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The latest weapons for the war on microbes are coming from new players.
Microbes evolve and society’s growing use of antibiotics for medical and agricultural purposes guarantees the continuing evolution of resistance to antibiotics by microbes. Many in the infectious disease community are concerned that the current repertoire of antibiotics is increasingly insufficient for controlling infections. Key “Bad Bug” microbes have evolved a wide range of resistance mechanisms, including broad spectrum efflux pumps, acquiring new genes, and chemically inactivating antibiotic drugs.
The pipeline of new products, especially those with new mechanisms of action, is very limited. Historically, large pharmaceutical companies provided the portfolio of antibiotics. However, market forces have diminished Big Pharma’s investments. Increasingly, the supply of antibiotic products is emerging from smaller, specialized pharmaceutical companies, which face different market and development challenges.
In the early 1940s, streptomycin and penicillin were introduced for treatment of staphylococcus, streptococcus, and Mycobacterium tuberculosis infections with life-saving results. Today, more than 130 antibiotic products are available, saving lives, shortening hospital stays, and improving patient outcomes.
But, there is a problem. Despite (or some believe, because of) the number of antibiotic products, many in the infectious disease community believe that microbes are getting the upper hand, evolving resistance faster than the pharmaceutical industry can bring new products to the market.
For a percentage of patients infected with resistant microbes, alternative antibiotic choices are often very limited, with impacts on the health of those patients, on their outcomes, and on the cost to the hospitals where they are treated. Although the number of infected patients is small, the economic burden is high. The number of drug resistant infections is expected to increase over time.
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The Infectious Disease Society of America (IDSA) has documented the microbial infections that are especially troublesome in a “Bad Bugs, No Drugs” policy statement and provided a call to action from the infectious disease community. (Spellberg, et al., 2008). Among the “Bad Bugs,” Methicillin-Resistant Staphylococcus aureus (MRSA) has received appropriate notoriety. S. aureus, a normal skin flora, becomes a problem when the skin is broken—from abrasions, traumas, surgeries, and placements of in-dwelling devices. MRSA infection has been a health problem in hospitals for more than a decade; more than 60% of US hospital-acquired S. aureus infections are now MRSA (Klein, et al., 2007). A new MRSA strain has become prevalent in community-acquired infections. A recent study showed that the total number of infections due to MRSA increased 119% between 1999 and 2005 (Klein, et al., 2007).
Staphylococcal infections can quickly become deadly; those infected rely on antibiotics to eliminate the infection. MRSA infections have increased incidence of mortality when compared with infections caused by susceptible S. aureus, and have large economic costs—estimated in the billions in the US—due to longer hospital stays and increased expenses of treatment (Abramson, et al. ,1999; Klein, et al., 2007; Shorr, 2007).
Until very recently, antibiotic therapy for hospital acquired MRSA was limited to vancomycin, a drug first approved in the US in 1958. New antibiotic therapies approved for treatment of hospital acquired MRSA include Zyvox (Pfizer); Cubicin (Cubist) and Synercid (King Pharmaceuticals) but resistance to these products is already posing challenges.
Challenges and product opportunities
Since the introduction of penicillin, new antimicrobial products have sought to overcome the limitations of previously-introduced products. The first-generation penicillin products were intravenous. Subsequently, products for oral administration were introduced. At the same time, microbes were evolving beta-lactamase resistance to penicillins. Second and third generation beta-lactam antibiotics, able to control infections caused by beta-lactamase-resistant organisms, were discovered and developed.
The creativity of antibiotic researchers continued to bring new antibiotic products to the market during the 1950s, 1960s, and 1970s and resulted in new, lucrative antibiotics that were active despite resistance mechanisms. GlaxoSmithKline’s Augmentin—a combination product of a beta-lactam (amoxicillin) and a beta-lactamase inhibitor (clavulanic acid)—and Roche’s Rocephin were consistent blockbusters since gaining approval in 1984 as were Abbott’s Biaxin and Pfizer’s Zithromax, both macrolide antibiotics, introduced in 1991 and 1994, respectively.
However, microbes were persistently clever in evolving resistance to antibiotics soon after introduction. Even vancomycin, purported initially to be “resistance-proof” because its target is a necessary component of the bacterial cell wall—not an evolvable protein—proved vulnerable. A wide range of molecular mechanisms of resistance have emerged. Sometimes the mechanism of resistance confers resistance to multiple antibiotics. Broad spectrum efflux pumps, which eliminate most antibiotics from the bacterial cells possessing these pumps, and the expanded spectrum beta-lactamases (EBSLs), that inactivate the newest generations of beta-lactam products are especially troubling. These resistance mechanisms make the discovery of effective new antibiotics even more difficult, but create market opportunities for new products.
