Moving to the Next Level in Biomanufacturing

Biologics are playing a more prominent role in drug development. Although biologic-based drugs account for only roughly 10% of commercial drugs, they are an increasingly important strategic part of drug companies' pipelines, thereby creating opportunities for developing improved production methods.

Patricia Van Arnum

Crunching the numbers

Biopharmaceuticals accounted for approximately 10% of the global prescription drug market based on a 2007 global prescription drug market of $712 billion, according to data from IMS Health. The research firm PharmaVision offers comparable data, which showed that in 2009, biotherapeutics represented 7.5% of all drugs on the market and accounted for approximately 10% of the total expenditures for marketed drugs. The firm projects that the biologics market is growing at an annual rate of approximately 15%, and that biologics constitute more than 30% of all pipeline research programs (1).

The importance of biologics in the drug portfolios of Big Pharma is intensifying as well. The compound annual growth rate of prescription drug sales from Big Pharma is expected to be only 1.8% through 2013, increasing from $366.6 billion in 2007 to a projected $407 billion in 2013, according to an analysis in 2009 by the research firm Life Science Analytics. Biologics are expected to account for 20% of Big Pharma's prescription drug sales by 2013. At the same time, sales from its core products, largely small molecules, are expected to fall by nearly 50% to $47 billion by 2013 (2).

IMAGE: DON BISHOP, BRAND X PICTURES, GETTY IMAGES

The market research firm Evaluate Pharma projects that biologics will account for 50% of the top 100 drugs in 2014, compared with 28% in 2008, and 11% in 2000. Only one biologic, epoetin alfa, marketed as Epogen by Amgen (Thousand Oaks, CA) and as Procrit by Johnson & Johnson (New Brunswick, NJ), was among the 10 top-selling drugs in the global market in 2000. In 2008, five biotech products made Evaluate Pharma's top 10 list: Avastin (bevacizumab), Enbrel (etanercept), Epogen/Procrit, Remicade (infliximab), and Rituxan (rituximab). The firm projects that by 2014 the six top-selling products will be biologics: Avastin, Enbrel, Humira (adalimumab), Rituxan, Lantus (insulin glargine), and Herceptin (trastuzumab). Remicade is projected to occupy the ninth spot, meaning that 7 out of the 10 top-selling drugs will be biologics (3).

New biologics

The rise of biologics is further evident in recent drug approvals. In 2009, the US Food and Drug Administration's Center for Drug Evaluation and Research approved 19 new molecular entities and 6 new biologic license applications (BLAs). The BLAs approved in 2009 were: Simponi (golimumab) and Stelara (ustekinumab) from Centocor Ortho Biotech, a subsidiary of Johnson & Johnson (New Brunswick, NJ); Dysport (abobotulinumtoxinA) by Ispen Biopharma (Paris); Ilaris (canakinumab) by Novartis (Basel, Switzerland); Arzerra (ofatumumab) by GlaxoSmithKline (London); and Kalbitor (ecallantide) by Dyax (Cambridge, MA).

Four BLAs approved in 2009 were monoclonal antibodies (mAbs). Simponi is an mAb that targets and neutralizes excess tumor necrosis factor-alpha, a protein that when overproduced in the body, due to chronic inflammatory diseases, can cause inflammation and damage to bones, cartilage, and tissue. Stelara is an mAb that selectively targets the cytokines interleukin-12 and interleukin-23, naturally occurring proteins that are believed to play a role in the development of psoriasis. Ilaris is an mAb that blocks action of the inflammatory protein interleukin-1 beta (IL-1 beta) and was approved to treat cryopyrin-associated periodic syndrome, a rare auto-inflammatory disease. Arzerra is an mAb that causes the body's immune response to fight against normal and cancerous B-cells by attaching to portions of a surface molecule called CD20. The other two BLAs approved in 2009 were Kalbitor, a plasma kallikrein inhibitor to treat acute attacks of hereditary angioedema, and Dysport, an acetylcholine release inhibitor and neuromuscular blocking agent to treat cervical dystonia.

The supply side

Greater interest in biologics is creating opportunity on the supply side. The market for biopharmaceutical contract manufacturing was estimated at $2.6 billion in 2009, and long-term growth prospects remain strong through 2014, according to a 2009 study by the research firm High Tech Business Decisions. Although contractor capacity utilization was slightly lower in 2009 compared with recent levels, the decline in utilization was believed to be temporary resulting from a combination of previous investment in capacity, improved expression yields, and a slowdown in biotechnology investments because of the downturn in financial markets. During the next few years, demand is expected to grow as new biopharmaceuticals move through the clinical pipeline and become commercial products. Demand for biopharmaceutical contract manufacturing services is expected to grow 16% annually through 2014 as biopharmaceutical business models shift toward more outsourcing of production and some large pharmaceutical companies elect not to expand their internal capacities. Moreover, other productivity gains such as better expression systems, more efficient cell lines, and improved media present new opportunities, said the firm in a June 2009 press release.

Aptamers: a potential bridge between monoclonal antibodies and small molecules

Nigel Darby, vice-president of biotechnologies at GE Healthcare Life Sciences (Uppsala, Sweden), pointed to improvement in yield in an recent interview with Pharmaceutical Technology (4). Darby was also a speaker at a biologics forum, The Rapid Evolution of Biomanufacturing and the New Supplier Reality organized by the Drug, Chemical, and Associated Technologies Association.

