The Pharmaceutical Journal
Vol 275 (Supplement) F30-F31
October 2005

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FIP Congress 2005

Pharmaceutical biotechnology and its impact in the post-genomic era

Amr Karim, of the genetic engineering research services unit, Ain Shams University, Cairo, spoke on the current issues surrounding biotechnology products in the African continent. He maintained that in Africa there were opportunities for outsourcing where small start-up companies with specific expertise can provide services for larger companies. However, biotechnology research and development requires serious investment in infrastructure and of all the continents in the world, Africa has the smallest share of publications in biotechnology (per 100,000 population).

The New Partnership for Africa’s Development (NEPAD) has been started to aid economic renewal of the continent. Leaders of African countries are involved in administering NEPAD, and calls have been made for a plan to bridge many gaps within the continent, including in the areas of science and technology. Twelve flagship areas, including biotechnology, have been identified aimed at promoting public/private partnerships in science and technology. A minimum of 1 per cent of gross domestic product is to be committed to research and development and four networks have been set up (north, west, south and east Africa) as centres of excellence. Within north Africa, the National Research Centre in Egypt serves as the regional centre.

Supply chain

Roger Tredree, chief pharmacist, St George’s Healthcare NHS Trust and visiting professor, Kingston University, UK, discussed the importance of appropriate handling and storage of biotechnology products in the supply chain from manufacture to patient use. The most stringent controls currently in place are those surrounding transport from manufacturer to distributor. The vast majority of biopharmaceuticals require low (2–8C) storage to maintain potency and efficacy — too low a temperature can lead to denaturation of the product while elevated temperatures can have a similar effect. For example, insulin can be stored out of the refrigerator for many weeks and still retain potency, while freezing the product leads to rapid degradation and the production of allergenic by-products.

Professor Tredree estimated that during the supply chain of any one biopharmaceutical product there is the potential for it to remain out of the refrigerator for up to eight hours. This is a consequence of delays in unpacking and storage at the pharmacy (some materials can be left on loading bays for up to one hour), dispensing to patients or wards, transport to wards and subsequent storage, and getting the product from the dispensary to the patient’s home. It is vital that patients, as well as nursing staff, are educated in the need for cold storage of biopharmaceutical products and the fact that efficacy of the product can suffer significantly if guidelines are not adhered to.

Challenges

Daan Crommelin, chairman of the FIP Board of Pharmaceutical Sciences and dean of the faculty of pharmaceutical sciences, Utrecht University, the Netherlands, discussed the “bottlenecks” and challenges facing protein formulation and delivery for biopharmaceuticals. He explained how biotechnology products are being developed for indications where there is unmet medical need and for the treatment of a number of serious diseases. Pharmaceutical biotechnology is a relatively small but growing area, although the fact that such products are invariably delicate, complex protein molecules that are hydrophilic, usually charged and therefore have difficulty in passing across membranes makes delivery of such products difficult. Indeed, almost all biopharmaceuticals need to be injected although non-parenteral delivery alternatives, eg, oral, rectal and pulmonary, are being investigated. Unfortunately, the bioavailability of biopharmaceutical products tends to be low and is unpredictable (eg, it might only achieve around 2 per cent bioavailability via oral route). Some companies are investigating delivery of biopharmaceuticals via the pulmonary route (eg, Pfizer has a dry powder formulation that is now in stage III clinical trials).

PEGylation is being used to improve the half-life of a number of products, either as a route to mask uptake-receptor sites, to reduce clearance via glomerular filtration or to reduce immunogenicity in some cases. For example, PEG-interleukin-2 has a much improved half-life (49.3min) versus IL-2 alone (2.8min). PEG-interferon-alpha and PEG-G-CSF are also under investigation. One advantage for the patient is that injection intervals are much longer in PEGylated products. Although PEGylation can lower the intrinsic activity of a molecule (eg, PEG-INFalpha is 10 times less active than the original molecule), it does tend to increase circulation times (PEG-INFalpha circulation times are more than 10 times longer than the original molecule), therefore, there is an overall benefit of the PEGylated formulation.

Professor Crommelin ended his presentation with data to support the importance of immunogenicity in biopharmaceuticals. Certainly, in long-term treatment regimens, eg, INFalpha, where treatment can last for months or even years, immunogenicity can become a real problem for continued efficacy. Unfortunately, predicting immunogenicity in a biopharmaceutical product is not currently possible, although ensuring purity of product, performing epitope analysis, reaction of product to a patient’s sera and animal experiments (eg, in immune tolerant transgenic mice) will prove helpful in this respect.

New heart agents

Gavin Brooks, head of the school of pharmacy at the University of Reading, UK, described how targeting specific molecules that control cell division and growth (cell cycle molecules) in cardiac myocytes is being used as an approach to develop novel therapeutic agents for the treatment of post-infarct damage to the myocardium and for the prevention of heart failure. Professor Brooks showed how molecules such as the cyclin-dependent kinase, CDC2, and its partner, cyclin B1, when over-expressed using an adenovirus delivery system in differentiated, cell cycle arrested adult cardiac myocytes lead to the formation of new heart muscle cells. This is a major step forward in attempts to regenerate new muscle cells following a myocardial infarction.

Professor Brooks also showed data that demonstrated how targeting the transcription factor, E2F, with small peptides that block the association of E2F with its partner protein, DP, in cardiac myocytes blocks the maladaptive hypertrophy (increase in cell size without cell division) leading to heart failure that occurs following injury to the heart such as that caused following a myocardial infarction or as a result of hypertension. He highlighted the importance of targeting components of the cell cycle machinery for treating a variety of cardiovascular diseases and demonstrated how some of these molecules, eg, E2F, are being targeted in clinical trials for certain cardiovascular disorders.

