Magazine Article | March 1, 2009

The Antibiotics Paradox

Source: Life Science Leader

By Cliff Mintz

Despite a rapidly growing need, most pharma companies have avoided developing new stronger antibiotics due to a perceived poor ROI. Yet, Cubist Pharmaceuticals, which focuses on antibiotics, grew net revenue 47% last year.

From 1986 to 1992, Barry Eisenstein, M.D. served as chairman of the department of microbiology at the University of Michigan (UM) in Ann Arbor. During his tenure there, he was recruited to Abbott Pharmaceutical’s scientific advisory board and experienced firsthand the industrial approach to antibiotic drug discovery and development. The stark differences between what can be accomplished in antibiotic drug development in academia versus industry prompted Eisenstein to leave UM in the early 1990s to join Eli Lilly and Co. as a VP of research. At Lilly, he oversaw the development of two antimicrobial agents and ironically, helped kill development of daptomycin, an antibiotic, which ultimately garnered FDA approval by Cubist Pharmaceuticals, Eisenstein’s current employer.

When Lilly abandoned antibacterial drug discovery in the late 1990s, Eisenstein returned to academia, this time as VP of Science and Technology at Beth Israel Deaconess Medical Center in Boston and Professor of Medicine at the Harvard Medical School. However, he was unable to abandon his lifelong commitment to antibiotic drug discovery and development and joined Cubist Pharmaceuticals in 2003 first as senior VP of research and development and now in his current position as senior VP of scientific affairs. In June 2008, Eisenstein, a recognized expert in antibacterial drug resistance and antibiotic drug discovery and development, testified before the Senate HELP (Health, Education, Labor, and Pensions) committee on “Emergence of the Superbug: Antimicrobial Resistance in the United States” on the dire need to develop new antimicrobial agents.

I had an opportunity to chat with Eisenstein about the ongoing threat of bacterial antibiotic resistance and the shortage of new antibiotics that can be used to treat infections caused by antibiotic-resistant bacteria and what the future may hold for us.

Life Science Leader (LSL): Since the discovery of the first antibiotics in the 1940s and 1950s, infectious disease experts were concerned about the likely emergence of antibiotic-resistant strains of bacteria, the reality of which resulted in the development of newer generations of antibiotics to overcome increasing resistance. But, the 1990s brought a surge in the number of bacterial infections caused by particularly difficult-to-treat strains, most notably vancomycin-resistant enterococci (VRE) and methicillin-resistant staphylococcus aureus (MRSA). What factors led to the emergence of these antibiotic-resistant pathogens, and why are physicians running out of options to treat infections caused by these organisms?

Eisenstein: Bacterial antibiotic resistance began to appear shortly after the introduction of the first antibiotic, penicillin. This was not unexpected because Darwin’s theory of natural selection predicts this. That is, if selective pressure is placed on an organism, it will accumulate mutations that enable it to adapt to or overcome the pressure. For example, penicillin-resistant S. aureus began appearing in the 1950s (penicillin was introduced in the 1940s) and MRSA were first reported in the 1960s following introduction of the next-generation penicillin, methicillin, in 1959.

In 1980, roughly 3% of staphylococcal isolates were MRSA; today over 60% of all S. aureus clinical isolates are resistant to methicillin. Vancomycin-resistant isolates were not reported until 1988, and today over 30% of all enterococci isolates are VRE. The rapid increase in antibiotic resistance during the past 30 years has been attributed to the use of antibiotics as growth enhancers in animal feeds and misuse and overprescription of antibiotics by physicians. Regardless of the cause, we are running out of options to effectively treat bacterial infections because of the increasing prevalence of antibiotic-resistant bacteria. For example, methicillin previously was the drug of choice to treat staphylococcal infections. However, the emergence of MRSA reduced its effectiveness as an antistaphylococcal treatment, and physicians reluctantly began using vancomycin (the so-called last line of defense) to treat staphylococcal disease. The appearance of VRE isolates forced physicians to more carefully consider the empiric use of vancomycin to treat staphylococcal disease because of the fear that vancomycin resistance would be genetically transferred from VRE to MRSA and other staphylococci. Unfortunately, those fears were realized in 2002 when the first report of a vancomycin-resistant strain of S. aureus (VRSA) appeared. Although these high-level vancomycin-resistant strains of S. aureus are still rare, strains still with the ‘susceptible’ designation are becoming significantly less responsive to vancomycin therapy.

LSL: During the last 25 years, only two new antibiotics with novel mechanisms of action (daptomycin and linezolid) have been discovered and commercialized. Why is it so difficult to discover and develop new antibiotics?

Eisenstein: It is inherently more difficult today to identify and develop new antibiotics than it was 30 to 50 years ago when most of the better-known, orally bioavailable, and broad-spectrum antibiotics were discovered. Bacterial targets, by their nature, are not easy; they must be essential, conserved across bacterial species and unique to bacteria. However, many of the original antibiotics were potent, nontoxic small molecules that were derived from natural products and could be easily modified by traditional medicinal chemistry — to improve their potency and safety and overcome emerging resistance mechanisms. This gave rise to various generations of certain antibiotics including the cephalosporins, macrolides, and aminoglycosides. Each generation had incremental improvements over the last, but the mode of action remained the same. Companies in the antibiotic discovery space relied on this model to develop new products until the mid-1990s when it became evident that new antibiotics were going to be needed to treat infections caused by increasingly prevalent antibiotic-resistant pathogens.

