Special Report: Stronger 'superbugs,' and no new drugs to fight them

Innovation Pharmaceuticals

15/12/2016 14:05

(For more Reuters Special Reports, double-click on  SPECIAL/ ) 
    By Andrew Chung, Yasmeen Abutaleb and Deborah J. Nelson 
    Dec 15 (Reuters) - For nearly two years, a killer stalked 
the patients of Providence Alaska Medical Center. 
    It was a bacteria called Acinetobacter baumannii, a common 
cause of infections in hospitals. This one was different. 
    After a rash of mild cases in early 2011, doctors began 
seeing highly drug-resistant infections in patients, said Dr 
Megan Clancy, an infectious-disease specialist at the Anchorage, 
Alaska, hospital. And the bacteria was attacking more patients 
than just the severely ill ones who are the usual victims of 
drug-resistant "superbugs." 
    Clancy took emergency measures. Infected patients were 
isolated. Staff and visitors had to adhere to strict 
hand-washing and other infection-control protocols. Furniture 
and equipment were scrubbed to remove a microbe that can 
stubbornly persist on all sorts of surfaces. 
    Clancy also contacted outside researchers for help. They 
found that a strain of the bacteria had acquired a rare 
combination of traits. Bacteria typically are either highly 
resistant to drugs or highly virulent. This strain was both. 
Doctors quickly burned through the antibiotics used as the 
second and third lines of defense against superbugs. This strain 
shook them off. 
    "When you start running out of medications, it gets pretty 
desperate," Clancy said. 
     
    LAST RESORT 
    Eventually, they turned to colistin. This powerful 
antibiotic was largely abandoned in the 1960s for its toxic side 
effects. Out of necessity, it has become in recent years a 
weapon of last resort against the worsening superbug scourge. 
    But in some of the Alaska cases, even colistin didn't work. 
For public health officials, that's the nightmare scenario. 
    "It's the worst of all possible worlds: You have a bacteria 
that is good at establishing infection, and it can't be treated 
with antibiotics," said Dr Robert Clifford, a microbiologist at 
the Walter Reed Army Institute of Research who studied the 
outbreak. 
    In early 2013, the infections stopped as mysteriously as 
they had begun. By then, the virulent strain had infected 19 
patients and contributed to the deaths of five of them. A sixth 
died after contracting another highly resistant A. baumannii 
strain. 
    The Alaska outbreak, and others like it that make headlines 
with increasing frequency, illustrate a major weakness in the 
fight against superbugs: The arsenal of antibiotics is nearly 
empty. And significant financial and legal hurdles are getting 
in the way of the already challenging process of discovering 
effective new ones. 
    It's been 30 years since the discovery of a new class of 
antibiotic that has hit the market. Each class is defined by its 
chemical structure, which determines how it kills bacteria. The 
longer an antibiotic is in use, the more time bacteria have to 
develop resistance to it. Penicillin and its ilk date back to 
World War Two, and resistance to this group is now widespread, 
as it is becoming for other extant classes. 
    Thirty-seven antibiotics are currently undergoing clinical 
trials, according to the Pew Charitable Trusts, which keeps 
track of the U.S. pipeline. Most, however, are based on existing 
drugs. While these derivatives are cheaper and easier to develop 
than new classes of drugs, bacteria have a head start in 
developing resistance to them. 
    Further, most drugs in the pipeline target so-called 
Gram-positive bacteria, a group that includes the well-known 
superbug methicillin-resistant Staphylococcus aureus (MRSA). But 
recently, the main emerging threats have come from the group 
known as Gram negatives, which are harder to treat because they 
are encased in tough membranes that repel many drugs. Among 
them: the lethal Acinetobacter that hit the Providence Alaska 
Medical Center. 
    That's why colistin has seen a resurgence in use. It is 
effective in particular against Gram-negative bacteria. 
Prescriptions of the drug dispensed by long-term care facilities 
and retail and online pharmacies increased 74 percent from 6,513 
in 2005 to 11,322 in 2015, according to a Reuters analysis of 
data provided by QuintilesIMS, a healthcare research and 
services company in Durham, North Carolina. And those numbers 
don't include prescriptions at regular acute-care hospitals. 
    Now, as happened in Alaska, doctors are encountering 
superbugs that are developing resistance to colistin, too. 
    "We are losing the standoff with pathogens," said antibiotic 
researcher Kim Lewis, a Northeastern University biochemist. 
"Without antibiotics, essentially you do not have modern 
medicine." 
     
