BU Law School Guides Global Effort to Combat Antibiotic-Resistant Superbugs

$350 million aimed at new antibiotics and rapid diagnostics

“Anything that reduces the human burden of resistant bacterial disease is on our table,” says Kevin Outterson, a BU professor of law, who will lead the CARB-X effort to spur the development of new antibiotics. Photo by Jackie Ricciardi

Antibiotics are a cornerstone of modern medicine, saving hundreds of millions of lives around the world since the discovery of penicillin in 1928. Today, however, emerging antibiotic-resistant superbugs are outstripping the supply of new drugs to treat deadly bacterial infections. The lack of financial reward has led the pharmaceutical industry to all but abandon the development of new antibiotics. Both the Centers for Disease Control and Prevention (CDC) and the World Health Organization have identified antibiotic resistance as one of the greatest threats to public health worldwide.

As part of its sweeping effort to tackle the problem, the United States Department of Health and Human Services (HHS) announced on July 28, 2016, that it has selected the Boston University School of Law (LAW)—and Kevin Outterson, a BU professor of law—to lead a novel $350 million trans-Atlantic public-private partnership to spur the preclinical development of new antibiotics and antimicrobial rapid diagnostics and vaccines. The partnership is called Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator, or CARB-X.

“The grant to establish the CARB-X project, with Kevin Outterson of the School of Law as executive director, is a major milestone for Boston University,” says BU President Robert A. Brown. “That the leadership for this collaboration among very distinguished public and private entities comes from Boston University is testament to our range and depth as a research university. Most of us understand the arms race that is ongoing between the natural evolution of bacteria harmful to humans and our development of the drugs that combat them. The CARB-X project will accelerate drug development in this critical race with nature.”

“Anything that reduces the human burden of resistant bacterial disease is on our table,” says Outterson, who is a leading expert on the economic and legal framework needed to refuel the antibiotics pipeline and will serve as CARB-X principal investigator as well as executive director. “We’re looking for game-changing products that will make dramatic improvements in human health—not incremental change. We’re going to spend this money on the areas of greatest health need, focusing on things that major pharmaceutical companies have abandoned.”

Joining Outterson’s executive team at BU will be two physician-scientists with decades of experience in antibiotic drug development. John H. Rex, senior vice president and chief strategy officer for AstraZeneca Pharmaceuticals’ Infection Business Unit, will serve as chief strategy officer; and Barry I. Eisenstein, a distinguished physician in antimicrobials at Merck (previously at Cubist Pharmaceuticals), will begin working with CARB-X as chair of the Scientific Advisory Board after he retires from Merck in January 2017. Eisenstein helped lead the US Food and Drug Administration (FDA)–approval process for Cubicin (daptomycin), among the most successful antibiotics developed for life-threatening infections caused by drug-resistant bacteria, like MRSA, in the last 25 years.

“Kevin has brought together a team of interdisciplinary researchers and policy advocates to tackle this very complex global public health problem,” says LAW Dean Maureen O’Rourke. “He brings a deep understanding of the economic, environmental, and regulatory policies that are among the factors underlying the problem.”

The Biomedical Advanced Research and Development Authority (BARDA), within HHS, will provide $30 million in grants to CARB-X during the first year and up to $250 million over five years. The Antimicrobial Resistance Centre, a British government–sponsored public-private initiative that supports the development of new antibiotics and diagnostics, will provide an additional $14 million the first year and up to $100 million over five years. Another British partner, Wellcome Trust, a London-based global charitable foundation that supports biomedical research, will contribute further funding. After a strategic review last year, Wellcome made drug-resistant infections one of its priority areas. CARB-X is one component of that work and Wellcome says it can’t be more specific about funding until it finalizes its overall portfolio in that area, which it hopes to do later this year.

“The bulk of the money will go to research labs and small companies developing innovative products all over the world,” says Outterson, who is LAW’s N. Neal Pike Scholar in Health and Disability Law and co-director of the health law program. “We will fund the best science, wherever found. The goal is to invest money so that the products society needs will be ready in a decade. This is a social investment. We’re trying to build a fire station before the buildings catch on fire.”

How did Kevin Outterson, a law professor, put together the proposal, and the trans-Atlantic team of leading scientists, biotech innovators, and funders, that won the $350 million grant to spur antibiotic drug development? Outterson says it’s all about relationships and the network of people who have been working to combat resistance for over a decade.

