Few New Drugs: Why the Antibiotic Pipeline Is Running Dry
To address a major drought in antibiotic discovery, lawmakers have given pharmaceutical companies incentives to research and design new drugs to fight deadly bacteria.
Dr. Dennis Maki addressed the importance of antibiotic stewardship with his colleagues during a meeting at the Infectious Disease Society of America in 1998.
“The development of new antibiotics without having mechanisms to insure their appropriate use is much like supplying your alcoholic patients with a finer brandy,” he said.
Since Maki spoke those now-infamous words, the U.S. Food and Drug Administration (FDA) has approved just 11 new antibiotics. Meanwhile, drug-resistant bacteria have spread in community and healthcare settings, where they sickened 2 million Americans in 2011. Of those, 23,000 died.
Maki’s comments reflect the very nature of antibiotics: The more they’re used, the less effective they become.
The more often bacteria are exposed to a certain antibiotic, the more opportunities they have to evolve defenses to combat it. This renders antibiotics, the hallmark of modern medicine, nearly ineffective against what some call “nightmare bacteria.”
“The resistance rates we saw in the ‘90s were at 10 to 15 percent. Now it’s up to 60 percent in hospitals,” said Steve Gilman, chief scientific officer for Cubist Pharmaceuticals. “I’m not generally an alarmist, but I don’t want my grandkids in the hospital in the future worrying about this.”
While these drug-resistant bacteria continue to spread across the U.S. and other parts of the world, the medicine chest of effective antibiotics is quickly emptying. The World Health Organization states that we’re in “a race against time to develop new antibiotics.”
But discovering and testing new antibiotics takes time and money, two things that have caused many major pharmaceutical companies to abandon the field.
The Decline of Antibiotic Development
Many major pharmaceutical firms back out of antibiotic discovery.
In the 1970s, when the effects of antibiotic overuse first began to emerge, the discovery of novel classes of antibiotics slowed. While scientific research continued to explore how humans could stay ahead of bacteria, interest from drug companies dwindled because antibiotics, like all other drugs, are expensive to develop.
On average, pharmaceutical companies spend $5 billion in research and testing for each new drug they bring to market. Because about 80 percent of the drugs emerging from labs fail in safety or efficacy testing, pharmaceutical companies need to recoup billions from each drug that comes to market.
Pharmaceutical companies can make greater profits on drugs that can be used regularly without losing effectiveness, such as antidepressants, statins, and anti-inflammatory medications.
Historically, Pfizer was a champion of antibiotic development. The company manufactured large amounts of penicillin for troops during WWII, including for soldiers on D-Day. The drugs were highly profitable during the 1940s, when the advent of antibiotics quickly eradicated once-untreatable diseases.
Pfizer continues to make four different antibiotics that the World Health Organization deems necessary for a basic health system. But in 2011, Pfizer closed its antibiotic research facility in Connecticut for financial reasons, ending research into gram-negative bacteria, those that are resistant to numerous drugs and antibiotics.
Three major pharmaceutical companies—Aventis (now Sanofi), Eli Lilly, and Bristol-Myers Squibb —haven’t researched and developed antibiotics since the 1990s.
The FDA has approved only two systemic antibiotics in the past five years, an 88 percent drop from the mid-1980s.
Because of this lull in antibiotic development, the Infectious Diseases Society of America hopes to spur the development of 10 new antibiotics by 2020.
To help lure companies back into antibiotic research and development, Congress passed the Generating Antibiotic Incentives Now (GAIN) Act, which President Obama signed into law in July 2012. Besides creating the Antibacterial Drug Development Task Force, the law extends drug-patent exclusivity for an additional five years, fast-tracks the FDA-approval process, and requires the FDA to provide updated trial guidance.
As of February 2014, 17 of the 45 new antibiotics in development qualified for benefits under the GAIN Act, according to PEW Charitable Trusts.
