orthoclone OKT3 (muromonab).
Orthoclone OKT3 was introduced in 1986. This highly innovative market has moved
from murine to chimeric, humanized and fully human antibodies. Oncology, autoimmune,
and inflammatory disorders are the traditional markets for these drug technologies.
Also, the market has seen
vast clinical growth globally as a result of its pivotal role in the development
of effective targeted treatments to prevent these chronic and life-threatening
diseases. Technological advancements are aiding in further investigation and
development of novel antibody drugs, including antibody drug conjugates and
bi-specific antibodies that attack the proteins present inside a cancerous cell.
In addition, therapies that more effectively suppress the progression of diseases
like arthritis, multiple sclerosis, hepatitis, Crohn’s disease, and AIDS are
indication strategies (approval for two or more indications) are also supporting
the growth of this market. The broad spectrum mode of action is another
remarkable advantage of monoclonal antibodies that makes for use of therapy in various
diseases. For instance, bevacizumab (Avastin) is used to treat various cancers,
including colorectal cancer, lung cancer, breast cancer, kidney, and ovarian
Recombinant DNA technology
also has brought enormous change in the market with increase in different
expression systems like transgenic mice, E. coli expression systems, and yeast
expression systems. Research is going on using transgenic plants as a source for
expression systems, thus changing the way antibodies are produced and bringing
growth in the market.
The mAb market has
benefited considerably from the participation of a wide range of pharmaceutical
companies, including Roche, Biogen, GlaxoSmithKline, Abbvie, Johnson &
Johnson, Novartis, and Merck Serono. Companies are keen on developing new
technologies to produce antibodies that are more efficient with fewer side
achievements earned by mAbs within the past few years are incomparable with any
other drug class. As a result, the global antibody drug market is expected to reach
$122.6 billion by 2019 and expected to grow at a CAGR of 12.2% through 2019.
Humanized mAbs are the largest segment in terms of revenues followed by other
mAb categories like human, chimeric, and murine. The use of mAbs in therapeutics
such as oncology, auto immune and inflammatory diseases are expected to
increase as well.
However, the mAb market
scenario is expected to change with the onset of biosimilars by 2015.
Rituxan/MabThera (rituximab) will be the first biosimilar mAb to emerge in the
market, possibly in 2015. AcellBia from Biocad Biopharmaceutical is the first
rituximab biosimilar to be approved by the Ministry of Health of the Russian Federation
in May 2014. Sandoz declared the entry of GP2013, a rituximab biosimilar for the
treatment of follicular lymphoma, into
Phase III clinical trials.
These will be followed by
the launch of eight other biosimilar molecules, one by one, by 2020, which are
being investigated. The series of launches, however, may not immediately shake
the branded antibody market because the complex structure of mAbs, long complex
manufacturing process, and high regulatory requirements will restrict the entry
of biosimilar manufacturers within the market.
RNA INTERFERENCE (RNAI)
Nobel-prize-winning discovery of RNA interference (RNAi) in 1998, considerable resources
have been invested to study the therapeutic potential of RNAi - an evolutionarily
conserved, endogenous process for post-transcriptional regulation of gene expression
- and its application in understanding human diseases. Recently, RNAi therapeutics
have shown tremendous growth and have moved forward in clinical trials.
RNAi’s popularity stems
from its utility as a molecular biology tool, which enables the in vivo functional
analysis of thousands of genes. Recent advances in the field include the design
of new libraries of RNAi effectors, effective delivery systems, and read-out methods.
In 2005, delivering RNAi triggers was the biggest obstacle in creating effective
RNAi-based therapies. Research into new and effective delivery methods has
taken place, although there are still major issues to be addressed. The first
human trials of a systemic RNAi-based therapeutic were initiated in 2007 by
Quark Biotech. Understanding of the mechanism of action and intracellular
pathways of micro RNA (miRNA) has developed over the years. miRNA is also now
an alternative gene knockdown technology that is being applied in research, and
for therapeutic and diagnostic applications.
RNAi as a mechanism to
selectively degrade messenger RNA (mRNA) expression has emerged as a potential
novel approach for drug target validation and the study of functional genomics.
