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Andrew Huang: “ADC’s Are Among the most Powerful Options to Increase Drugability of a mAb”

With a population of 1.4 billion [*] and a rapidly expanding economy, China has become a manufacturing powerhouse. In addition, China is pursuing a goal of becoming a major hub for international bio-pharmaceutical product research, development and manufacturing. In realizing the first steps in this ambitious goal, China has, over the past decade, become a major destination for the global pharmaceutical industry to conduct R&D activities. This growth has drastically changed the pharmaceutical landscape, challenging Chinese companies in raising the quality of their products, while, at the same time, challenging them in expanding their development and manufacturing capacity to serve both global and national markets. [1]

Partly the results of China’s population growth and increasing domestic medical needs, the country has, according to a recent report published by UBM’s CPhI China, become the world’s biggest producer and exporter of active pharmaceutical ingredients or APIs.  Today, the country is responsible for nearly 40% of global API production. But the Chinese pharmaceutical market has still huge opportunities for growth. 

With government’s increasing investment in healthcare and R&D, China offers unique opportunities for innovative products and technologies, and collaboration between global and domestic pharmaceutical companies.

According to the China Food and Drug Administration (CFDA), the government’s significant investment in healthcare led to an increased – and more innovative – R&D pipeline and a growing importance of China as center of bio-pharmaceutical development and manufacturing.  The government’s investment has also cultivated companies with capabilities that are comparable – and competitive – with North American and European R&D, putting high-cost, global-centric R&D models at a real disadvantage.

Eliminating Concern
The growth of China’s bio-pharmaceutical industry is also the result of effectively securing Intellectual Property (IP) rights.  IP rights are among the most valuable resources for pharmaceutical and biotech companies, and their  protection often dictates the future success of the companies involved. While poor IP protection and enforcement have often been cited as limiting factors in the growth of pharmaceutical companies’ drive to carry out R&D in China, recently revised patent laws have increased overall global trust and are expected to effectively deter copycat drug makers.  And while, according to the US-China Business Council, some concern remains, China’s IP laws and regulations increasingly reflect international standards, allowing Chinese authorities to better protect and enforce IP rights.[2]

According to a study about the business of life sciences, pharmaceuticals and healthcare sector in China, published by Deloitte China Life Sciences and Health Care in Shanghai, the increased IP protection and enforcement has resulted in a growing number of global pharmaceutical companies being increasingly attracted to the idea of having a R&D center in China or, alternatively, partnering with Chinese partners.[3]

Furthermore, a general low cost base, a large pool of highly qualified research subjects, increasing scientific capabilities, the local industry’s knowledge, a general lack of regulatory and cultural impediments often found in other countries and insight into the country’s growing drug markets have made China an attractive country for R&D.

Ambitious Plans
In China, regulatory approval for pharmaceutical agents is based on clinical trials that have been carried out in the country. This requirement has also contributed to the global pharmaceutical industry’s interest in conducting clinical trials in China – and, as a result, work with a Chinese contract research organization (CRO) and contract (development) and manufacturing organizations (C(D)MO).

The regulatory environment has, no doubt, boosted China’s ambitions plans to be a primary market for CROs and CDMOs. Most of the top 20 multinational pharmaceutical companies have been expanding their footprint in China by setting up R&D facilities through various enterprise structures. Large companies including Bristol-Myers Squibb (BMS), Pfizer, Roche, GlaxoSmithKline (GSK), Johnson & Johnson and Novo Nordisk continue to develop partnerships with Chinese companies.

This approach mitigates traditional development risks but also leverageg local efficiencies, allowing companies to add operational value due to familiarity with the market and regulatory requirements, leading to shortened approval times and reduced development costs. In turn, Chinese CROs are recruiting expert Chinese nationals with research experienced nurtured at top Western pharmaceuticals companies to staff domestic CROs.

Moreover, global pharmaceutical companies are starting to conduct R&D activity specifically related to Asian markets. The specificity is linked to the environmental, cultural and genetic factors, liver disease, certain cancers, and some communicable diseases that are more common in Asian countries, such as China and Thailand than in other countries around the world.