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This self-renewing marketplace continues today. NXL-104 (Novexel), a new ESBL inhibitor now in Phase I trials, aims to inactivate a key resistance mechanism found in gram-negative organisms, such as Escherichia col. Inhibitors of microbial efflux pumps, which aim to control microbes harboring efflux pumps, by combining an efflux pump inhibitor and an antibiotic agent, have been discovered. MP-376 from MPEX Pharmaceuticals, now in Phase I clinical trials, would be combined with a fluroquinolone for treatment of multi-drug resistant Pseudomonas aeruginosa infections.
Other antimicrobial agents have also emerged recently in the form of “specific spectrum” agents. These products will likely rely on the recent emergence of new FDA-approved molecular diagnostics, which can assess the infectious agent in hours, rather than days. Affinium Pharmaceuticals has a new class of antibiotic that targets staphylococci including MRSA in Phase I studies, but are relatively inactive against other bacterial species. The utility of this new specific-spectrum antibiotic agent likely will depend on rapid molecular diagnostics for MRSA, such as the FDA approved the BD GeneOhm StaphSR Assay from BD Diagnostics.
This type of product specialization aimed at specific species and resistance targets runs counter to the blockbuster model of large pharmaceutical companies. Smaller, newer companies are attracted to the targeted model. For these companies to achieve credible revenues and returns on investment, they will likely rely on premium pricing strategies, justifiable since antibiotics are very often lifesaving, and courses of therapy are generally short.
Following the money
The maturation of the antibiotics market over the past decade has resulted in a large number of marketed antibiotics products, each with relatively low annual sales revenues. In 2001, six antibiotic products (Rocephin, Bayer’s Cipro, Levaquin, Zithromax, Biaxin, Augmentin) had blockbuster status (Dartmoniter, 2002). Today only Augmentin and the Levaquin/Floxin franchise (Ortho-McNeil) have billion-dollar annual revenues. Patents expirations, generic competition, and the withdrawal due to safety challenges or limited use have fragmented the market.
Recent introductions, including Zyvox (Pfizer) in 2000, Avelox (Bayer) in 2001, Cubicin in 2003, and Tygacil (Wyeth) in 2005 have failed to reach blockbuster status. The loss of profitability of antibiotics has caused the departure of many pharmaceutical companies from investing in the discovery of new antibiotic products (Porjan, et al., 2004 and Rice, 2006).
Enter small biotech
As large pharmaceutical companies abandoned the discovery of new antibiotic products, smaller companies have seen opportunity. In addition, some generic drug companies have expanded into proprietary products. Forest Laboratories invested significantly in new antibiotic products. In 2007, it acquired Cerexa, which gave them the Phase III product ceftaroline. In January 2008, Forest Laboratories licensed Novexel’s Phase I beta-lactamase inhibitor, NXL-104.
In abandoning their own efforts at antibiotic discovery, several large pharmaceutical companies spun out their antibiotic discovery and development efforts into new companies, or licensed their later-stage products to biotechnology companies (Table 1).
The new entrants into antibiotic development face cash constraints that often limit the size and complexity of clinical trials. Cubist obtained approval for their gram-positive agent Cubicin, based on just two indications; in contrast, the resources of Pharmacia-Upjohn allowed them to run trials to demonstrate efficacy and safety of Zyvox for five different indications.
| Table 1 – Antibiotics Companies with Major Assets from Pharmaceutical Companies that Abandoned Antibiotics Discovery | ||
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Antibiotics Company |
Pharmaceutical Company Source |
Licensed Product(s) |
| Advanced Life Sciences | Abbott | Cethromycin; ABT-210 |
| Arpida Ltd. | Hoffmann-La Roche | Diaminopyrimidine inhibitors of DHFR (iclaprim) |
| Basilea Pharmaceutica Ltd. | Hoffmann-La Roche Ltd. | Ceftobiprole |
| Cubist | Lilly | Daptomycin (Cubicin) |
| Nabriva Therapeutics | Novartis | Pleuromutilins |
| Novexel SA | Aventis | NXL-103 (oral streptogramin); NXL-104 (beta-lactamase inhibitor) |
| Replidyne | Asubio Pharmaceuticals (formerly Suntory) | Faropenem |
| Targanta | Lilly | Oritavancin |
| Cerexa | Takeda Chemical | Ceftaroline |
| King Pharmaceuticals | Aventis | Synercid |
Funding impacts pipeline
US government programs and philanthropic funding are impacting the discovery and development of new antibiotic products. Federal government incentives to develop antibiotics include hundreds of millions of dollars invested in biodefense measures, which aim to monitor and defend against acts of bioterrorism. Research grants and Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases are creating an infrastructure, new ideas, and hopefully new products to defend against bioterrorism agents such as plague, tularemia, anthrax and others. Whether these efforts will have substantial benefit in the control of natural infectious diseases remains to be determined.