Small interfering RNA (siRNA) therapeutic have developed rapidly and already
there are clinical trials ongoing or planned. Although other challenges remain,
delivery strategies for siRNA become the main hurdle that must be resolved,
prior to the full-scale clinical development of siRNA therapeutics.
There has been immense progress
in the field of nanotechnology for drug delivery, and efforts have been
dedicated to the development of nanoparticle-based RNAi delivery systems. A
carefully engineered, multifunctional nanocarrier with targeting capabilities
is needed to address the delivery challenges. New developments show
positive growth and confidence in RNAi therapeutics. The future of RNAi drugs
depends on IPOs like the newly public RNAi therapeutics company, Dicerna. The
company initiated its first Phase I study of a
Dicer-substrate-based RNAi therapeutic this year. DCR-MYC targets the well-known
Myc oncogene utilizing a liposomal delivery formulation (EnCore) for targeting
a variety of cancers - solid and hematological malignancies.
Global RNAi therapeutics
are forecast to generate sales of around $3 billion by 2018, and this market
has significant potential. Therapeutic companies in this space have many challenges,
the most critical being delivery. Recently, Novartis decided to leave the RNAi
therapeutics development field, due to lack of suitable delivery technologies.
The RNAi market has been
very dynamic and to some extent unpredictable. Some of the key companies
operating in this space are Alnylam Pharmaceuticals, Isis Pharmaceuticals,
Tekmira Pharmaceuticals, Calondo Pharmaceuticals, Dicerna Pharmaceuticals,
Marina Biotech, Quark Pharmaceuticals, RXi Pharmaceuticals, and Silence Therapeutics.
Earlier this year, Alnylam decided to acquire Merck's wholly owned subsidiary
Sirna Therapeutics, with intellectual property and RNAi assets including
preclinical therapeutic candidates, chemistry, siRNA-conjugates, and other delivery
The markets for RNAi are
difficult to define as no RNAi-based product is in clinical development yet.
The global RNAi drug delivery market was worth nearly $11.7 billion in 2013 and
is expected to grow to more than $38.8 billion by 2018 at a 5-year compound
annual growth rate (CAGR) of 27.2%. However, RNAi delivery is not easy and
challenges are expected.
technology enables therapeutics to pass through the previously impenetrable
blood-brain barrier (BBB), which protects neural tissue from chemicals and
infections and helps to regulate the brain’s environment (ie, levels of ions
and peptides and the movement of water and salts). The barrier provides such a protective
shield to the brain that approximately 98% of small molecule drugs and 100% of
large molecule drugs cannot cross it. Advanced BBB drug delivery technologies
essentially produce central nervous system (CNS) drugs that can pass the BBB
using a platform technology or drug delivery technologies.
Through this type of
technology, therapeutics are delivered orally or through injection and have
reached the brain in therapeutic amounts to treat whole new areas of CNS
disease. Currently, treating the brain largely involves treating only a
fraction of CNS diseases through the BBB using small molecules, or bypassing
the BBB, such as nasally with a spray or opening the head to insert a catheter
or some other device, the latter of which is not desirable unless it is the only
option. The CNS disorders treatable with small molecules to date include
schizophrenia and bipolar disorder,
depression, pain, epilepsy, insomnia, and attention deficit
(ADHD), or similar disorders. Largely cut off from most treatments, large and
small, have been: cerebrovascular disease, the neurodegenerative diseases (Alzheimer’s,
Huntington’s, and Parkinson’s disease, and cognitive effects from AIDS), and
amytrophic lateral sclerosis (ALS), multiple sclerosis, brain cancer, stroke, brain
or spinal cord trauma, autism, lysosomal storage disorder, Fragile X syndrome, inherited
ataxias, and blindness. This means the potential upside for successful BBB technologies
The most common means of
BBB passage or type of technology is receptor-mediated transport, or RMT, which
involves crossing the BBB via certain receptors that include the insulin or
transferrin receptors. This refers to transcytosis, whereby a cell encloses
extracellular material in an invagination of the cell membrane to form a vesicle,
and that vesicle carries the enclosed material through the cell and disposes of
it outside of its membrane on the other side.