Expanding facilities
Among the growing CRO/CDMOs in China is MabPlex International. Based in Yantai, a port city in Shandong province, China, and founded in 2013, the company specializes in the development and GMP manufacturing of recombinant proteins, antibody therapeutics and antibody-drug conjugates for its global customers. To accommodate growing demand, MabPlex, in October 2016,  broke ground on the expansion of its bio-manufacturing facilities.

The construction of company’s new 428,000 sq. ft. facility is expected to be completed by August of 2017, with utility and HVAC validation finished by December 2017.  The fill/finish facility will be completely validated by March of 2018.

Earlier this year we interviewed Andrew C. Huang, MabPlex’ Senior Vice President of R&D. Huang has developed a robust and proprietary technology platform for the manufacturing antibody-drug conjugates based on covalent thiol conjugation Technology. The resulting Hertuzumab Vedotin, the first ADC being developed in China, has entered Phase I and Phase II clinical trials.

Prior to joining MabPlex International, Huang served for more than 17 years as a biomedical researcher at the University of California, Los Angeles (UCLA), a public research university in the Westwood district of Los Angeles, engaging in molecular medicine, including brain aging, diabetes, stem cells and protein folding research. He has published near 100 research articles, journal reviews and book chapters. During our interview we asked him about his company, the role his company plays in global bio-pharmaceutical development and manufacturing, the current expansion, the potential for antibody-drug conjugates and the regulatory env

Question/Peter Hofland: What excites you the most about the potential of ADCs?

Answer/Andrew Huang: Antibody drug conjugates are one form of combinatorial therapy that uses tumor-targeting antibodies and high-potency chemical drugs. Most antibodies alone have limited efficacy against malignant cancers. The efficacy of an antibody often increases synergistically when conjugated to a high-potency chemical drug. In addition to the enhancement efficacy, the ADC platform can rescue some  cytotoxic drugs, which are too toxic or have poor bioavailability on their own.

PH: What are your company’s major accomplishments over the past 12 months?

AH: We have completed several ADC projects, including providing ADCs for phase II clinical trials and one successful IND with better than expected results.

PH: … and what are your expectations for the next 12 months?

AH: Our ADC projects from US-based clients gradually increased over the last 12 months. And we expect that this will continue in the foreseeable future. That’s why we are expanding our ADC manufacturing capacity to accommodate [the doubling of the number of ADC projects].

PH: As a CDMO, what are the top three things that sets your company’s next-generation ADC platform apart?

AH: I think that there are three things that set us apart. The first thing includes our cysteine conjugate platform and our product quality in terms of conjugation efficiency and fraction of DAR4. The second differentiator is our proprietary thiol covalent conjugation technology and finally, our faster speed and efficiency of completing client’s task as compared to (other) leaders in the field.

Pharma/Industry Questions
PH: MabPlex International is based in China. How big is the role of Chinese CDMOs in the world?

AH: The Chinese are gradually increasing their role as a worldwide CDMO family. However, right now, Chinese CDMO companies are limited in capacity because most Chinese companies focus mainly on Chinese business and they are not familiar with rules and business outside China. But that’s changing. Currently, more and more Chinese companies are starting (representative) offices in the United States and Europe to explore opportunities.

PH: How is the approach of Chinese companies different (or similar) to the approach of CDMOs in North America and Europe?

AH: Most CDMO companies in China are led by US/Europe “returnees” so most approaches are likely to be the same or (very) similar. The significant difference will be to fit Chinese “culture” and how to bridge the Eastern culture to Western one.

Regulatory landscape
PH: The unique properties of ADCs create technical challenges that require careful CMC considerations. Based on your experience in the development of ADCs what are some of the current regulatory challenges (with special focus on CMC)?

AH: A few years ago, during the Cambridge Healthtech Institute’s inaugural CMC Strategies for Antibody-Drug Conjugates meeting in Boston, Massachusetts, someone answered the same question by saying that antibody-drug conjugates are conceptually, very simple, but in practice, extremely complicated.  And I must agree with that. In it’s ‘simple’ complexity ADCs combine a monoclonal antibody, a chemical linker and a cytotoxic drug. Simply stated, as a result of the complex nature of an ADC, we need triple the amount of control and characterization to achieve the right formulation, stability and consistency for effective scale up and manufacturing if we want to meet the regulatory requirements.