Read more


A Network Rallies for New Antibiotics

Kevin Outterson, professor of health law, Boston University School of Law, and John Rex, senior vice president at AstraZeneca Pharmaceuticals
Kevin Outterson (left), a BU professor of law, turned to John H. Rex, a senior vice president at AstraZeneca Pharmaceuticals and a leader in antibiotic drug development, for help in putting together the CARB-X team that won the $350 million grant. Outterson photo by Jackie Ricciardi. Rex photo by Cydney Scott

Kevin Outterson’s first phone call was to John H. Rex, a leader in antibiotic drug development, who is a senior vice president at AstraZeneca Pharmaceuticals and a colleague from Outterson’s antibiotic resistance policy work for the European Union.

It was the end of February 2016. The Biomedical Advanced Research and Development Authority (BARDA) had just announced a $250 million grant opportunity to establish a novel partnership to accelerate the preclinical development of new antibiotics.

Outterson, a professor of law, wanted to put together a trans-Atlantic team of leading scientists, biotech innovators, and major funders with an unusual decentralized structure that would spur innovation without adding layers of bureaucracy—and apply for the grant.

Would Rex join the team? The completed 50-page application was due in less than 60 days.

“When he proposed it, my jaw sort of hit the floor,” says Rex. “As I listened to Kevin, I thought it was a brilliant idea.”

BARDA was especially interested in applicants who could come in with significant additional funds. “Wellcome Trust was at the top of our list and John had been working with them for several years on drug innovation,” Outterson says. “I got on a plane to London.” He joined Rex at a meeting at the global foundation’s London headquarters.

“They had been in the process of a strategic review of how they funded biomedical R&D,” Outterson says. “Our discussions were amazingly fruitful.”

Outterson and Rex left that meeting, on March 8, 2016, with nothing more than a handshake, but by April 15, Wellcome Trust had not only signed a commitment letter, they had recruited another major partner, the AMR Centre, a new UK government-sponsored public-private initiative to develop antibiotics and diagnostics. The AMR Centre would provide $100 million over five years for Outterson’s proposed accelerator while Wellcome would supply “further funding.”

Outterson and Rex also signed on as partners biotech accelerators from two of the world’s hottest life science innovation hubs—the Massachusetts Biotechnology Council in Cambridge and the California Life Sciences Institute in San Francisco.

Outterson reached out to Deborah Hung, who co-directs the Broad Institute’s infectious disease program. “He asked me, ‘What is the biggest problem that gets in the way of innovation in antibiotic resistance and drug discovery being developed into translational reality?’” recalls Hung. “We had a discussion about how you would bridge the gap.”

Hung’s answer to the question was the Broad’s new interdisciplinary Collaborative Hub for Early Antibiotic Discovery (CHEAD), which will offer its expertise in such areas as medicinal chemistry, pharmacokinetics, and analytical screening to CARB-X grantees.

This is how the BU School of Law, and Outterson, won one of the largest biomedical research grants the federal government has awarded in recent years—and one of the largest in BU history.

Gloria Waters, BU’s vice president and associate provost for research, says, “Kevin has the best Rolodex of anyone in antibiotics. He knows everybody in this field. He deserves a lot of credit for having the vision and the courage to undertake this extremely ambitious project. He was working under incredible deadline pressure and managed to get the necessary people on board to pull off a winning proposal in record time.”

“Relationships really matter when you want to build something innovative,” Outterson says. He credits the connections he made during his 2014 sabbatical at Chatham House, an independent policy institute in London, and through DRIVE-AB—Driving Reinvestment in R&D and Responsible Antibiotic Use—a public-private consortium funded by the European Union’s Innovative Medicines Initiative.

“It’s really not about me,” says Outterson, who was a founding member of the CDC’s Working Group on Antimicrobial Resistance in 2011. “It’s about the network of people who understand the complexity of this problem and have worked together in various projects over the past decade.”

“One of the good things about this [CARB-X],” says Rex, “is that the executive director—Kevin—is not in the game the way the rest of us are. He’s able to see things from a different viewpoint.”

Before becoming a law professor, Outterson, who graduated from the Northwestern University School of Law and the University of Cambridge in England, was a partner in two major corporate law firms, working on complex transactions.

“Kevin’s specialty was deals no one else could get done,” says Rex. “His consummate skill, deep down, is getting people to do complicated deals, to work together.”

—Sara Rimer

CARB-X, which grew out of President Obama’s 2015 Combating Antibiotic-Resistant Bacteria (CARB) initiative, comes amid a global consensus that urgent action is needed. “The establishment of CARB-X is a watershed moment,” says Richard Hatchett, BARDA’s acting director. “Governments, academia, industry, and nongovernmental organizations have come together to operate under a common strategic framework to tackle a monumental public health threat of our time.”

Another CARB-X partner is the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). In a July 28 telephone briefing with reporters, NIAID director Anthony S. Fauci said that his agency’s support of CARB-X reflects its steadily growing commitment to basic research into antimicrobial resistance as well as to the development of new antibiotics and other tools to address the problem. CARB-X, said Fauci, “consolidates antimicrobial research strategy into one package.”