One new intravenous antibacterial drug, Dalvance, received expedited review under GAIN. In May, the FDA approved the drug to treat adults with skin infections, including those caused Staphylococcus aureus, Streptococcus pyogenes, and methicillin-resistant Staphylococcus aureus (MRSA). Vicuron Pharmaceuticals developed Dalvance under a research and development agreement with Pfizer.
Specialized Firms Seeing Success in Antibiotics
Smaller biotech companies are bringing new antibiotics to market.
Pharmaceutical giants need annual sales of up to $800 million to recoup their company’s research and development costs, while smaller companies may need as little as $100 million to cover investments before larger companies buy their successful drugs, according to a report from the European Observatory on Health Systems and Policies.
One of the newest antibiotics leaders is Cubist Pharmaceuticals, which has pledged $400 million for antibiotic discovery and development in 2014. The FDA approved one of the company’s new antibiotics, Sivextro, in June to treat skin infections.
The company recently reported positive phase-3 trial results for treating common, problematic urinary tract infections and complicated intra-abdominal infections.
Cubist researchers are now targeting tough-to-treat gram-negative bacteria.
“Boy, the gram-negatives are scary,” Gilman told Healthline. “They have a variety of multi-drug resistance tricks.”
However, only about 14 percent of patients with the common infection will qualify for Cubicin because of its specific, targeted use, Gilman said.
While the drugs are costly, they don’t cost an arm or a leg, which is their purpose.
“The patients we treat don’t have a good outcome,” Gilman said. “In giving them a therapy that helps save a limb, save a life, we’ve been able to create an economic model.”
That model includes more-expensive therapies, but it could shave costs down the line if it helps patients leave the hospital earlier. With the financial success of Cubicin and the approval of Sivextro, Cubist has found a niche market—“the sickest of the sick”—that makes financial sense out of antibiotic development.
“Then we can invest in new antibiotics because bacteria will always become resistant to them,” Gilman said.
But Cubist isn’t alone in the market. Numerous public and private entities are addressing antibiotic-resistant threats, as is the case with GlaxoSmithKline’s partnership with the Wellcome Trust and the U.S. Defense Threat Reduction Agency.
GlaxoSmithKline is one of many partners involved in the new startup Spero Therapeutics, which is developing drugs to disrupt the virulence of gram-negative bacteria.
Roche, another of Spero’s partners, is back in the antibiotics field after bowing out in 1999. Teaming up with smaller biotech firms to fight gram-negative bacteria, Roche made an initial $16 million investment in antibiotics, with up to $175 million payable for each resulting drug, Fierce Biotech reported.
Earlier this year, pharmaceutical giant AstraZeneca entered into a research and development agreement with FOB Synthesis, a small biotech company, to develop a novel antibiotic to treat gram-negative bacteria.
“No single company can meet all the challenges alone, which is why we’re actively participating in private- and public-sector partnerships to address key barriers to effective antibiotic development,” Alisha Martin, an AstraZeneca spokesperson, told Healthline.
Research hospitals and universities are making large contributions as well. Just this year, researchers at St. Jude Children’s Research Hospital discovered a new class of antibiotics, spectinamides, for the treatment of drug-resistant tuberculosis. In March, researchers at the University of Notre Dame discovered oxadiazoles, which have been shown to help treat MRSA in mice.
One recent discovery in the fight against gram-negative bacteria came from research at the University of British Columbia. Researchers there discovered a peptide that can break up biofilms, or clusters of bacteria that are impossible to treat with antibiotics.
Because the trickle of new, effective antibiotics entering the market cannot compete with the pace at which bacteria evolve, the CDC is pushing hospitals to enact antibiotic stewardship programs to ensure that antibiotics are used only when they are truly necessary.
“Improving antibiotic prescribing can save today’s patients from deadly infections and protect lifesaving antibiotics for tomorrow’s patients,” Dr. Tom Frieden, CDC director, said during a press conference in March. “Health care facilities are an important part of the solution to drug resistance and every hospital in the country should have a strong antibiotic stewardship program.”
