The Present 31 Pharma and the crisis

Although there is a sector of the Pharma industry that focuses on the sale of generic versions of agents discovered and developed by the research-based companies, these activities mainly require only manufacturing and distribution expertise. Now, as in the past, it is the research-based companies to which we need to continue to look to for the provision of agents for the future.

The discovery, development, and appropriate use of new agents is a key theme in the major antibacterial strategies and policies to combat resistance which have been reviewed by Carbon et al. (2002). Against this background it may be considered surprising or even alarming that the Interscience Conference on Antimicrobial Agents and Chemotherapy for 2003 (ICAAC, 2003) includes a symposium entitled Why is Big Pharma Getting Out of Anti-Infective Drug Discovery? A review of abstracts on new antibacterial agents or targets/methods presented at ICAAC 2002 indicates some 47 companies involved in this field including 10 of the "top 12" companies as determined by sales (Table 1).

Of the total, 32 companies presented data from established classes (p-lactams/ inhibitors, lipopeptides/glycopeptides, fluoroquinolones, oxazolidines, protein synthesis inhibitors) and 8 of these companies were from the top 12 companies by sales. Twenty-one companies presented data on targets or methods, thirteen exclusively, and seven on novel agents or immunomodulators (Table 1). This analysis represents only a snapshot of those companies presenting at ICAAC and not the total discovery programmes currently being undertaken, some on areas not yet disclosed, others since terminated.

Despite the wide range of presentations by Pharma at ICAAC 2002, there has undoubtedly been a consolidation in antibacterial R&D in the large Pharma companies, and a dearth of novel agents emerging from the pipelines.

Table 1. Companies involved in the development of new antibacterial agents presented at ICAAC 2002

Type of agent

Companies involved

Carbapenems Cephalosporins

Oxapenems

Lipo- and glycopeptides

Fluoroquinolones

Oxazolidines

Protein synthesis inhibitors (macrolides and ketolides)

Other new agents and immunomodulators

Targets and discovery methods

Meiji Seika Kaisha Ltd, Sankyo Company Ltd LG Chem Investment Ltd, Takeda Chemical Industries Ltd, Basilea Pharmaceutica AG, Shiongi & Co Ltd, Johnson & Johnson Amura Ltd

Cubist Pharmaceuticals Inc, Eli Lilly & Co, Wyeth Research, Biosearch Italia SpA, Aventis, Theravance Inc Wakanuga Pharmaceutical Co Ltd, Abbott

Laboratories, Wockhardt Research Centre, Bayer AG, Dong Wha Pharm Co Ltd Ranbaxy Research Laboratories, AstraZeneca, DongA Pharm, ImaGene, Morphochem AG, Johnson & Johnson, Versicor Inc, Pharmacia Corporation, Dr Reddy's Laboratories Ltd Aventis, Johnson & Johnson, Enanta

Pharmaceuticals Inc, Versicor Inc, Novartis Pharmaceuticals Corporation, British Biotech Pharmaceuticals Ltd, Optimer Pharmaceuticals Inc, Bayer AG

F Hoffman La Roche AG (diaminopyrimidine), Meiji Seika Kaisha Ltd (caprazamycin), Bayer AG (dipeptide), Versicor (LpxC inhibitor), Genesoft (hetero-aromatic polyamides), Xechem Inc (rapamycin), Biocryst Pharmaceuticals Inc (purine nucleoside phosphorylase inhibitor) AstraZeneca, Aventis, Quorex Pharmaceuticals,

Daiichi Pharmaceutical Co Ltd, Proteomic Systems Inc, Arrow Therapeutics, Genome Therapeutics Corporation, GPC Biotech AG, Eli Lilly & Co, British Biotech Pharmaceuticals Ltd, NewBiotics Inc, PanTherix Ltd, Schering-Plough Research Institute, Wyeth Research, GlaxoSmithKline Pharmaceuticals, Influx Inc, Genelabs Technologies Inc, Bayer AG, ImaGene, Pantheco A/S, Pharmacia Corporation

Note: Names in italics are major pharmaceutical companies that feature in the top 12 (by sales).

Increasing discovery activity in smaller companies may offset this, although the capabilities of smaller companies to develop antibacterials to market may be limited in the face of increasing development hurdles. The future model of discovery and development may well have to rely on collaborations and cooperations between small/discovery and large development/supply Pharma.

