GLOBAL DELIVERY MARKET - Advanced Drug Delivery Systems: mAb, RNAi, & Breaking the Blood-Brain Barrier

INTRODUCTION

A 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.

Indeed, 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.

Advances 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%.

ANTIBODY DRUGS

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 moving forward.

Horizontal broadening 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 cancer.

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 effects.

The commercial 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)

Since the 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 technologies.

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.

BLOOD-BRAIN BARRIER (BBB) TECHNOLOGY

Blood-brain barrier 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

hyperactivity disorder (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 is enormous.

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, visit www.bccresearch.com.

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 breast disease.

 

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 pharmacokinetics.