The US government has been under pressure to create incentives for the large pharmaceutical companies to remain in antibiotic discovery, which have largely been resisted. However, the Food and Drug Administration Amendments Act (FDAAA) of 2007 includes creative incentives for the development of new treatments for tropical diseases, including tuberculosis, malaria, and other specifically named diseases, as well as “any other infectious disease for which there is no significant market in developed nations, and that disproportionately affects poor and marginalized populations, designated by regulation by the Secretary.” Priority review vouchers are awarded for the successful approval of new products to treat these “tropical diseases.” The priority review vouchers can be transferred or sold to the sponsor of any new drug application (NDA). While falling short of the pharmaceutical industry’s desire for patent extension vouchers, this initiative may have sufficient value to influence the discovery and development of new agents for treatment of these diseases.
Additionally, the FDAAA provides a mechanism in which new drugs for the treatment of antibiotic-resistant infections may qualify for Orphan Drug status and the incentives associated with Orphan Drugs, such as access to government funding of clinical trials.
Several philanthropic organizations have invested in the discovery and development of new anti-infective agents as an important step in improving global health. Organizations such as Medicines for Malaria Ventures (MMV), One World Health, Global TB Alliance and the Gates Foundation each have investments in bringing new products for treatment of malaria, TB, and other infectious diseases of the developing world. These funds are influencing and increasing the variety and availability of products for treatment of these diseases.
Disincentives remain
The IDSA and others have documented the uncertainty of antibiotic clinical trial designs and the lack of guidance documents for antibiotic development (Spellberg, et al., 2008). A recent FDA draft guidance document (FDA, 2007), outlined recommendations for clinical trial designs, especially regarding when the use of non-inferiority or placebo-controlled superiority trial designs should be used. This may be one-step forward in providing clarity, but another step backward in making the development of antibiotic products for certain indications larger, and thus more expensive.
About the Author
Dr. Schmid teaches entrepreneurship and the science and business aspects of drug discovery and development. Her research focus is on chemical genetics and antimicrobial drug discovery. While an Assistant Professor of Molecular Biology at Princeton University her research group discovered Topoisomerase IV in Salmonella typhimurium, as well as a genetic strategy for identifying new antimicrobial targets.
References
- Abramson, M. A. and D. J. Sexton (1999) “Nosocomial methicillin-resistant and methicillin-susceptible Staphylococcus aureus primary bacteremia: at what costs?” Infect Control Hosp Epidemiol 20(6): 408-11.
- Datamonitor (2002). Market Dynamics: Antibacterials.
- DiMasi, J. A., R. W. Hansen, et al. (2003) “The price of innovation: new estimates of drug development costs.” J Health Econ 22(2): 151-85.
- DiMasi, J. A., R. W. Hansen, et al. (1995) “Research and development costs for new drugs by therapeutic category. A study of the US pharmaceutical industry.” Pharmacoeconomics 7(2): 152-69.
- FDA, C. A. (2007). Guidance for Industry Antibacterial Drug Products: Use of Noninferiority Studies to Support Approval.
- Klein, E., D. L. Smith, et al. (2007) “Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005.” Emerg Infect Dis 13(12): 1840-6.
- Projan, S. J. and D. M. Shlaes (2004) “Antibacterial drug discovery: is it all downhill from here?” Clin Microbiol Infect 10 Suppl 4: 18-22.
- Rice, L. B. (2006) “Unmet medical needs in antibacterial therapy.” Biochem Pharmacol 71(7): 991-5.
- Shorr, A. F. (2007) “Epidemiology and economic impact of meticillin-resistant Staphylococcus aureus: review and analysis of the literature.” Pharmacoeconomics 25(9): 751-68.
- Spellberg, B., R. Guidos, et al. (2008) “The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America.” Clin Infect Dis 46(2): 155-64.
Filed Under: Drug Discovery
