A new federal-private partnership will devote more than $350 million over the next five years to one of the trickiest aspects of the problem of drug resistance: encouraging pharmaceutical companies to make new antibiotics.
Antibiotic resistance kills 23,000 Americans each year and possibly 700,000 people around the globe. Over time, bacteria have been able to develop, and pass on, molecular defenses against the drugs we’ve sent against them. Compounding the problem: Once bacteria run through the drugs we’ve got now, we haven’t got anymore.
The new partnership targets that critical lack of new drugs. Called CARB-X, which is short for the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, it’s a joint project of the Boston University School of Law; the Biomedical Advanced Research Authority (BARDA) in the U.S. Department of Health and Human Services; and the philanthropic Wellcome Trust and the Antimicrobial Resistance Centre in the United Kingdom.
It launches with a commitment of up to $250 million over five years from BARDA, up to $100 million from the AMR Centre, and an undefined (but probably substantial) additional commitment from the Wellcome Trust, all going to one goal: bringing new antibiotics to market even though companies find them unprofitable to make.
“There is nothing like this for antibiotics now,” Kevin Outterson, a BU law professor and internationally recognized researcher in pharmaceutical markets and incentives, who will be the project’s executive director, said in a phone call.
Luring In Small Developers
Antibiotic resistance has been a problem since the 1940s, but for most of that time, whenever bacteria defeated one drug, there was always a better one to take its place. It took until about the year 2000 for antibiotics manufacturers to become so discouraged by the pace of resistance and the price of developing new compounds that they decided, en masse, to leave the business.
As documented in a report last year by a British project called the Review on Antimicrobial Resistance, getting any antibiotics maker back into the market requires a mix of incentives: funding for early stage research, rewards when new drugs are achieved, and some kind of mechanism that could keep companies from seeking big sales numbers to recoup their R&D costs.
CARB-X aims to create at least some of those incentives for researchers who are still interested in looking for new antibiotics—who are mostly not part of the big corporations that formerly dominated the market, but in small biotech firms with little access to funding.
The partnership hopes to identify promising new antibiotics and allied products by inviting these small developers to apply through a process that it will set up on its site (which goes live today). Once selected, companies can choose to work with one of four existing accelerator sites in Boston, San Francisco, or England. The assistance includes funding and helping with the logistics of organizing research but also takes in mentoring, business strategy, and studies of commercial feasibility. The goal is to coach nascent companies through preclinical lab research and up to the point of registering their products with the Food and Drug Administration so that clinical trials can begin.
“The product scope can include antibiotics or any other therapeutic, such as monoclonal antibodies, any diagnostic device that addresses bacterial infection, any vaccine that is antibacterial,” Outterson said.
An Early-Stage Boost
The impetus for CARB-X comes from the Obama Administration’s initiative against antibiotic resistance, which in March 2015 produced a national strategy and action plan. One of the first achievements was getting an appropriation for accelerating antibiotic R&D through Congress to BARDA, which was created after the 2001 anthrax attacks revealed how unprepared the United States was for biomedical threats. BARDA funds drug and vaccine development and has been called “a venture capital firm buried in the U.S. government.”
Joe Larsen, a microbiologist who is BARDA’s acting deputy director, said in a press briefing today that advance research revealed that the vulnerable moment in antibiotic development is after scientists confirm the composition of their new drug but before it can be tested in human trials that prove a compound is safe. (Later stages of trials confirm whether a new drug works and how well it scores against other drugs already being sold.) If new companies could be supported in their early lab work, he said, “we can create an environment where private sector investment is increased at later stages of development.”
Larsen said CARB-X expects to admit 20 groups at a time, expecting that the products will come into the program at different stages, from the earliest moments of design to being almost ready for human trials. It plans to get two new compounds into human trials within 5 years.
Allan Coukell, the senior director for health programs at the nonprofit Pew Charitable Trusts, where antibiotic innovation is a research focus, said the funding and the accelerator that will dispense it solve a knotty problem.
“Companies that are in this business now, a lot of them are small and pre-revenue,” he said by phone. “They don’t have anything on the market yet, so it is a struggle to raise capital to get their products through the development process. Providing these funds will help their businesses remain viable and help them get far enough along to succeed.”
A New Approach
It may also solve a second problem. One longstanding issue in antibiotic resistance is that new drugs get used up quickly once they reach the shelf. That’s due partly to companies pushing physicians and hospitals to buy their new drug, because they need to make back their R&D investment; but the faster a drug is deployed throughout medicine, the faster bacteria learn to counter it.
If the accelerator funds early-stage research in the manner it plans, giving money as an unrestricted grant and not taking an equity stake in the way a venture capital firm would, that might also reduce the pressure to make profits quickly. And if sales are slower, reducing the speed at which a new drug moves out into the world, that could also reduce the speed at which bacteria develop resistance to it.
CARB-X has already acquired personnel who know that process intimately. Outterson said he will be joined at BU by two experienced drug developers, John Rex of AstraZeneca Pharmaceuticals and Barry Eisenstein of Merck & Co. and formerly of Cubist Pharmaceuticals. It will also be overseen by a Joint Operating Committee, similar to a board of directors, that includes personnel from BARDA and the National Institutes of Health, which fund late-stage drug development. If the CARB-X participants compete for funds from those agencies, “the hand-off will be so much easier,” Outterson said.
A major criticism of the small amount of antibiotic development that has occurred recently has been that companies tend to develop “me too” drugs, ones that are based on existing compounds. They are cheaper to concoct, because they require only minor molecular tinkering, but they fall to resistance faster because bacteria have already encountered their close relatives. (According to the Pew Trusts, the last novel class of antibiotics debuted in 1984.)
CARB-X will not support work like that, Outterson said. “We will have a high regard for the novelty of a product,” he told me. “We are not going to insist on only new classes of antibiotics, but there is no enthusiasm to fund anything that is ‘me too.’ The goal is: Will this product have a dramatic impact and address an unmet need?”