Vaccines

Gideon Kersten, head of assay development and formulation, Netherlands Vaccine Institute, discussed the development of new vaccines from biotechnology products. He described a number of new concepts that should be considered when designing a new vaccine, including epitope identification, better process definition using process analytical technology (ie, an approach used to maximise reproducible quality in a product) and the importance of formulation of any product. Professor Kersten showed how the efficacy of any vaccine is dependent upon its formulation. Thus, he described how the pore protein A (Por A) from Neisseria meningitidis is a vaccine candidate and has shown that Por A-lipopolysaccharide-adjuvated liposomes are superior in terms of delivery of Por A than other formulations.

Research and development

Khalil Ahmed, executive director, Shantha Biotechnics Ltd, Hyderabad, India, gave an account of the development of Shantha Biotechnics, the largest dedicated biotech laboratory in the private sector in India with a subsidiary, Shantha West Inc, in San Diego, California. Mr Ahmed discussed the differences between research and development in large pharmaceutical companies, which is product driven, and in the biotechnology industry, where it is largely technology driven. In large pharmaceutical companies, there is limited investment in generics, there are many products to choose from and they can be introduced in a relatively short time. In contrast, in the biotechnology industry there is high investment in generics, there are few products available and there is a long development cycle.

According to Mr Ahmed, investment in biopharmaceuticals requires a different mind set to conventional thinking in large pharmaceutical companies. Although initially it proved difficult to obtain funding for the company, Mr Ahmed perservered with his ideas and eventually formed an Indo-Arab joint partnership. The rationale for forming the company was based on the need within India to treat and vaccinate patients against hepatitis B. There are approximately 50 million hepatitis B carriers (around 10 per cent of the population) in India, where hepatitis B is one of the biggest killers in the country. Although a vaccine was available commercially, its unit cost ($80/dose) prohibited the majority of patients from being treated (the unit cost equals around 15 days’ salary of an average middle class family in India). Therefore, Shantha Biotechnics Ltd invested its efforts in producing a generic form of the vaccine. The product, SHANVAC-B, was launched in 1997 at a significant saving over the proprietary vaccine and has since become the top brand in the developing world. World Health Organization certification for SHANVAC-B was received in 2002 and the company has now become the leading supplier to UNICEF for hepatitis B immunisation programmes in the poorest parts of the world. The company has since gone from strength to strength, having introduced five recombinant products over the past eight years, and this has led to a thriving biotechnology industry in India.

Regulatory aspects

Bill Dawson, director of Medicines Network, University of Manchester, director of Proteome Sciences and director of Bionet Ltd, covered the regulatory aspects surrounding the use of biotechnology products. Since the first biopharmaceutical product came to market in 1982 (recombinant human insulin), a total of 87 approved biotechnology products have become available (59 replacement proteins/close analogues, 20 monoclonal antibodies and five vaccines) for a total of 108 indications. Professor Dawson reported that a total of 324 biotechnology medicines were in development (154 for cancer and related conditions, 43 for infectious diseases, 26 for autoimmune disorders and 16 for neurological disorders).

It was noted that the therapeutic area drove the development of biopharmaceutical products such that the majority of products were being developed for life-threatening conditions, eg, cancer, asthma and infection, where acute therapy and simple endpoints could be obtained. Where development costs were high, clinical trials were long (eg, in rheumatoid arthritis, osteoporosis and neurodegenerative disease) and, where acute therapy was possible but efficacy trials were complex (eg, myocardial infarction, stroke, cardiac arrythmias), then investment in research and development of biopharmaceuticals for treatment of such diseases was much less.

Professor Dawson highlighted a number of specific issues that need to be addressed by regulators in close collaboration with the manufacturers of biotech products. These included agreement on appropriate analytical characterisation, suitable efficacy/stability indicating assays, agreement on appropriate testing for immunogenicity and how to avoid prion “carry over” from the production method (a problem in vaccine production). Professor Dawson concluded by stressing that good dialogue with regulators is key to the success of introducing a new biopharmaceutical product and that a case-by-case analysis is crucial.

Gene delivery

Hideyoshi Harashima, from the graduate school of pharmaceutical sciences, University of Tokyo, Japan, discussed current issues in gene delivery.

Professor Harashima focused on non-viral gene delivery systems and described how, when using this approach, tissue distribution needed to be controlled. He described a multifunctional, envelope-type nano device (MEND) that has a nuclear localisation sequence, a targeted ligand and a PEG-lipid wrapped around condensed DNA. Many non-viral methods of gene delivery use classical receptor-mediated endocytosis to enter cells, eg, transferrin. However, Professor Harashima described the existence of an alternative entrance pathway that constitutes a specialised high-capacity endocytic pathway for lipids and fluid, similar to macropinocytosis in lower eukaryotic cells.

Professor Harashima had synthesised an octa-arginine (R8) peptide (based on the TA peptide from the HIV virus) to aid delivery of molecules into cells. Using his MEND complex linked up to R8 (R8-MEND) he found an extremely effective luciferase gene readout that was similar to that achieved only with toxic levels of adenovirus. The R8-MEND complex was found to be primarily taken up via macropinocytosis. This new delivery system holds promise for future development of non-viral gene delivery regimens.