    A TOUGH PATH 
    Previous stories in this series revealed how the lack of a 
coherent national surveillance system hinders the ability of 
federal and state public health officials to track what the U.S. 
government 15 years ago called a grave threat to public health. 
    Hundreds of thousands of antibiotic-resistant infections and 
tens of thousands of related deaths go uncounted each year. But 
even if they were closely tracked, the lack of new drugs to meet 
the rising tide of resistance means the toll will only mount. 
    To regain the advantage, medical science needs to overcome a 
daunting set of hurdles. 
    Bringing a new drug to market can cost upward of a billion 
dollars. The return on investment is much lower for antibiotics 
than it is for drugs that patients take for years to treat 
chronic conditions like high cholesterol or diabetes. 
Antibiotics are typically prescribed for short periods, usually 
seven to 14 days. 
    More recently, court rulings have made it difficult to 
patent the natural compounds from which most antibiotics are 
derived. And ironically, efforts to slow the development of 
resistance by curbing prescriptions have further damped the 
commercial allure of antibiotics. 
    Small wonder that Big Pharma has fled the business. In 1980, 
36 large U.S. and European pharmaceutical companies were 
involved in research into new antibiotics. Today, there are 
four: Novartis AG, Merck & Co  MRK.N , GlaxoSmithKline Plc 
 GSK.L  and Sanofi SA, said Karen Bush, a biochemistry professor 
at Indiana University Bloomington who studies the issue. 
    "It's all about the bottom line," Bush said. 
    To that end, Big Pharma tends to pump out new, more 
expensive versions of existing drugs. In a study published in 
May in the Annals of Internal Medicine, researchers found that 
almost no antibiotics approved by the Food and Drug 
Administration (FDA) since 2010 showed better results for 
patient survival or disability than older, cheaper ones. 
    For example, Merck's Zerbaxa, a combination of drugs from 
two existing classes, cost more than $2,000 for a weeklong 
course to treat a urinary tract infection. That's nearly 3,000 
times the roughly 67-cent cost of seven days of a generic, 
levofloxacin, the study reported. 
    "As a group, these aren't the antibiotics that health 
experts really need," said Kevin Outterson, a Boston University 
law professor and co-author of the study. "None of them 
represent a novel class. None of them are really a 
breakthrough." 
    In an emailed statement to Reuters, Merck said it spends 
significantly on research and development related to infectious 
diseases "to address unmet public health needs." It cited a 
clinical trial showing that Zerbaxa was effective against 
urinary tract infections, including some that were resistant to 
levofloxacin. 
    Small biotechnology start-ups have filled the void left by 
Big Pharma. But these companies face the same hurdles. In 
addition, they lack the cash to shepherd promising discoveries 
through the multimillion-dollar process of clinical trials. The 
venture capitalists and other private investors they rely on 
expect returns in time frames shorter than scientific research 
allows. 
    "Forces well outside of science and medicine can come to 
bear and have disastrous consequences" on drug development, said 
biochemist William DeGrado, a professor of pharmaceutical 
chemistry at the University of California, San Francisco. 
    The company that he and a team at the University of 
Pennsylvania founded 14 years ago to develop what would be the 
first drug in a new class of antibiotic went bankrupt after 
investor support withered. Under new owners, the drug is still 
awaiting funding for clinical trials. 
    Government has attempted to prime the process. Under its 
2014 national action plan to combat the superbug crisis, 
President Barack Obama's administration got Congress to approve 
increased funding for public health agencies. 
    The National Institutes of Health received a $100 million 
increase, to about $413 million, in part for grants to fund work 
on new antibiotics. And the Biomedical Advanced Research and 
Development Authority (Barda), an office in the Department of 
Health and Human Services that develops medical products for 
emergencies, funds some trials and research. Barda also is 
underwriting a program to support pre-trial work on promising 
compounds. 
    In 2012, a new law empowered the FDA to designate certain 
drugs "qualified infectious disease products." The drugs can get 
priority review for approval, and if approved, may be eligible 
for an additional five years of market exclusivity. Most of the 
37 drugs now in the pipeline have received the designation. 
    In the four years since the law took effect, there has been 
a "mild uptick in antibacterial drug development," the FDA said. 
However, it added, "the pipeline remains very fragile." 
     