The Broad Institute at Harvard and MIT is another CARB-X partner. Deborah Hung, co-director of the Broad’s infectious disease program, recently created the Collaborative Hub for Early Antibiotic Discovery, an interdisciplinary center whose researchers will share with product developers their expertise in medicinal chemistry, analytical screening, pharmacokinetics, and other areas of early-stage drug development.

“The reason that this [CARB-X] is such a big deal is that we have essentially not had a new class of antibiotics for decades,” says Hung, an associate professor of microbiology and immunobiology at Harvard Medical School. Because of what is viewed as the broken business model for new antibiotics, and the scientific and regulatory barriers, says Hung, “big pharma and everyone else has gotten out. So here is a new model for antibiotic discovery and development. It’s not going to solve all the problems, but it’s going to solve a piece of it.”

CARB-X expects to build a portfolio of more than 20 high-quality antimicrobial products—drugs as well as rapid diagnostics and vaccines that will cut down on the misuse of antibiotics. That is many more products than a company can normally take on, says BARDA’s deputy director, Joe Larsen, who points out that 80 to 90 percent of drugs fail during the early stages of development, “so our chances of getting innovative products into clinical testing within five years are higher than normal. By working together, we can accelerate at least two products to reach clinical testing within five years.”

In addition to awarding grants to product developers, CARB-X partners—a group that includes two nonprofit life sciences accelerators, one in Massachusetts, the other in San Francisco—will pool their broad scientific, technical, business, and legal expertise to help grantees navigate the maze of regulatory steps, studies, and data collection required for new drugs and other products to gain approval from the FDA. At that point, Outterson says, the new antibiotics and other products will be in a position to attract private investment to continue advancing to the marketplace.

The business support is crucial, says Michael Kurilla, who directs NIAID’s Office of Biodefense Research Resources and Translational Research and is a member of the CARB-X executive team. “Many promising therapeutics fail, as a result of business deficiencies,” he says. “A number of start-ups are unsuccessful because their corporate structure is not organized or managed appropriately for the long-term commitment of drug development that would instill confidence for future support by investors.”

Among the things that distinguish CARB-X from previous efforts to refuel the antibiotic pipeline, Kurilla says, is that it is being led, not by a scientist, but by a law professor. “Kevin brings to this enterprise a broad overview of the big picture associated with all of the issues surrounding the market failure of antibiotic development,” Kurilla says. “As a lawyer who understands the economics involved and a member of several global advisory groups working on antibiotic resistance, he is a tremendous asset. We like to think that drug approval is determined by the scientific, technical, and medical aspects of just the product, but the reality is that the management of the business itself has to be successful for promising candidates to succeed.”

Other CARB-X partners include RTI International (RTI), the Massachusetts Biotechnology Council, and the California Life Sciences Institute. RTI, a global research support organization based in North Carolina’s Research Triangle Park, will provide research support for product developers. “Small companies often lack experience with contract research organizations and the protocols necessary to move a compound toward human clinical trials,” says Outterson, who holds a joint appointment at BU’s School of Public Health as a professor of Health Law, Ethics & Human Rights. “RTI will fill that vital need.” RTI will also build and run the computing systems to identify, track, and monitor all research programs and lead in the evaluation process of new products.

The Cambridge-based Massachusetts Biotechnology Council and the California Life Sciences Institute in San Francisco will both provide mentoring and business support to CARB-X innovators, so that their products will merit the private or public investment needed to advance to approval by the FDA, the UK’s European Medicines Agency, and other drug regulatory authorities.

At the outset, CARB-X will focus on Gram-negative bacteria that the CDC has classified as “urgent” or “serious” threats and which are increasingly resistant to most available antibiotics. These include:

  • Carbapenem-resistant Enterobacteriaceae (CRE), like E.coli, which usually cause infections in patients in health care settings. One report says that CRE infections can contribute to death in up to 50 percent of patients who become infected, according to the CDC.
  • Clostridium difficile or C. diff., which can cause life-threatening diarrhea and occurs mostly in people who have had both recent medical care and antibiotics. C. diff. caused nearly half a million infections among patients in a single year, according to a 2015 CDC study, and an estimated 15,000 deaths.
  • Neisseria gonorrhoeae, which causes gonorrhea, a sexually transmitted disease that is increasingly becoming resistant to antibiotics.

CARB-X will begin operating over the next few months and expects to begin reviewing applications to determine the most promising products to fund in September 2016. Decisions will be made by the Scientific Advisory Board, which will include independent scientists from all over the world, with input from funders. Applicants should register on the website for updates.


Post Your Comment