The Antibiotic Pipeline — Challenges, Costs, and Values
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《新英格兰医药杂志》
In 1941, Skinner and Keefer vividly chronicled an astonishing 82 percent mortality among 122 consecutive patients who had been treated for Staphylococcus aureus bacteremia in the preantibiotic era.1 Of the 41 patients older than 50 years of age, only 1 (2 percent) survived. Imagine the elation a few years later over the availability of penicillin, the prototype of a new therapeutic class of drugs (see page 524). In the next few decades, well-intentioned academic leaders predicted the demise of bacterial infections.
(Figure)
Penicillin G.
Such irrational exuberance over the sustained benefits of antibiotics should have been tempered by at least two observations. Within five years of penicillin's first use, 50 percent of S. aureus isolates expressed resistance through the actions of an enzyme that disrupted the rectangular beta-lactam ring. In the late 1950s, Abboud and Waisbren linked this antibiotic resistance to an increased risk of death among patients with S. aureus bacteremia who were treated with penicillin.2 None of the 52 patients infected with organisms that had a resistance level of 6 μg per milliliter or higher survived "despite massive doses of penicillin," whereas 20 of 29 with lower levels of drug inhibition (69 percent) survived.
Fortunately, in 1960, methicillin — a beta-lactam analogue with activity against penicillin-resistant strains — was discovered. However, methicillin-resistant staphylococci were identified widely in Europe by the 1970s and in the United States beginning in the late 1980s. Unexpectedly, the use of antistaphylococcal antibiotics resulted in the emergence of gram-negative rods in hospitals, but industry responded with the development of effective new therapies. A predictive scenario emerged: a novel antibiotic followed by the selection of resistant organisms and an urgent need for a still newer drug.
Currently, the antibiotic era is threatened by the convergence of three adverse circumstances (see Figure): high levels of antibiotic resistance among important pathogens, an uneven supply of novel classes of antibiotics, and a dramatic reduction in the number of pharmaceutical companies engaged in the discovery and development of antiinfective agents. Consider the following facts: in U.S. communities, almost 50 percent of strains of pneumococci express high or intermediate levels of resistance to penicillin. In hospitals, 50 percent of S. aureus isolates are methicillin-resistant, and 30 percent of enterococci are vancomycin-resistant. Of Pseudomonas aeruginosa strains, 20 percent express resistance to available quinolone drugs, and 15 percent express resistance to imipenem.
Figure. Recent History of Antiinfective-Drug Discovery.
As large pharmaceutical companies backed away from antiinfective-drug discovery after 1985 (Projan S: personal communication), the emergence of strains of Staphylococcus aureus with intermediate resistance to vancomycin (VISA) and subsequently fully resistant strains (VRSA) appeared. Since the 1990s, the increasing prevalence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) species has challenged physicians, as has that of multidrug-resistant Pseudomonas aeruginosa. Since 2000, two new classes of antiinfective agents have been approved for clinical use against gram-positive cocci: linezolid (an oxazolidinone), which became available in 2000, and daptomycin (a cyclic lipopeptide), which became available in 2003.
In 2004, there are few antibacterial agents in the pipeline. Recall that in the 1930s and 1940s, four new classes of antibiotics were approved, each with novel antibacterial targets: sulfonamides, beta-lactams, aminoglycosides, and chloramphenicol. In the 1950s and 1960s, six more new classes became available (tetracycline, macrolides, glycopeptides, rifamycins, quinolones, and trimethoprim). In the 1970s, 1980s, and 1990s, however, no novel classes were licensed, and all the new drugs that became available were derivatives of existing classes. Since 2000, two new classes of antibiotics have been approved for the treatment of gram-positive bacteria: the oxazolidinones (linezolid) and the cyclic lipopeptides (daptomycin).
A relatively unfavorable return on investment is apparently deterring large pharmaceutical companies from engaging in antibiotic-drug discovery, and the Infectious Diseases Society of America has suggested extending the life of drug patents as an incentive to industry. The key metric used to prioritize investments in industry is the risk-adjusted net present value (NPVR): the return in future dollars after adjustment for the investment and any lost income, usually expressed as the number of millions of dollars.3 Imagine a pharmaceutical company with a promising candidate antibiotic that will enter a $500 million market and is expected to capture 10 percent ($50 million). With future advertising and distribution costs, patent-attorney fees, and initial costs totaling 50 percent of that amount, it will yield $25 million annually. If the patent lasts 10 years, the return is $250 million over the life of the antibiotic. However, as highlighted incisively by Stewart and colleagues, there are three other liabilities — cost, risk, and time.3 There are direct costs of studies in animals and in vitro studies, and one can assign a dollar value to setbacks that might be encountered at each of the three testing phases — toxicity experiments in animals, the first studies in humans, and the pivotal clinical trials. There are also opportunity costs, in the form of the loss of money earmarked for the project that could have been invested during the time required for drug development. Each of these costs must be subtracted from the estimated $250 million return to obtain the NPVR of the investment. Speaking for industry, Steven Projan, of Wyeth Research, has estimated that antibiotics have an NPVR of 100, but that oncologic drugs have an NPVR of 300, neurologic drugs an NPVR of 720, and muscloskeletal drugs an NPVR of 1150.4 In blunt terms, a pharmaceutical company budgeting for mutually exclusive projects usually chooses those with the highest positive NPVR.