Mergers and acquisitions have resulted in the key players becoming significantly fewer and each withdrawal from antibacterial development has an increasingly significant impact on the potential for new antibacterials becoming available. The top 12 leaders in the field of antibacterials in terms of sales in 2002 (GlaxoSmithKline Pharmaceuticals, Pfizer/Pharmacia, Bayer AG, Abbott Laboratories, Aventis, Johnson & Johnson, Roche-Chugai, Bristol-Myers Squibb, Wyeth Research, Shionogi Seiyoku, Eli Lilly & Co, and Merck & Co) have evolved from some 20 to 30 companies with antibacterial R&D heritages. Some are the result of none or few amalgamations while others are many-fold.

Of the top 12 companies, less than half are believed to be currently active in antibacterial R&D. Within the remaining companies the discovery effort has been directed towards either defined niche disease areas, or large "blockbuster" commercial areas, with a consequent reduction in diversity across the industry. Individual specializations within Pharma, such as was the case when companies almost exclusively worked on penicillins (Beecham Research Laboratories), cephalosporins (Glaxo), or quinolones (Bayer AG), for example, are becoming less as the companies look to satisfy commercially attractive target product profiles from whichever molecular classes that are available through their R&D efforts or in-licensing. The emphasis on development of line extensions of existing molecules has also increased as a means to improve patient benefits such as convenience and efficacy and importantly for Pharma, to maintain development and commercial activity to offset patent loss and bridge the gap to the introduction of new agents. Critically, of the companies which have exited or severely reduced their antibacterial R&D (e.g., Aventis, Bristol-Myers Squibb, Eli Lilly & Co, Roche-Chugai, and Wyeth Research) (IDSA, 2003), these decisions have been taken relatively recently at a time when the need for new effective antibacterials is arguably greater, but also at a time when policies and regulations for the development and use of antibacterials have proliferated.

The crucial issue will be the ability of companies, big or small, alone or in collaboration, to bring novel agents to the market and whether the agents being discovered and developed today will satisfy both the medical and the commercial needs to provide a sustainable future for antibacterial chemotherapy. Continued investment and commitment of big or small Pharma into research for new antibacterials to meet current and future clinical needs is crucial and yet is at a crisis and being impacted by antibacterial policies which are increasingly being developed and implemented.

The Infectious Disease Society of America (IDSA) newsletter, March 12, entitled The Future of Antimicrobial Drug Availability: An Impending Crisis (IDSA, 2003), highlights the current issues facing the development of antimicrobial drugs. Infectious diseases are the second leading cause of death and the leading cause of disability-adjusted life years worldwide. Antibacterials are key tools in treating many globally important infectious diseases, including meningitis, pneumonia, diarrhoeal illness, skin and bone infections, tuberculosis, sexually transmitted infections (gonorrhoea, syphilis, and chlamydia),

HIV/AIDS-related bacterial infection, and diseases that may be spread as a result of bioterrorist acts. Withdrawal from antibacterial research will have a major impact on global health. A letter to the journal of the American Society for Microbiology (Appelbaum, 2003) states that, "A crisis has developed and we are doing nothing about it," highlighting that Pharma companies are reducing or closing their antibacterial research and that pipelines are, "practically empty." Appelbaum suggests that, unlike drugs for long-term treatments, there is a lack of funding for research into antibacterials, one of the reasons for this being the overly stringent approval criteria imposed by the Federal Drug Agency (FDA), making it practically impossible or prohibitively expensive to bring new antibacterials to market (Appelbaum, 2003).

For those who have worked in the antibacterial field from the hey-day of discoveries in the 1960s and 1970s it is very apparent that the number of new chemical agents being progressed to man and subsequently marketed is much reduced. IDSA reported that of 89 new medicines reaching the US market in 2002 none was an antibacterial, with only 7 new antibacterials being approved since 1998 (IDSA, 2003). A review of company reports for the 11 major Pharma companies listed only 4 new antibacterials in the drug pipeline out of 290 agents listed (1.38%) (IDSA, 2003) and that on average the time to develop new antibacterials was 7-10 years from discovery to first approval. Although Pharma has continued to explore ways to increase efficiencies and decrease development times, these have largely remained stable due to the increased numbers of patients required for new drug applications (NDAs), as well as increased complexity and costs in meeting regulatory approval requirements (Kaitin and DiMasi, 2000). An important consideration for Pharma companies involved in R&D and commercialization of therapies for a range of disease areas, is that other therapeutic areas are increasingly more profitable than antibacterials. Today, there are fewer large companies specializing in antibacterials as a main R&D area. Investment decisions are made across and between therapeutic areas and Pharma has an obligation to maintain shareholder value and commercial viability or else no new drugs would become available in any therapy area.

The reasons for the "crisis" in antibacterial R&D, manifested by fewer new agents or classes reaching clinical use, are complex and multifactorial but undoubtedly the impact of the changing environment of regulations, guidelines, and policies on the development and use of antibacterials is an important contributory factor.

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