And with the increased number of ADCs coming down the pipeline, it becomes imperative for pharmaceutical and biotechnology companies to consider the manufacturability of the ADCs. This means that they have to incorporate process design and CMC strategies early on in the development stage of an ADC.

Looking at our experience, some of the technical challenges require careful CMC considerations include homogeneous drug distribution, the highest possible fraction of DAR4 and the lowest possible fraction of DAR6 or higher with cysteine conjugation.

PH: Overall…What do you see is the biggest challenge in the development of ADCs?

AH: That’s the degree of homogeneous drug distribution.

But manufacturing ADCs not only involves technical challenges but also challenges in the areas of externalization of manufacturing, supply chain management and new technology considerations. That’s why regulators, looking at the highly toxic nature of ADC payloads, as well as the monoclonal antibody and linker chemistry thta make up an ADC, are concerned about the safety, potency and stability of the product and the workers involved in manufacturing it.

Regulatory implications
PH: How is the regulatory landscape in China different than the European of North American regulatory landscape?

AH: A few years ago, regulations in China for CDMOs were significantly different when compared to Western regulations. At that time the drug license and MFG (Drug Manufacturing) license had to be the same. This greatly limited Chinese CDMO development. However, after November 2015, China adopted a new policy for Marketing Authorization Holders (MAH). This new policy is similar to policies in the United States and Europe: the licenses for marketing authorization and manufacturing are separate.

PH: How has the creation of the China Food and Drug Administration (CFDA) and a restructuring of its regulatory system benefited Chinese CDMOs and in particular, your company?

AH: As mentioned, starting in November 2015, China enforced a new policy for Marketing Authorization Holders similar to policies in the United States and Europe. Prior to 2015, all bio-pharmaceutical companies were required by the China Food and Drug Administration (SFDA) to complete the biologic drug CMC and formulation-fill-finish by themselves. Only a chemical drug could be outsourced or contracted out to CRO/CDMOs. Now, biologics, like any chemical drugs, can be outsourced to CRO-CDMO, like MabPlex.  This includes  R&D and CMC, formulation, fill-finish and even IND submissions.

PH: One often heard concern from companies in North America and Europe is that despite vast improvements, concerns still persist about enforcement of intellectual property (IP) and patent laws in China. How does that impact CDMO business in China?

AH: These concerns have a deep impact on CDMO’s in China. We believe the only thing we can do is to continuously improve our IP enforcement, which is already at Western standards. In addition to our secure enforcement of IP protection, MabPlex has a morning meeting each day to emphasize to all our employees three things: IP, GMP and Safety!

PH: … and how does this, specifically, impact your business?

AH: Companies, especially North American and European companies, are still a little hesitant in dealing with new companies like us. However, we see more and more companies from the United States starting ADC business with us. We are confident that we will prove to our US and European colleagues that we are a trustful and reliable partner.

PH: Your company is experienced in ADC development and manufacturing. Are you planning to expand with additional development and manufacturing facilities in North America and Europe?

AH: We already established a branch (MabPlex Inc. USA) in USA last year. But our US branch will not include manufacturing.


[*] 2017

Last Editorial Review: May 24, 2017

Photo 1.0: Andrew C. Huang, MabPlex International’s Senior Vice President of R&D. Courtesy: © 2017 MabPlex  Featured Image: MabPlex headquarters, Yantai, Shandong, China. Courtesy: © 2017 MabPlex. Used with permission.

Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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EAG Laboratories: Unifying Brands to Leverage Global Contract Research and Testing Capabilities

Earlier this week, Evans Analytical Group®, better known as EAG, a global scientific services company offering testing, analysis and characterization to technology- and life-science-related industries, announced that it has combined its 11 corporate brands, including ABC Laboratories, under a new, singular, entity: EAG Laboratories.

Following a number of acquisitions in recent years, the move is designed to bring together broad capabilities in the materials, engineering and life sciences sectors. The new company expects to leverage scientific talent in its 20 locations in the United States, Europe and Asia-Pacific regions, strengthening its offering for industries including pharmaceutical, biopharmaceutical, medical devices, crop protection, aerospace, defense, semiconductor, wearables (and other consumer products), among others.