Preserving Antibiotics Through Rapid Diagnostics
Quick tests can help doctors prescribe the right drugs to treat the right bugs.
Prescribing antibiotics only when needed and making sure the proper drugs are used on the right bacteria are the cornerstones of antibiotic stewardship.
Rapid diagnostic testing, which reveals results within hours instead of days, is one type of advanced technology that can help patients and doctors kick their bad antibiotic habits.
While patients may believe they need antibiotics for their colds and sore throats, a simple test strip could help prove to them that a virus, not bacteria, is causing their illness.
“If it’s viral, antibiotics won’t help and it’s a waste of antibiotics,” said James Cottam, global product manager of the healthcare-associated infection division at Alere, a diagnostics company. “There’s a huge part that rapid diagnostics can play in the appropriate use of antibiotics.”
Alere’s “Test. Target. Treat.” campaign encourages the proper use of antibiotics by employing rapid diagnostics to ensure the correct antibiotics are matched with specific strains of bacteria. This kind of specialized care helps preserve the drugs’ effectiveness and speed the patient’s recovery.
Alere’s test strips are approved for use in the U.S. and the United Kingdom, one of many European countries that has reduced antibiotic resistance through stewardship campaigns and strict regulation concerning how the drugs are used in animals.
Rapid diagnostics that can separate viruses from bacteria, like one developed by Duke University scientists last year, are set to become the cornerstone of appropriate antibiotic use.
“If new antibiotics are developed, and I’m sure they will, they still need to be used in the right way so they are effective for future generations,” Cottam said.
But developing effective policy takes expansive and up-to-date data. Without the data, experts can’t make informed decisions about where to target their policy measures.
While experts have the data to assess how 20 percent of antibiotics used in the U.S. are currently utilized, the numbers concerning the widespread use of antibiotics in agriculture are very hard to come by.
A Gaping Hole of Missing Antibiotic Data
The U.S. doesn’t have a public reporting system for antibiotic use, leaving policymakers in the dark.
Sumanth Gandra, a research fellow for the Centers for Disease Dynamics, Economics, and Policy in Washington, D.C., is unnerved by this lack of data, especially in light of the antibiotic-resistance epidemic.
“We need to be aggressive,” Gandra told Healthline. “The bacteria are spreading rapidly.”
Gandra collects and analyzes data to help guide policies on a variety of health issues, including combatting the threat of deadly bacteria. As studies have shown, a decrease in the use of antibiotics directly translates to lower rates of drug-resistant bacteria.
Canada and a number of countries in Europe require veterinarians to report their antibiotic use to government officials, which helps health analysts like Gandra develop stewardship policies.
But in the U.S., this data is private and five years old.
In 2014, Gandra has access to data only from 2009, despite the fact that the information is collected every year. That data includes only how many and how often antibiotics are sold for use in humans, despite the fact that 80 percent of the drugs are used in animals destined for human consumption.
“We don’t have good data for how antibiotics are used in animals,” Gandra said.
The U.S. Government Accountability Office (GAO) agrees, stating that federal agencies don’t collect critical data regarding antibiotic use in agriculture, and little progress is being made on the issue.
In a 2011 report, GAO recommended that the Department of Health and Human Services, as well as the U.S. Department of Agriculture, collect the necessary data to review the effectiveness of the FDA’s voluntary guidance measures to industry.
“Without detailed use data and representative resistance data, agencies cannot examine trends and understand the relationship between use and resistance,” the GAO report states.
In December 2013, the FDA issued another voluntary guidance regarding antibiotic use in animals, asking antibiotics manufacturers to remove their drugs from over-the-counter status and place them under veterinary supervision.
While the majority of companies have said they will comply, many experts say the voluntary system doesn’t work.
The next story in this series examines how the FDA has responded to widespread antibiotic use in animals, the problems with its voluntary guidance measures, and how the agency is defending its policies to federal judges.
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