He pointed out in the interview that cell-culture productivity expressed as product titer has increased to a level of 2-4 g/L in established production processes and to 4-6 g/L in preclinical and some clinical manufacturing processes. "This is a combined effect: optimized expression systems turn the cells into more efficient production systems and culture-media developments, including the feed strategy, lead to significantly increased cell density in the bioreactor," he said. "Cells would be capable of even higher yields up to 10 g/L, but this benefit, more often than not, comes with 50–70% prolonged culture time and deletes part of the productivity gains made with high titers." Furthermore, longer culture times can reduce the flexibility in production scheduling and may thus limit the benefits of cell-culture optimization.

Production strategies

Producing proteins more efficiently is an ongoing goal by pharmaceutical companies, their suppliers, and academia. As a case in point, Merck & Co. (Whitehouse, NJ) acquired the biotechnology firm GlyoFi (Lebanon, NH) for $400 million in 2006 to gain access to the company's proprietary technology for producing recombinantly engineered yeast strains capable of specific human glycosylation at high fidelity. The company's recombinant yeast-based approach seeks to overcome limitations in manufacturing methods based on mammalian-cell culture that do not allow for the control of glycosylation and so produce a mixture of different glycoforms, some of which are more active than others and some of which may have no activity at all. By expressing a given protein in different glycoengineered yeast strains, a library of glycoproteins, all with an identical peptide backbone but with different sugars attached to them, can be generated. This process allows drug developers to identify the glycoform with the highest therapeutic potency. Because many therapeutic characteristics such as pharmacokinetic stability, bioavailability, immunogenicity, and tissue-specific targeting are affected by sugar attachment, the technology can be broadly applied to all glycoproteins, including growth factors, fusion proteins, and mABs, according to the company.

Sugar-engineered technology. In September 2009, the biotechnology company Seattle Genetics (Bothell, WA) launched its sugar-engineered antibody (SEA) technology, an approach to increase the potency of mAbs. The SEA technology consists of modified sugars that inhibit the incorporation of fucose into the carbohydrate chains of mAbs, resulting in enhanced antibody-dependent cellular cytotoxicity (ADCC) activity in preclinical models. The company says that the modified sugars can be readily added to standard cell-culture media without affecting manufacturing processes while still maintaining yields and reproducible product quality. The technology can be applied to existing cell lines without cell-line reengineering. In model systems, the technology has been shown to be applicable across a range of antibodies and antibody-producing cell lines.

Seattle Genetics filed a patent application covering its SEA technology and intends to use the technology in its internal early-stage pipeline and in external collaborations. The development of mAbs possessing enhanced effector function is an emerging area of therapeutic research. The company estimates that there are at least 10 ADCC-enhanced antibodies in clinical trials using a variety of technologies.

Bacterial methods for producing eukaryotic N-glycoproteins. Researchers recently reported a new method that may provide a general platform for producing eukaryotic N-glycoproteins, which would offer an efficient way to customize glycoproteins such as mAbs. The method involves producing homogeneous eukaryotic N-glycoproteins that involves the engineering and functional transfer of the Campylobacter jejuni glycosylation machinery in Escherichia coli to express glycosylated proteins with GlcNAc-Asn linkage. The bacterial glycans were subsequently trimmed and remodeled in vitro by enzymatic transglycosylation to fulfill an eukaryotic N-glycoslyation. Although homogenous N-glycoproteins can be made via chemical synthesis or engineered yeast, the new method uses a bacterial system to produce the homogeneous eukaryotic N-linked glycoproteins, which offer the potential of reducing some of the challenges found in chemical and yeast-engineered approaches (5, 6).

Vaccines

Although vaccines are a relatively small part of the overall pharmaceutical market, they are part of the growth strategy of certain pharmaceutical majors such as sanofi-aventis, GlaxoSmithKline, Novartis, Merck & Co., and Pfizer via its recent acquisition of Wyeth (Madison, NJ). In an investor-relations presentation on vaccines in December 2009, sanofi aventis estimated the value of the vaccine market at EUR 15 billion ($21 billion) in 2008 and projected the market would reach EUR 23 billion ($32 billion) by 2013.

Private and public funding is helping to create opportunity in the vaccines market. Earlier this year, the Bill and Melinda Gates Foundation announced it will commit $10 billion during the next 10 years for research, development, and delivery of vaccines in poor and developing countries, which is in addition to $4.5 billion the foundation previously committed. The funding will be used to increase access to existing vaccines and support development for new vaccines for diseases such as malaria and tuberculosis. The Global Alliance for Vaccines and Immunization, a private–public partnership, is developing vaccines for diarrhea and pneumonia. This funding and high-profile government intervention into vaccine development as in the case of pandemic flu is transforming the vaccine sector from a traditionally lower-valued sector to a more value-added one.

Vaccines for meeting unmet medical needs commonly found in developing nations, as well as prophylactic vaccines such as cancer vaccines, have become important areas of research. For example, in March 2010, Novartis signed an option worth up to EUR 700 million ($950 million) with the biotechnology firm Transgene (Parc d' Innovation d'Illkirch, France) conditioned on the successful development of the cancer vaccine TG4010, which is being developed for non-small cell lung cancer. This type of vaccine research is another example of the evolving market opportunities in biologics.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.

References

1. F. Pavlou, C. Lawrence and S. Sutton, Pharm. Tech. Europe 22 (2), 20–21 (2010).

2. P. Van Arnum, Pharm. Technol. Sourcing and Management, Apr. 2009, PharmTech.com, accessed Mar. 15, 2010.

3. P. Van Arnum, Pharm. Technol. 33 (8), 38–41 (2009).

4. P. Van Arnum Pharm.Technol. Sourcing and Management, Mar. 2010, PharmTech.com, accessed Mar. 15, 2010.

5. F. Schwarz, Nature Chem. Bio. DOI:10.1038/nchembio.314 (2010).

6. S. Borman, Chem. Eng. News 88 (10), 11 (2010).