Despite Growing Crisis, Few New Antibiotics Are in Pipeline

Jenni Laidman

April 22, 2013

The creation of new antibiotics targeting the growing threat of multidrug resistance is a goal that remains "alarmingly elusive," according to a report released by the Infectious Disease Society of America (IDSA) and published online April 18 in Clinical Infectious Diseases.

The IDSA reports that only a single new antibiotic (ceftaroline fosamil) has been approved by the US Food and Drug Administration (FDA) since 2010, and few new drugs are in the pipeline. The report found that only 7 new antibiotics targeting multidrug-resistant gram-negative bacilli have reached phase 2 or phase 3 trials since 2010, when IDSA established its 10 × '20 Initiative, with the goal of developing 10 new antibiotics by 2020.

"Antimicrobial resistance has really reached a crisis," report lead author, Helen W. Boucher, MD, told Medscape Medical News. Dr. Boucher, from the Division of Infectious Disease and Geographic Medicine, Tufts Medical Center, Boston, Massachusetts, and colleagues combed the medical literature and clinical trials registry and interviewed leaders of pharmaceutical and biotechnology companies to find oral and intravenous compounds in phase 2 or phase 3 of development.

The report showed that none of the drugs in the works targets the resistance mechanism of a class of what Tom Frieden, MD, MPH, director of the Centers for Disease Control and Prevention called "nightmare bacteria": carbapenem-resistant Enterobactertiaceae species resistant to last-resort antibiotics and lethal in half of all cases. Some of these Enterobactertiaceae employ an enzyme called metallo-carbapenemase to disarm carbapenem, but of the antibiotics under development, none addresses this resistance activity.

Also missing from development are drugs targeting Acinetobacter baumannii, community-acquired bacterial pneumonia, hospital-acquired bacterial pneumonia, or bloodstream infection, the report notes.

The 7 drugs in phase 2 or phase 3 trials target complicated urinary tract infection, complicated intraabdominal infection, and acute bacterial skin and structure infection. The report did not cover promising drugs in phase 1 development because of the high failure rates common in early development and the lack of publically available data.

Dr. Boucher cautioned that having 7 drugs in the pipeline does not mean 7 drugs will reach the market. "Given where compounds are in development, there is little chance, history tells us, that all 7 [would] succeed anyway. We need more."

The IDSA report tracks a steady decline in new antibiotics, from a high of 16new compounds approved from 1983 to 1987 to only 2 approved since 2008: ceftaroline fosamil and telavancin. Of the 14 systemic antibacterial drugs approved since 1998, only 4 introduced a novel mechanism of action.

Among the 7 drugs in development, 2 are in phase 3 and 5 are in phase 2. In addition, the fate of one of those phase 2 drugs, Brilacidin (PMX-30063), is uncertain because its developer, PolyMedix, filed for chapter 7 bankruptcy in early April. This drug was the only 1 of the 7 believed to have a novel mechanism of action, the report reveals.

Lack of Incentive

The firm's bankruptcy highlights one of the critical problems in antibiotic development: a decline in the number of companies engaged in antimicrobial research. Dr. Boucher noted that several multinational pharmaceutical firms have fled the field. Most recently, Pascal Soriot, the new chief executive of AstraZeneca, which is developing 2 of the 7 new drugs, announced in March that the company would reduce its investment in anti-infectives.

"Antibiotics are not economically the most viable of drugs," Dr. Boucher said. "Most drug companies and sponsors want to make drugs patients will take for the rest of their life, drugs for hypercholesterolemia and obesity. Antibiotics, by design, are used for a short period of time and often are priced in a reasonable way, to meet a public health need."

The economic disincentive, combined with what Dr. Boucher called a "lack of regulatory clarity," has contributed to drug development stagnation.

"They delay in regulatory clarity to go with the advancing science has been really chilling," she said. There have been instances in the past where companies conducted research to meet one set of regulatory guidelines only to be held to newer guidelines later, she said. Some of the companies caught in that regulatory switch left the field, and others started the process over again.