    STUCK IN THE PIPELINE 
    On a bright summer day in June 2000, William DeGrado 
sketched a ribbon-like molecule on a piece of scrap paper. 
    It may not have looked like much, but it so excited the 
biochemist and his team of fellow researchers at the University 
of Pennsylvania in Philadelphia that they all signed the sketch 
and set to work building the molecule in a laboratory. 
    The source of their excitement was the molecule's 
resemblance to antimicrobial peptides, or AMPs. These tiny 
proteins are produced by the body's own tissues as a first line 
of defense against all sorts of infections. AMPs don't have to 
enter a pathogen to kill it - they literally punch holes through 
bacteria cell walls. That means they can kill both Gram-positive 
and thick-skinned Gram-negative bugs. 
    Scientists have long recognized the potential of AMPs. But 
previous efforts to turn the proteins into effective drugs 
failed: The products were too costly, too toxic or too 
chemically unstable. DeGrado's sketch suggested it was possible 
to create a synthetic version of an AMP without those drawbacks. 
    "I thought, if it works, we've got a simple drug that would 
be cheap to make that could go to the developing world and cure 
all sorts of things," said Michael Klein, a computational 
chemist who was tasked with creating computer models of the 
molecule. 
    Within two years, they had formed a company, called 
PolyMedix, and raised a few million dollars in funding from NIH 
grants and private investors. Soon after, they obtained patents 
and published their first scientific paper on the potential of 
their new drug, eventually called brilacidin. 
    In early lab tests, the molecule showed potency against 
bacteria known for resistance to powerful drugs, including Gram 
positives and well-known Gram-negative killers Klebsiella 
pneumoniae and Escherichia coli. Even more encouraging, testing 
showed bacteria had little propensity to acquire resistance to 
the drug. 
     
    BURNING THROUGH CASH 
    As they barreled toward clinical trials to test the safety 
and efficacy of the drug, they raised more money by getting 
PolyMedix listed on the over-the-counter market. "We believe it 
is less likely that resistance will develop against our product 
candidates compared with conventional antibiotic drugs," the 
company told investors in 2006. 
    But the company was burning through cash. By 2012, after the 
first phase II trials of brilacidin, PolyMedix had accumulated a 
$96 million deficit, according to regulatory filings. 
    Investors grew impatient with the slow pace of the trials 
and the fact that the drug proved more effective against 
Gram-positive infections than harder-to-kill Gram negatives, 
said Richard Scott, a PolyMedix founder. 
    On April 1, 2013, after defaulting on a loan, PolyMedix 
declared bankruptcy. "It just didn't work, given the reality of 
having to make progress in very short time periods (to offer) a 
return on investment," Scott said. 
    Another small biotechnology company, Cellceutix Corp 
 CTIX.PK , paid $5 million in cash and stock for PolyMedix's 
assets. 
    Cellceutix is housed in the first floor of a nondescript 
gray building in the back of an office park in Beverly, 
Massachusetts, near Boston - a far cry from the sprawling 
research centers Big Pharma operates. On a recent November day, 
just eight people were at work, out of total staff of 18. 
    In 2014, Cellceutix completed a second phase II trial of 
brilacidin. It found that a single dose of the drug was as 
effective against MRSA as a weeklong course of daptomycin, a 
popular antibiotic widely used in hospitals against the 
superbug. 
    A phase III trial - typically larger and more expensive than 
earlier trials - has been planned for more than a year now. But 
the company needs $30 million to move forward, chief scientist 
Krishna Menon said. It's also seeking a special assessment from 
the FDA to speed up the trial and approval process. 
"We have the contractors, the medicine, the vials all ready!" 
Menon said. "Everything is set." 
    Investors, however, haven't shown much interest in advancing 
the process. Some sued the company last year, alleging that 
Cellceutix misled them about the potency of brilacidin against 
Gram-negative bugs. A judge in federal court in Manhattan threw 
out the case last June, but the damage was done. Shares of 
Cellceutix have dropped to around $1.15 from more than $4.50 
after the successful phase II trial. 
    Meanwhile, scientific interest in the potential of AMPs has 
only grown. A Ph.D student in Australia made international 
headlines in September after she created an AMP-based molecule 
that has the potential to kill Gram-negative pathogens, 
including those resistant to colistin. But the research is still 
in its earliest stages and far from clinical trials. 
     