Molecular biologists had been optimistic that the time and costs of drug discovery would be reduced in the era of genomics, especially given the aid offered by computer-generated, three-dimensional views of bacterial targets. However, the young sciences have not yet proved so fruitful. As a result of the failure to identify new drug targets, some researchers are now focusing in part on virulence factors rather than directly on organisms. For example, it is now known that after a threshold of high cell density — a quorum — is reached, bacteria sense one another's presence. The result is an orchestrated production of virulence factors or protective biofilm. This process, quorum sensing, implies the existence of a complex microbial communication system that is vital for transforming previously independent predators into a disciplined army. Recently, studies have suggested a promising role for anti–quorum-sensing drugs, possibly as adjuvants to standard antimicrobial therapy.
Industry laments the costs related to the licensing process, citing bureaucratic barriers. However, the Food and Drug Administration (FDA) has documented that antiinfective agents have had the highest approval rate of all therapeutic classes since 1964, as well as the shortest or second-shortest development time during each four-year period since 1982.5
With increasing levels of antibiotic resistance, an insecure pipeline, and a dwindling number of companies investing in antiinfective agents, we have reached an unsettling impasse in medicine. The public's health, appropriate business incentives, and reasoned government regulations are all at risk. An urgent dialogue among committed advocates should begin and should be based on three accepted tenets. First, biologic explorations will eventually yield new targets. Second, society entrusts its safety to the FDA. And finally, good public companies need to be profitable and know the cost of disease, but great companies also aspire to serve and to know the value of health.
Dr. Wenzel reports having received consulting fees from Aventis, Merck, Pfizer, and Roche and grant support from Pfizer.
Source Information
From the Department of Internal Medicine, Virginia Commonwealth University, Richmond.
References
Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med 1941;68:851-875.
Abboud FM, Waisbren BA. Correlation between in vitro studies and response to antibiotic therapy in staphylococcic bacteremia. AMA Arch Intern Med 1959;104:226-33.
Stewart JJ, Allison PN, Johnson RS. Putting a price on biotechnology. Nat Biotechnol 2001;19:813-817.
Projan SJ. Why is big Pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6:427-430.
Powers JH. Development of drugs for antimicrobial-resistant pathogens. Curr Opin Infect Dis 2003;16:547-551.
Related Letters:
The Antibiotic Pipeline
Kunin C. M., Montgomery A. B.(Richard P. Wenzel, M.D.)
(Figure)
Penicillin G.
Such irrational exuberance over the sustained benefits of antibiotics should have been tempered by at least two observations. Within five years of penicillin's first use, 50 percent of S. aureus isolates expressed resistance through the actions of an enzyme that disrupted the rectangular beta-lactam ring. In the late 1950s, Abboud and Waisbren linked this antibiotic resistance to an increased risk of death among patients with S. aureus bacteremia who were treated with penicillin.2 None of the 52 patients infected with organisms that had a resistance level of 6 μg per milliliter or higher survived "despite massive doses of penicillin," whereas 20 of 29 with lower levels of drug inhibition (69 percent) survived.
Fortunately, in 1960, methicillin — a beta-lactam analogue with activity against penicillin-resistant strains — was discovered. However, methicillin-resistant staphylococci were identified widely in Europe by the 1970s and in the United States beginning in the late 1980s. Unexpectedly, the use of antistaphylococcal antibiotics resulted in the emergence of gram-negative rods in hospitals, but industry responded with the development of effective new therapies. A predictive scenario emerged: a novel antibiotic followed by the selection of resistant organisms and an urgent need for a still newer drug.
Currently, the antibiotic era is threatened by the convergence of three adverse circumstances (see Figure): high levels of antibiotic resistance among important pathogens, an uneven supply of novel classes of antibiotics, and a dramatic reduction in the number of pharmaceutical companies engaged in the discovery and development of antiinfective agents. Consider the following facts: in U.S. communities, almost 50 percent of strains of pneumococci express high or intermediate levels of resistance to penicillin. In hospitals, 50 percent of S. aureus isolates are methicillin-resistant, and 30 percent of enterococci are vancomycin-resistant. Of Pseudomonas aeruginosa strains, 20 percent express resistance to available quinolone drugs, and 15 percent express resistance to imipenem.
Figure. Recent History of Antiinfective-Drug Discovery.
As large pharmaceutical companies backed away from antiinfective-drug discovery after 1985 (Projan S: personal communication), the emergence of strains of Staphylococcus aureus with intermediate resistance to vancomycin (VISA) and subsequently fully resistant strains (VRSA) appeared. Since the 1990s, the increasing prevalence of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) species has challenged physicians, as has that of multidrug-resistant Pseudomonas aeruginosa. Since 2000, two new classes of antiinfective agents have been approved for clinical use against gram-positive cocci: linezolid (an oxazolidinone), which became available in 2000, and daptomycin (a cyclic lipopeptide), which became available in 2003.
