[Ip-health] Reuters: As ‘superbugs’ strengthen, an alarming lack of new weapons to fight them

Thiru Balasubramaniam thiru at keionline.org
Thu Dec 15 07:32:30 PST 2016


http://www.reuters.com/investigates/special-report/usa-uncounted-drugs/

<SNIP>

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,
GlaxoSmithKline Plc 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.

<SNIP>


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.’ ”

--

As ‘superbugs’ strengthen, an alarming lack of new weapons to fight them

By Andrew Chung, Yasmeen Abutaleb and Deborah J. Nelson



Filed Dec. 15, 2016, 1 p.m. GMT

Lethal bacteria are showing resistance to more and more antibiotics, and
financial and legal hurdles are making it harder than ever for science to
create effective new drugs.

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.

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.

“We are losing the standoff with pathogens … Without antibiotics,
essentially you do not have modern medicine.”

Kim Lewis, biochemist, Northeastern University

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,
GlaxoSmithKline Plc 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.

William DeGrado, professor of pharmaceutical chemistry, University of
California, San Francisco

“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.

Fighting deadly superbugs: Why science is not the only problem

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.

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, 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.

AMPED UP: William DeGrado (center) and a team of researchers at the
University of Pennsylvania, here pictured around 2002, created a synthetic
version of a molecule called an antimicrobial peptide, or AMP, to kill
bacteria. The company they formed to develop the drug went bankrupt, and
the drug still hasn’t reached the market. REUTERS/Handout/Felice Macera

The excitement surrounding teixobactin isn’t just about its potential to
kill bacteria. It’s also about how the compound was isolated.

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.

DIG IT: After the NovoBiotic researchers announced they had found a way to
grow soil bacteria that until then couldn’t be cultured in a lab,
volunteers from across the U.S. began sending them soil samples as possible
sources of new drugs. REUTERS/Brian Snyder

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.

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.

BROADENED HORIZON: The isolation chip, or “iChip,” is what Novobiotic’s
founders invented as a simple means to grow all sorts of bacteria in lab
settings. REUTERS/Brian Snyder

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.

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.’ ”

EARLY PROMISE: NovoBiotic Pharmaceuticals isolated a strong antimicrobial
molecule called teixobactin from a soil bacteria, here shown growing in the
Cambridge, Massachusetts, company’s labs. REUTERS/Brian Snyder

Additional reporting by Ryan McNeill

—————

The Uncounted

By Andrew Chung in Boston, Yasmeen Abutaleb in San Francisco and Deborah J.
Nelson in Washington, with additional reporting by Ryan McNeill in New York.

Data: Ryan McNeill

Photo editing: Steve McKinley

Graphics: Christine Chan

Video: Jane Lee

Edited by John Blanton



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