“Over the last decade, EAG Laboratories has quietly added capabilities through complementary acquisitions and service line expansions in the high-growth contract research and testing space,” explained Siddhartha Kadia, PhD, president and CEO of EAG Laboratories.


Following the discovery of a potential therapeutic drug or biologic, regulatory agencies around the world are requiring an increasingly complex and demanding process of pre-clinical and clinical trials. A large part of this development process is required to demonstrate drug safety and therapeutic efficacy.


Strength
“We’ve built a problem-solving culture in which our scientists and engineers go beyond simply delivering data. Our scientists interpret results and find answers that support our clients’ commercial success. That is something today’s technology-driven companies need from their outsourcing partners, and it makes EAG unique in the scientific services arena. By unifying multidisciplinary expertise under one brand, we simplify delivery of our services to enhance our customer relationships,” Kadia further noted.

Siddhartha C. Kadia joined EAG as President and Chief Executive Officer in April, 2014.
Photo 1.0: Siddhartha C. Kadia, PhD, joined EAG as President and Chief Executive Officer in April, 2014.

“With our unique, multidisciplinary, expertise in the life-, materials- and engineering-sciences, we help our clients innovate and improve their products, ensure quality and safety, protect intellectual property and comply with the ever evolving global regulatory demands,” Kadia added.

ABC Laboratories
One of the original EAG companies, ABC Laboratories (Columbia, MO), a GLP and cGMP-compliant Contract Research Organization (CRO), established 1968 and acquired by EAG in 2015, offers a range of product development, structural characterization, analytical testing, custom synthesis and radio-labeling services, as well as testing capabilities for small- and large-molecules.

Drug development
Following the discovery of a potential therapeutic drug or biologic, regulatory agencies around the world are requiring an increasingly complex and demanding process of pre-clinical and clinical trials. A large part of this development process is required to demonstrate drug safety and therapeutic efficacy.[1]

With a large number of antibody-drug conjugates (ADCs) in development, companies require extensive characterization and analytical services in order for a novel (ADC) drug candidate to enter a clinical trail. Because of the relatively low odds of success in the development of novel therapeutic agents and the large investments required, biotechnology companies are generally focusing on potential therapies with the highest likelihood of generating commercial success. [1]

This is where EAG Laboratories plays a role.

“We have a thorough knowledge of the regulatory landscape in a various global jurisdictions as well product-specific knowledge and understanding of the (clinical) drug development process,” explained Glenn Petrie, PhD, EAG Laboratories’ Senior Scientific Advisor. “This gives us the unique opportunity to support our clients’ and help them find specific answers and, ultimately, help them reach commercial succes,” he added.

Characterization and analysis
The physico-chemical properties influencing the safety and therapeutic efficacy of novel biologics are their Critical Quality Attributes or CQAs. For therapeutic monoclonal antibodies there is an increasing number of studies explaining which attributes are really critical.

Because conjugation methods can influence heterogeneity, and therefore impact the pharmacokinetic, safety and therapeutic efficacy of an ADC, the Critical Quality Attributes for ADCs may overlap those of the monoclonal antibody intermediate, while others involve size variants (aggregates and fragments), drug distribution, average drug-to-antibody ration or DAR, and free drug level.

Other Critical Quality Attributes may include charged variants associated with the monoclonal antibodies, as well as process impurities such as those related to the cytotoxic anti-cancer drug, the linker chemistry, conjugation and product isoforms. Each of these Critical Quality Attributes can be used during the development of antibody-drug conjugates to demonstrate that a manufacturing process can reproducibly meet defined criteria.

“Using state-of-the art instrumentation and a pioneer approach to methodologies, we’re a highly technical, experienced and innovative partner for companies seeking characterization and analytical services for their antibody-drug conjugates development tracts,” Petrie noted.

“The combination of analytical as well as process knowledge, helps us to support our clients develop antibody-drug conjugates with consistent quality, safety, and therapeutic efficacy for both clinical and commercial use,” Petrie added.