The other technology to
emerge as a vehicle for taking a drug across the BBB is carrier-mediated
transport. In this type of technology, a protein typically exists at the BBB
that is a “transporter” with an active site so that it effectively brings the
“nutrient” that it is expected to bring, such as glucose, into the brain area.
XenoPort has been working on a BBB technology using the LAT1 transporter
to carry a form of L-Dopa
across the BBB for Parkinsonism.
According to BCC Research,
all of the top pharmaceutical companies are involved in BBB technology or have
explored it, with six of the top 10 companies having active licensing deals
with BBB technology companies that have chosen to specialize in the competency
of delivery compounds, including MedImmune (AstraZeneca) with Bioasis (that is
looking at lysosomal storage disease), GlaxoSmithKline with Angiochem (also
looking at lysosomal storage), Lundbeck with Ossianix and
Nanomerics (looking at several targets). Rather than develop this expertise
in-house, which pharmaceutical companies have tried to do, the emerging industry
model is for larger companies to license or acquire this expertise - with the exception
of Genzyme that developed its own BBB-branded technology called LipoBridge - now
called Cerense, after being bought by UK-based Pharmidex.
Today, three compounds
using BBB technology are currently in the clinical development pipeline, but
by 2019 they will number approximately eight. The global market for BBB technologies
was valued at $21.8 million in 2013 and $38.7 million in 2014. The market is
expected to grow to $471.5 million by 2019, and register a tremendous 64.9%
CAGR from 2014 through 2019.
In addition to the sheer
potential of the untapped CNS market, near-term growth in the BBB segment will
be driven by patent expiries, increasing commercialization of biologics-based
drugs (and moving away from small molecules) that require some sort of BBB
technology adaptation to move across the barrier, as well as greater numbers of
commercialized biologics, such as antibodies. Additional growth will be spurred
by the overall expansion of the CNS therapeutic area further into brain cancer,
neurodegeneration, and psychiatric medications for disorders such as schizophrenia,
bipolar disorder, and depression.
Some of the challenges
involved in BBB technologies or even in developing CNS therapeutics include the
lack of cooperation among companies specializing in BBB technology; lack of
sufficient investment due to risk avoidance; CNS side effects (given the significant
role of the brain and nervous system in the human body), and the lack of suitable
biomarkers or preclinical models for BBB simulation.
This article is based on
the following market analysis reports published by BCC Research: Global
Markets & Technologies for Advanced Drug Delivery Systems (PHM006J) by
Shalini Shahani Dewan, Blood-Brain Barrier Technologies & Global
Markets (PHM075B) by Kim Lawson, and RNAi Drug Delivery: Technologies
& Global Markets (BIO076B) by Usha Nagavarapu. For more information,
To view this issue and all
back issues online, please visit www.drug-dev.com.
Kevin James is a New York City-based healthcare
and medical communications professional with more than 15 years of experience
in the private and public health sectors.
Shalini Shahani Dewan earned her Master’s degree
in Pharmaceutical Chemistry and has more than 14 years of industry experience.
Ms. Dewan was awarded a Gold Medal by the Prime Minister of India for her work
and has worked with top companies in India and in the US.
Kim Lawson is a graduate of Mount
Holyoke College with a degree in English Literature. She acquired experience as
a healthcare journalist, including working for John Wiley & Sons as a print
reporter, before serving as a research analyst in a small market research firm
that focused on pharmaceuticals and biotechnology in the Research Triangle Park
area of NC. Before joining that firm, Ms. Lawson published reports on emerging
and established diagnostics and therapeutics for
benign and cancerous
Usha Nagavarapu is an experienced pharmaceutical
professional with business development experience. She has more than 10 years
of preclinical, alliance management, discovery, and technology development marketing
experience. Her strong focus areas include oncology and cardiovascular
diseases, with expertise in molecular and cell biology and complex cell-based
biological assays ranging from drug discovery, in vitro and in vivo screening,
in vivo model development, and