The advent of genomics and bioinformatics in the late 1990s supplied us with several new bacterial targets of potential value. The challenge is whether or not we can identify compounds that possess the appropriate ‘druggability characteristics’ (including mode of action, permeability, lack of toxicity, and ability to overcome resistance mechanisms) to be effective against a particular target on the bacterial cell when it is actually causing disease in the patient. That is, can we get a compound that works on a molecular target in a test tube to be effective in animal models of disease and ultimately in humans? There are certainly new compounds out there, but it is getting progressively harder to turn them into true antibiotics, and they are becoming increasingly expensive to commercialize.
LSL: In the past, most major companies were actively involved in antibacterial drug discovery. Today, there are only a handful of pharmaceutical companies involved in antibiotic research. What sparked so many pharmaceutical companies to forsake antibiotic research and development?

Eisenstein: Pharma’s collective (though not universal) decision to exit the antibacterial drug discovery space is multifaceted. First, the treatment and/or cure of chronic diseases like cancer, psychiatric/neurological illnesses, rheumatoid arthritis, obesity, and metabolic diseases have a perceived greater ROI than treatments for acute diseases like bacterial infections. When compared with other classes of drugs, antibiotics have rarely achieved blockbuster status. And, since, from an unmet medical needs perspective, chronic diseases represent a far greater overall health burden on society than bacterial infections, it could be argued that pharmaceutical companies’ bias towards chronic diseases is actually consistent with societal needs.

Second, there is a perception that clinical development costs for new antibiotics are extremely high, in part, because of increasing regulatory hurdles. For example, Sanofi-Aventis conducted a 24,000-patient clinical trial — that cost hundreds of millions — to get Ketek approved in 2005. And, the primary use of most new antibiotics for niche indications (i.e. specifically for infections due to drug-resistant organisms) doesn’t justify the high development required for regulatory approval.

Finally, the rise in antibiotic resistance has forced many physicians and infectious disease specialists to engage in something called antibiotic stewardship, which is designed to limit antibiotic usage. Antibiotic stewardship, among other things, limits the use of the newest agents, for example, to the most severe cases when other treatments have failed and the patient is at risk of death. This is done to limit emergence of resistance to new agents because they increasingly represent the last line of defense against many infections caused by multiple drug-resistant pathogens. Ironically, while antibiotic stewardship helps on the demand side, it hurts on the supply side by disincentivizing commercial development of new antibiotics.

LSL: Why, in the face of rising antibiotic resistance, is it so difficult to win regulatory approval for new antibacterial agents?

Eisenstein: The questions and controversy surrounding the approval of Sanofi-Aventis’ new antibiotic Ketek has caused the FDA to become more risk-adverse. Because of this, the FDA now requires unprecedented amounts of safety and efficacy data before it will consider approving new antibiotics — data that can be obtained only by conducting very large clinical trials at great cost. Also, the FDA and its advisory boards contend that older antibiotics can no longer be reliably used as standards in noninferiority clinical trials; and placebo-controlled superiority trials are often unethical. These changes have created an extremely challenging regulatory environment, which in turn has reduced the inherent commercial value of new antibacterial agents. Moreover, even if new antibiotics were to be approved, their therapeutic use and overall commercial potential would be limited by antibiotic stewardship practices.

LSL: Should the U.S. government intervene to help avert the current antibiotic crisis?

Eisenstein: We cannot always rely on the marketplace to do what is right and in the best interests of society as a whole. Therefore, sometimes government intervention is needed, as with the antibiotic shortage crisis we are now facing. The government can intervene in a number of ways by increasing support to government agencies like the NIH (for additional basic and clinical research), CDC (surveillance and infection control), and FDA (streamlined regulatory review processes and updated guidance on older, nearly obsolete drugs). More importantly, it can provide financial inducements to reinvigorate antibacterial research in the private sector, as it has helped with vaccine development. This could include: extension of orphan drug exclusivity to antibiotics, R&D tax credits, guaranteed loans and liability protection, and assurances of purchasing and stockpiling antibiotics that are the most active against important resistant bacteria. These types of push-and-pull strategies can have an enormous impact on the private sector and may induce companies to return to or get into the antibiotic discovery business for the first time.

LSL: Where is the greatest need, and what do you think is the next big thing in antibiotic drug discovery?

Eisenstein: Most of our efforts over the past decade have focused on new antibiotics to combat infections caused by Gram-positive bacteria like MRSA and VRSA. Currently, there are no antibiotics in development to treat infections caused by antibiotic Gram-negative bacteria, which are increasingly on the rise. I foresee a growing medical need in that arena.

Advances in diagnostics and detection systems that can rapidly identify the causative agent(s) of clinically relevant infections would reduce the need for empiric treatment and enable physicians to prescribe the most effective antibiotic to treat bacterial diseases. This would help to minimize bacterial resistance to new antibiotics and optimize the practice of antibiotic stewardship.

LSL: What happens if new antibiotics aren’t approved or discovered over the next 10 years?

Eisenstein: Continued natural selection favoring resistance is inevitable such that increasingly difficult treatment situations will become ever more common. Hopefully, the free enterprise system will kick into gear before this scenario plays out. Unfortunately, while improved surveillance and infection control and responsible use of antibiotics can help to minimize antibiotic resistance, ‘the horse is already out of the barn,’ and the mutations that confer antibiotic resistance don’t usually adversely affect the fitness of antibiotic-resistant bacteria.

I have no doubt that we as a society can collectively deal with the antibiotic shortage crisis. However, antibiotic drug discovery is currently at the mercy of the free enterprise system, and until the U.S. government intervenes with new legislation regarding antibiotic development incentives, the pace of new antibiotic approvals will remain inadequate to meet our increasing medical needs. The fact that it takes 10 years or so to develop new antibiotics, and there is so little in the pipeline, is causing me some personal anxiety concerning the health of those I know and love.