Edward Cox, MD, MPH, director of antimicrobial products, Center for Drug Evaluation and Research, FDA, told Medscape Medical News that several regulatory changes are improving the oversight process, streamlining efforts to bring new antimicrobials to the market.

"There is a critical need for the development of new antibacterial drugs," Dr. Cox said, and the FDA is part of developing a "robust pipeline."

"We've worked to revise our guidance documents to get to clinical trial recommendations that are scientifically sound, feasible, and ethical," he said. Addressing feasibility allows the FDA to strike a balance between the need for precision in drug testing and the needs of acutely ill patients who may require therapy before there is time to enroll them in a trial.

The adoption of pathogen-specific clinical trials is another arena Dr. Cox said the Center for Drug Evaluation and Research sees as "particularly important." These trials would create a streamlined review mechanism for drugs targeting a specific pathogen with a limited target population.

Last year, Congress approved the Generating Antibiotic Incentives Now Act, which provides 5 years of additional market exclusivity for qualified antibiotics, as well as fast-track review. Thus far, 12 drugs have been identified as qualified infectious disease products, Dr. Cox said.

"It will take more time to see what the impact will be on antibacterial drug development," Dr. Cox noted. "Clearly, the intent is to provide incentive and mechanisms to accelerate antibacterial drug development."

Desperate Need

The report calls for enhanced cooperation between the FDA and the European Medicines Agency (EMA), an effort Dr. Cox said is underway.

"We work with the folks at EMA fairly closely," he said, especially since the 2009 formation of the Transatlantic Task Force on Antimicrobial Resistance, so that drug trials can meet the requirements of both the EMA and the FDA. "We are working to try to harmonize trials as much as we can."

Marcus J. Zervos, MD, head of the Division of Infectious Diseases for the Henry Ford Health Systems, Detroit, Michigan, said physicians and patients are in desperate need for new antibiotic compounds.

"It's been very disappointing," Dr. Zervos said. "We're seeing an increasing number of patients with bacteria resistant to most or all antibiotics, as are all hospitals. For some patients, these infections are untreatable. It's very alarming, and very difficult."

Even with efforts to support new drug development, such as the 10 × '20 Initiative, patients could be in for a long wait, he said. "It can take 5, 10 years to develop a new antibiotic from the lab, to in vitro experiments, to animal work, to clinical trials. And then, within a few years, you get strains that are resistant to those new agents," he said.

"We need to use the antibiotics we have more judiciously and really toughen up how we use them, and not overuse them to preserve them for the future," Dr. Zervos said. "We need to toughen up as clinicians. We need to do a better job."

Various authors reported financial relationships with Achaogen, Actelion, American Proficiency Institute, Anacor, ASM, Astellas, AstraZeneca, Basilea, , Bayer, Biosynexus, Calixa, Cempra, Cerexa, Contrafect, Cubist-Calixa, Daiichi, Dipexium, Durata, Enata, European Food Safety Authority's Innovative Medicines Joint Undertaking, FAB Pharma, Forest, Furiex, GlaxoSmithKline, IMS Consulting Group, Intercell, Johnson & Johnson, Kalidex, LegoChem Biosciences Inc, The Medicines Co, Meiji, Merada, Merck, Merck Schering-Plough, Mpex, Nabriva, Paratek, Novartis, Pfizer, Rempex, Rib X, Sanofi, Seachaid, Shionogi, Theravance, Thermo Fisher, Toyoma, Targanta/TMC, nonprofit Thrasher Research Foundation, Trius, UCB Pharma, UpToDate, and Wyeth/Pfizer, as well as receiving funding from the US government. Dr. Zervos is a consultant for Optimer Pharmaceuticals and has a paid lectureship for Sunovion Pharmaceuticals Inc, and Henry Ford Health Systems has a grant from Cubist Pharmaceuticals and Pfizer.

Clin Infect Dis. Published online April 18, 2013. Full text

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