In 2004, there are few antibacterial agents in the pipeline. Recall that in the 1930s and 1940s, four new classes of antibiotics were approved, each with novel antibacterial targets: sulfonamides, beta-lactams, aminoglycosides, and chloramphenicol. In the 1950s and 1960s, six more new classes became available (tetracycline, macrolides, glycopeptides, rifamycins, quinolones, and trimethoprim). In the 1970s, 1980s, and 1990s, however, no novel classes were licensed, and all the new drugs that became available were derivatives of existing classes. Since 2000, two new classes of antibiotics have been approved for the treatment of gram-positive bacteria: the oxazolidinones (linezolid) and the cyclic lipopeptides (daptomycin).
A relatively unfavorable return on investment is apparently deterring large pharmaceutical companies from engaging in antibiotic-drug discovery, and the Infectious Diseases Society of America has suggested extending the life of drug patents as an incentive to industry. The key metric used to prioritize investments in industry is the risk-adjusted net present value (NPVR): the return in future dollars after adjustment for the investment and any lost income, usually expressed as the number of millions of dollars.3 Imagine a pharmaceutical company with a promising candidate antibiotic that will enter a $500 million market and is expected to capture 10 percent ($50 million). With future advertising and distribution costs, patent-attorney fees, and initial costs totaling 50 percent of that amount, it will yield $25 million annually. If the patent lasts 10 years, the return is $250 million over the life of the antibiotic. However, as highlighted incisively by Stewart and colleagues, there are three other liabilities — cost, risk, and time.3 There are direct costs of studies in animals and in vitro studies, and one can assign a dollar value to setbacks that might be encountered at each of the three testing phases — toxicity experiments in animals, the first studies in humans, and the pivotal clinical trials. There are also opportunity costs, in the form of the loss of money earmarked for the project that could have been invested during the time required for drug development. Each of these costs must be subtracted from the estimated $250 million return to obtain the NPVR of the investment. Speaking for industry, Steven Projan, of Wyeth Research, has estimated that antibiotics have an NPVR of 100, but that oncologic drugs have an NPVR of 300, neurologic drugs an NPVR of 720, and muscloskeletal drugs an NPVR of 1150.4 In blunt terms, a pharmaceutical company budgeting for mutually exclusive projects usually chooses those with the highest positive NPVR.
Molecular biologists had been optimistic that the time and costs of drug discovery would be reduced in the era of genomics, especially given the aid offered by computer-generated, three-dimensional views of bacterial targets. However, the young sciences have not yet proved so fruitful. As a result of the failure to identify new drug targets, some researchers are now focusing in part on virulence factors rather than directly on organisms. For example, it is now known that after a threshold of high cell density — a quorum — is reached, bacteria sense one another's presence. The result is an orchestrated production of virulence factors or protective biofilm. This process, quorum sensing, implies the existence of a complex microbial communication system that is vital for transforming previously independent predators into a disciplined army. Recently, studies have suggested a promising role for anti–quorum-sensing drugs, possibly as adjuvants to standard antimicrobial therapy.
Industry laments the costs related to the licensing process, citing bureaucratic barriers. However, the Food and Drug Administration (FDA) has documented that antiinfective agents have had the highest approval rate of all therapeutic classes since 1964, as well as the shortest or second-shortest development time during each four-year period since 1982.5
With increasing levels of antibiotic resistance, an insecure pipeline, and a dwindling number of companies investing in antiinfective agents, we have reached an unsettling impasse in medicine. The public's health, appropriate business incentives, and reasoned government regulations are all at risk. An urgent dialogue among committed advocates should begin and should be based on three accepted tenets. First, biologic explorations will eventually yield new targets. Second, society entrusts its safety to the FDA. And finally, good public companies need to be profitable and know the cost of disease, but great companies also aspire to serve and to know the value of health.
Dr. Wenzel reports having received consulting fees from Aventis, Merck, Pfizer, and Roche and grant support from Pfizer.
Source Information
From the Department of Internal Medicine, Virginia Commonwealth University, Richmond.
References
Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus. Arch Intern Med 1941;68:851-875.
Abboud FM, Waisbren BA. Correlation between in vitro studies and response to antibiotic therapy in staphylococcic bacteremia. AMA Arch Intern Med 1959;104:226-33.
Stewart JJ, Allison PN, Johnson RS. Putting a price on biotechnology. Nat Biotechnol 2001;19:813-817.
Projan SJ. Why is big Pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6:427-430.
Powers JH. Development of drugs for antimicrobial-resistant pathogens. Curr Opin Infect Dis 2003;16:547-551.
Related Letters:
The Antibiotic Pipeline
Kunin C. M., Montgomery A. B.(Richard P. Wenzel, M.D.)