    A BUILT-IN DOWNSIDE 
    Resistance can develop fast, and is made worse through 
over-prescribing and misuse of drugs. To preserve existing 
antibiotics, public health officials have urged hospitals and 
doctors to implement "stewardship" programs to reduce 
unnecessary prescriptions and hold critical drugs in reserve for 
when others fail. 
    Beginning Jan. 1, 2017, the Joint Commission, the nonprofit 
group that accredits U.S. healthcare facilities, will require 
hospitals and nursing care centers to implement stewardship 
programs. And the Centers for Medicare & Medicaid Services 
proposed a rule in June that would require hospitals to have 
stewardship programs to participate in the two huge government 
insurance programs it administers. In 2014, California became 
the first state to enact a law that mandates stewardship 
programs. 
    Suburban Hospital, in Bethesda, Maryland, adopted a 
stewardship program in July 2015 to comply with new Joint 
Commission standards. In the first year, the hospital's 
antibiotic use fell about 7 percent, said Julie Trivedi, 
hospital epidemiologist and director of antimicrobial 
stewardship. That saved the hospital nearly $200,000 on 
antimicrobial drugs. 
    "Infectious disease is not like cardiology, where the latest 
drug on the market is the one you want to use," Trivedi said. 
"Infectious disease physicians drive that beat-up Beetle until 
the car falls apart  It's about utilizing the available drugs 
before moving on to new drugs." 
    GlaxoSmithKline's most promising experimental antibiotic, 
gepotidacin, is now in phase II clinical trials. If approved, it 
will be used as a last resort against superbugs. The company has 
been able to shepherd the drug through expensive research and 
clinical trials with support from the federal Barda program, 
said David Payne, head of GlaxoSmithKline's Antibacterial 
Discovery Performance Unit. 
    But, he said, since the drug should be used only when it's 
"desperately needed ... that creates a huge challenge in 
creating a viable return on investment." He said the company has 
invested roughly $1 billion in antibiotic research over the past 
decade. 
     
    PAY DIRT 
    In early 2015, researchers Kim Lewis and Slava Epstein at 
Northeastern University in Boston published an article in the 
journal Nature announcing the discovery of teixobactin, a 
compound that appeared to kill Gram-positive bacteria without 
any indications of resistance. 
    Major media carried the news. The New York Times wrote that 
teixobactin could "help solve an urgent global problem" by 
ushering in a new class of antibiotic for the first time in 
decades. 
    Since then, NovoBiotic Pharmaceuticals LLC, the Cambridge, 
Massachusetts, company the researchers founded to commercialize 
their products, has been receiving letters and emails from 
people around the world. 
    "I have chronic urinary tract infection, and would like to 
know when will be available teixobactin for sale?" wrote a 
patient from Brazil. Another, from Romania, wrote: "I have some 
big problems in my life because of staphylococcus aureus ... I 
would like to participate in a program for testing." 
    "It's really sad," said NovoBiotic President Dallas Hughes, 
"because I have to tell them we are two years away from clinical 
trials." The company's researchers are still tinkering with how 
the drug dissolves in blood, to make it suitable for use in 
humans. 
    The excitement surrounding teixobactin isn't just about its 
potential to kill bacteria. It's also about how the compound was 
isolated - from a soil microbe that could not previously be 
studied because it could not be grown in a lab. 
    Lewis and Epstein invented a way to cultivate it and other 
previously out-of-reach soil and marine bacteria. Developed in 
Epstein's lab, the isolation chip, or "iChip," holds out the 
promise of unearthing all sorts of natural compounds that could 
be turned into life-saving drugs. 
     