Small and large
“While we work for a large number of biotechnology companies involved in the development of antibody-drug conjugates, some of our smaller clients may involve ‘virtual’ companies. These clients may be working with Contract (Development) Manufacturing Organization (CDMO), but they don’t have their own (production) facilities or laboratories. Others may have an extensive infrastructure. But overal, our clients tell us that while they may have a great relationship with their CDMO, given the complex supply chain involving multiple partners, each with their own, specific, expertise, they prefer outsourcing characterization and analysis to us,” Petrie concluded.

Pursuing a vision
In 2008 Odyssey Investment Partners acquired EAG Laboratories.

“Since [the] acquisition, we have been following an aggressive strategy in adding some of the world’s most trusted names in contract research, development and testing. While the puzzle is not yet complete, our clients see us as  a global scientific services company with industry-leading expertise in testing, analysis and characterization services, bringing significant customer value to multiple markets,” Kadia said.

“Since day one, we’ve pursued our vision of being a world-class testing and analytical services company by adding more and more expertise and capability to a company we believed to have the best and brightest people in the industry,” added Randy Paulson, a managing principal at Odyssey Investment Partners, EAG Laboratories’ majority owner.

“We now have expanded services that match all our clients’ testing and analysis requirements, and also have been aggressive in augmenting our executive team in the last 18 months. We have all of the pieces in place to help grow EAG Laboratories, creating even more value for our worldwide customer base,” he concluded.

The new company employs 1,200+ employees across 20 laboratories in seven countries, serving more than 7,000 clients worldwide.


Last Editorial Review: July 12, 2016

Featured Image: Das letzte fehlende Stück in einem Puzzle wird in eine Lücke gelegt Courtesy: © 2016 Fotolia. Used with permission. Photo 1.0: Siddhartha C. Kadia, PhD, joined EAG as President and Chief Executive Officer in April, 2014. Courtesy: © 2016 EAG Laboratories. Used with permission.

Copyright © 2016 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Bio International: Innovation Driving Growth in the Biopharmaceutical Market

With our increasing understanding of disease mechanisms and our ability to unlock the power of the immune system to break significant barriers and change the standard of care for patients with cancer or hematological malignancies, analysts predict that the future of healthcare lies in expanding the clinical benefit of novel, targeted, therapeutics to a larger proportions of patients.

Among these novel therapies are antibody-drug conjugates or ADCs, which have, over the last decade, taken can­cer treatment to a new level.  Antibody-drug conjugates – and many other candidate biologics in clinical trials – are distinctly different  from ‘simple’ recombinant proteins. Based on increased global investments, and the expectation that ADCs may ultimately extend beyond cancer and hematological malignancies, the outlook for the next few years is optimistic.

BIO CONVENTION LOGO_VERTICAL_NODATES_CMYKHowever, the development and manufacturing of these novel, high potent agents and advanced next-generation targeted therapies, require significant advances in biomanufacturing technologies and more advanced characterization methods – during manufacturing – to identify and remove contaminants.

Characterization
In developing these new highly potent drugs, manufacturing scientists are continuously challenged to develop specific analytical methods to accurately determine the physico-chemical and structural properties, purity, potential contaminations and impurities, quality, biological activity and therapeutic properties. Overall, these challenges range from chemistry to analytics and from processing to formulation [1]

As part of the manufacturing process, advanced analytics and ADC-specific assays are required for batch comparability and toxicity detection. Furthermore, process optimization and scaling-up are critical to ensure a smooth transition from initial clinical to commercial phase, while dosage and formulation hold the key to patient safety and efficacy.

Although there are currently no specific guidelines targeting antibody-drug conjugates, regulatory agencies, including the European Medicines Agency (EMA) require monoclonal antibody-based products (including ADCs) to be thoroughly characterized. The European guidelines addresses quality issues for the marketing authorization of monoclonal antibodies intended for therapeutic or prophylactic use (including ex vivo application), and in vivo diagnostic use.[2]

Furthermore, the International Conference on Harmonization (ICH) guidelines provide a uniform set of internationally adopted principles for the characterization of these novel agents.[1]

Structural Characterization Physico-chemical Analysis
Amino acid sequence Molecular weight or seize
Amino acid composition Isoform pattern
Terminal amino acid sequence Extinction coefficient (or molar absorptivity)
Peptide map Electrophoretic patterns
Sulphydryl group(s) and disulfide bridges Liquid Chromatographic patterns
Carbohydrate structure Spectroscopic profiles

Based on the growing number of novel biologics drug candidates, changing expectations in the characterization of ADCs are driving improvement in the development of analytical equipment as well as the development of novel systems and processes.