    STUCK IN THE GROUND 
    That innovation, which is patented, addresses a fundamental 
issue that for decades has hindered development of new classes 
of antibiotics. 
    Bacteria started showing resistance to penicillin as early 
as 1940 - just 12 years after the drug's discovery, and even 
before it was mass-produced to treat British and U.S. troops 
during World War Two. That didn't cause much concern. New 
classes of antibiotics were regularly coming to market, derived 
mostly from compounds produced by bacteria. 
    But by the 1980s, scientists had pretty much exhausted the 
supply of available compounds. Untold multitudes of potentially 
beneficial compounds were locked away in bacteria that couldn't 
be grown in a lab. That's a major reason why Big Pharma started 
exiting antibiotic research in the 1980s, and why most 
investment today goes toward developing drugs that are analogs 
of old ones. 
    The iChip gets around the problem. Volunteers from across 
the United States send soil to NovoBiotic to help its scientists 
find new medicines. On a shelf in a back room of the company's 
single-floor premises sit dozens of clear plastic bags of soil, 
each labeled by location: "Jackson Falls, woods edge, New 
Hampshire," "Warwick, RI, woods." 
    So far, NovoBiotic has isolated more than two dozen 
compounds using iChip technology, though only teixobactin and 
one other are being developed as possible drug candidates. 
    With teixobactin and the iChip, NovoBiotic has also 
attracted $35 million from angel investors and through grants 
from the Bill and Melinda Gates Foundation and the NIH. 
    But while NovoBiotic is benefiting from the federal 
government's efforts to promote drug development, it and other 
biotech companies are also confronting a new legal impediment. 
    Two U.S. Supreme Court rulings, in 2012 and 2013, have made 
it harder to patent products derived from nature. The cases 
dealt with patent protection for human genes and blood products. 
But the court's decisions have been interpreted more broadly to 
limit intellectual property rights on all sorts of natural 
phenomena, including chemicals with antibiotic properties. 
    About 70 percent of the bacteria-fighting drugs approved 
worldwide since 1981 are natural products or derived from them, 
according to David Newman, former chief of the natural products 
branch at the National Cancer Institute, who continues to 
publish studies on the topic. 
    But since 2014, the U.S. Patent and Trademark Office has 
been rejecting applications for patents on natural products. 
    A patent allows for a limited time period of exclusive sales 
during which investors and companies can recoup their 
development costs. Without a patent, "anyone and your uncle can 
make the drug and sell it for less, so why take it to market?" 
said Ronald Evens, a researcher at the Tufts Center for the 
Study of Drug Development. 
    In NovoBiotic's first attempt to patent teixobactin, in 
2014, the patent office said it was "an isolated compound from 
nature" and not eligible for protection. The agency allowed 
NovoBiotic to patent only the method of treating patients, 
according to documents reviewed by Reuters. 
    That means the company holds a patent on specific uses, like 
administering the drug at a certain dosage, intravenously, for 
MRSA. 
    The company in August obtained a second teixobactin-related 
patent, this time as a "pharmaceutical composition," 
incorporating other ingredients mixed with the drug itself. 
    Such patents offer less protection from rivals that design a 
drug based on the same natural compound but using different 
mixtures and treatment methods. "Under these circumstances, if 
someone were to make just the compound, they would not infringe" 
on the patent, said biotechnology patent lawyer Kevin Noonan, a 
partner at Chicago-based firm McDonnell Boehnen Hulbert & 
Berghoff. 
     
    TOO MUCH LIKE NATURE 
    Some lawyers and doctors argue that fewer protections could 
promote scientific research by eliminating the monopolies 
patents create. But for biotech companies like NovoBiotic, the 
difficulty of obtaining patents on natural compounds could be 
problematic for drug development. 
    Brilacidin, the drug that Cellceutix is working on, is safe. 
It was patented before the rulings, and besides, it isn't a 
natural compound but merely mimics one. But rejections are 
hitting others seeking to patent AMPs or close copies of them. 
    In August, the U.S. Patent and Trademark Office rejected an 
application by a medical research arm of a foundation associated 
with German auto supplier Robert Bosch Gmbh to patent a fragment 
of a human AMP called defensin. In its application, the 
foundation cited its own research showing that the molecule was 
effective against Gram-negative and Gram-positive bacteria, 
non-toxic and easy to manufacture. 
    The patent officer examining the case said it was not 
"markedly different from what exists in nature." 
    Federal courts are in accord with the patent office. In six 
of seven cases in which natural products or diagnostic tests 
were at issue since 2012, courts have either canceled or 
rejected the patents. The Supreme Court has signaled its 
agreement with the trend so far, declining to review one case 
that had been appealed to the high court earlier this year. 
    "Research and development is complex, risky and expensive," 
said Corey Salsberg, head of intellectual property policy at 
Novartis, who wrote a brief for the Supreme Court on the topic. 
By restricting what drugs can be patented, he says, "you're 
telling companies  'Don't bother putting your resources here.'" 
 
 
 
    <^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 
WEB VERSION: As 'superbugs' strengthen, an alarming lack of new 
drugs to fight them    
www.reuters.com/investigates/special-report/usa-uncounted-drugs/ 
GRAPHIC: Dry spell    http://tmsnrt.rs/2h2gBR8 
GRAPHIC: Pharma's big retreat    http://tmsnrt.rs/2h2e3mc 
GRAPHIC: Slow drip    http://tmsnrt.rs/2h2iFbR 
A most unwanted list: 'superbugs' up close    http://www.reuters.com/investigates/special-report/usa-uncounted-cdc/ 
    ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^> 
 (Reporting by Andrew Chung in Boston, Yasmeen Abutaleb in San 
Francisco and Deborah J. Nelson in Washington. Additional 
reporting by Ryan McNeill in New York. Edited by John Blanton) 
 ((john.blanton@thomsonreuters.com;)) 
 
Keywords: USA UNCOUNTED/DRUGS (SPECIAL REPORT, SPECIAL REPOR