Growing number of ADCs
According to the Pharmaceutical Research and Manufacturers of America (PhRMA), which represents the country’s leading biopharmaceutical researchers and biotechnology companies, there have, to date, been three ADCs ap­proved, including Gemtuzumab Ogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories; withdraw from the market in 2010), Ado-trastuzumab Emtansine, also know as T-DM1 (Kadcyla®; Genentech/Roche) and Brentuximab Vedotin (also known as SGN-035; Adcetris® by Seattle Genetics) and nearly 50 investigational ADCs are progressing in more than 300 in clinical trials.

In early 2016, Immunomedics’ investigational ADC, Sacituzumab Govitecan, also known as IMMU-132, in development for the treatment of triple-negative breast cancer (TNBC), was awarded breakthrough therapy desig­nation by the U.S. Food and Drug Administration (FDA).[3]

In May 2016, Abbvie spent US $ 5.8 billion to buy Stemcentrx to get its hands on rovalpituzumab tesirine, also known as Rova-T, a novel biomarker-specific ADC-therapy that is derived from cancer stem cells and targets delta-like protein 3 (DLL3) that is expressed in more than 80% of Small Cell Lung Cancer (SCLC) patient tumors and is not present in healthy tissue. The investigational drug combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.[4]

In Phase I/II studies of relapsed SCLC patients who have previously failed one or more standard therapies, rovalpituzumab tesirine demonstrated overall response rates of 44% in the patients identified with high expression of DLL3. The expression of DLL3 suggests rovalpituzumab tesirine may also be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme, prostate, pancreatic and colorectal cancers, where DLL3 expression ranges from 50-80%.[4]

Clinical data for two other ADCs being developed by Astellas and Seattle Genetics, ASG-15ME and Enfortumab vedotin, also known as ASG-22ME and ASG-22M6E, were presented at the American Society of Clinical Oncology‘s (ASCO) 51st Annual Meeting held June 3-7, 2016, in Chicago, IL, showing strong clinical activity of these two novel ADCs.*

Photo: 1.0: Bio International Convention held June 6-9, 2016 in San Francisco, CA. The first BIO International Convention was held in 1993 and attracted approximately 1,400 attendees. The largest event to date was in Boston, Mass. in 2007, with more than 22,000 attendees. The BIO International Convention is the largest global event for the biotechnology industry and attracts the biggest names in biotech, offers key networking and partnering opportunities, and provides insights and inspiration on the major trends affecting the industry.

Taking flight
The development of ADC has taken flight.  In the “2016 Nice Insight CDMO Outsourcing Survey” responding companies said that they have biologic drugs in their pipelines: 57% are developing ADCs com­pared to 51% with ‘naked’ mAbs under evaluation.[5]

In earlier reports, Nice Insight highlighted a number of trends driving the growth and structure of the biopharmaceutical market. With the ability to address more complex diseases with novel, advanced, therapeutics, including antibody-drug conjugates, developing and manufacturing becomes more challenging – and more costly.  At the same time, payers are looking for ways to reduce the costs of therapies or find proper justification for treatments exceeding US $ 150,000 per patient per annum.[5]

Other targeted therapies
In addition to developing antibody-drug conjugates, a number of biotechnology companies are developing  promising gene and cell-based therapies (e.g., chimeric antigen receptor T-cell (CAR-T) for the treatment of a broad range of cancers.

These CAR-T cells combine an antigen recognition domain of an antibody with the intracellular signaling domain into a single chimeric protein.

Specific blockade of the PD-1 immunosuppressive pathway can significantly enhance the function of gene-modified T cells expressing a chimeric antigen receptor (CAR) leading to enhanced tumor eradication. [6] CAR T cell therapy in combination with PD-1 blockade overcomes PD-L1+ tumor immunosuppression, thereby leading to improved therapeutic efficacy.  These novel treatments are designed to allow the immune system to recognize and attack malignant cells as it would any other intruder. [6]

Many of these novel drugs, showing long term remission in some patients, are current in clinical trials. One example of an FDA-approved treatment is pembrolizumab (Keytruda®; Merck Oncology/Merck Sharp & Dome Corp/MSD), a first among immune-oncology drugs aimed at unlashing the human immune system against various cancer and hematological malignancies.

Although most analysts agree that the immuno-oncology era is off to a promising start, there are substantial obstacles to further clinical and commercial success. Among these obstacles are the large number of companies involved in the development of immune-oncology drugs.

According to a Tufts Center for the Study of Drug Development Impact Report published in March 2016 by Tufts University, more than 130 biotech and 20 pharma companies are developing immune-oncology therapies. This activity reflects—and is fueling—worldwide immune-oncology product sales, with annual revenues expected to reach $25 billion to $40 billion by 2020, up from $2.5 billion in 2015.

Other obstacles include developers identifying validated biomarkers to increase the likelihood of clinical success and reduce development time and cost, the growing difficulty of recruiting enough volunteers for clinical trials (on average less than 5% of cancer patients in the US participate in these trials), and cost-benefit metrics payers may adopt to guide reimbursement, which could limit market access and possibly healthy returns to investors.

Manufacturing
The global market for biopharmaceuticals, in 2014 valued at US $ 162 billion, is, according to Persistence Market Research (PMR), an innovative and specialized supplier of market intelligence reports and consulting services, expected to grow at a compounded annual growth rate (CAGR) of 9.4% to reach US $ 278 billion in 2020. [7] A previous PMR report showed that among different product segments, antibodies-based products are the largest, accounting for an estimated share of 25.6% in 2013, equating to US $ 51.1 billion.

Analysis shows that this market growth is primarily the result of an aging population and a more effective – personalized, targeted and precision – treatments with biologics (more effective than treatment with small molecule medicines).  However, the growing costs of developing and manufacturing biopharmaceuticals has, over the last decade, increased the pressure to reduce expenses.  This pressure is, according to many analysts, also expected to restrain market growth.

Single-use technology
The emergence of personalized medicine has resulted in an increased demand of smaller-volume products and the need for a more flexible manufacturing approach. Combined with the a response to the pressures of cost containment, manufacturers are installing new, state-of-the-art, small-volume manufacturing capabilities based on single-use technology. These systems are supplied by companies including Sartorius Stedim Biotech, Entegris Life Sciences, Thermo Fisher Scientific, MilliporeSigma, Pall Life Sciences and others, offer scalability (from lab scale to commercial manufacturing) for flexible manufacturing of antibody-drug conjugates and other biologics.

The the current Good Manufacturing Practice (cGMPs) regulation for human pharmaceuticals manufacturing requires that facilities must be designed to handle both biological species and highly potent cytotoxic small organic molecule drugs. This also applies to single-use manufacturing technology.

Today, single-use technologies are widely used by small biotech firms for (initial) process development and small volume clinical-scale manufacturing for late-stage clinical trials. But larger manufacturers are now also adopting single-use technology to meet expanded demand for new products more quickly.

Since the benefits of single-use technologies include the reduction in upfront capital costs of establishing traditional, stainless-steel, manufacturing facilities and reducing operating costs (various estimates show a reduction in capital costs of 40 – 50% and lower operational costs of 20 – 30%), they are in­creasingly employed in newer flexible manufacturing facilities. Furthermore, it reduced the requirement for traditional utilities such as clean-in-place reagents, water for injections and clean steam for equipment sterilization. Overall, these flexible systems allow greater design flexibility than traditional stainless steel equipment, enabling changes to be made quickly in order to select flexible – optimum –  processing configurations during development and scale-up. [8] As such, the adoption of single-use technology reduces cleaning and changeover times between various manufacturing campaigns.

However, some experts feel that, unless the industry moves towards a ‘health-based risk assessment’ approach to single-use technologies, innovation could be compromised – particularly for novel agents like antibody-drug conjugates. They believe that problem for a number of novel biologics is that single-use facilities may increasing the costs of development and, as a result, are putting promising novel agents at risk when they are deemed unviable before their true potential has been explored. [9]

Fill-and-Finish
According to a HighTech Business Decisions‘ report about Fill-and-Finish published in December 2015, the market for biopharmaceutical contract fill-and-finish services has grown at a compound annual rate of 17% over the past three years. HighTech’s analyst expect that this market will continue to expand and reach US $ 2.4 billion in 2020. Furthermore, executives from contract manufacturing organizations expect future annual market growth of 15% per year. Driving this growth for fill-and-finish services is the demand for biotechnology drugs, investment in biotechnology projects, and new service offerings. Manufacturers continues to rely on fill-and-finish CMOs to provide filling and lyophilization capacity for both its commercial- and clinical-phase drug product production.

From a strategic side, analysts expect more industry consolidations over the next few years, new market entrants, and greater in-house fill capacity. As a result of these trends, they expect industry capacity utilization rates will remain flat.[1o]

Mergers and acquisitions
In a recent report, Nice Insight analysts also predicted an increase in the number of mergers and acquisitions. Their prediction comes on top of the 2014 and 2015 boom years in which the number of initial public offerings and mergers and acquisitions of biotechnology companies reached historic highs. Furthermore, licensing activities in many therapeutic areas, including in oncology and hematology, were up sharply compared to previous years.[11]

One of the observed reasons behind this trend is the strategic shift in which many biotech companies are outsourcing innovative R&D to biopharmaceutical contract development and manufacturing organizations (CDMOs) and  academic partners. This new approach, no doubt, is a paradigm shift challenging existing ideas of business development in the biotechnology and pharmaceutical industry. [12]

Today, the biopharmaceutical contract manufacturing (CMO) and contract development and manufacturing (CDMO) sector is fairly fragmented with a large number of players. US-based market research company HighTech Business Decisions has identified more than 500 companies claiming to be a CMO or CDMO. [13] And while only a handful of these companies have the capability required to manufacture recombinant proteins and high potent agents like antibody-drug conjugates, one of the observed trends is that drug developing biopharmaceutical companies are not just looking for cost-savings when turning to a CMO/CDMO.  According to a report published by Roots Analysis, the most important drives is the need for technical expertise, operational efficiency, regulatory support and the ability to focus on core competencies. [14]

Given the current market – and strong growth, it should not be surprising to see an increase in consolidation.  One of the most notable in 2016 was the initial attempt by Swiss specialty chemicals and life sciences company Lonza, which has a market capitalization of 8.7 billion Swiss Francs (US $ 9 billion), to acquire US drug delivery technology company Catalent. While Lonza and Catalent have, so far, not  agreed on a price, and there is no certainty that negotiation will continue, this initial attempt confirms that 2016 is again an interesting year.

Although not all activities involved companies involved in the development of antibody-drug conjugates, mayor mergers in the last few years have included the mergers of Cambridge Major Laboratories with AAIPharma (forming a new company called Alcami) and Pantheon and (Royal) DSM Pharmaceutical Products (with the subsequent acquisition of DPx Holdings of Gallus Biopharmaceuticals). Furthermore, acquisitions have included the acquisition of Hospira, a leading provider of injectable drugs and infusion technologies, by Pfizer and more recently, Germany-based Merck KGaA‘s acquisition of Sigma Aldrich (forming Merck KGaA’s new business unit MerckSigma).

Discussions with experts during the Bio International Convention clearly confirm the excitement felt in the industry – among scientists, researchers and industry leaders – and reveal the potential to really revolutionize – accelerate drug development, manufacturing and healthcare.

In 2017 the Bio International Convention will be held June 19 – 22 in San Diego, CA.


This article is based on interviews conducted during the Bio International Convention held June 6-9, 2016 in San Francisco, CA.

* For an overview of clinical data of antibody-drug conjugates presented during the 2016 annual meeting of the American Society of Clinical Oncology, click here.

Last Editorial Review: June 12, 2016

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