In recent years, much of the news coverage around antibiotic development has been, for lack of a better word, gloomy.
There's good reason for that. As reports from the World Health Organization and other concerned groups have concluded, the pipeline for new antibiotics is not nearly robust enough to meet the growing challenge of antimicrobial resistance (AMR). Many large pharmaceutical companies have abandoned development because there's simply not enough money to be made on new antibiotics, especially with the increasing focus on antibiotic stewardship.
That leaves the bulk of antibiotic research and development (R&D) to small biotechnology companies which, despite having promising antibacterial and antifungal products that are urgently needed, face funding shortfalls and the prospect of bankruptcy.
But a new report from the Access to Medicine Foundation is highlighting innovative approaches that these small- and medium-sized enterprises, or SMEs, are using to navigate this challenging environment. These approaches could help ensure that powerful new antibiotics not only come to market, but are used judiciously and are available to the populations that need them the most.
"While we're highlighting urgency, we're also showing opportunities and glimmers of hope," said Fatema Rafiqi, PhD, author of the report and research program manager for the Antimicrobial Resistance Benchmark at the Access to Medicine Foundation. "These are companies that have no other choice, and so rather than waiting around for someone to do something for them, they are taking the incentive to do this on their own, forging these partnerships, forging these relationships, and taking a global approach."
The R&D 'valley of death'
Currently, an estimated 75% of the projects in the clinical-stage antibacterial pipeline are being developed by SMEs. Many of these companies have received grants and other "push" incentives from groups like CARB-X (the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) and the Biomedical Advanced Research and Development Authority for early stage development of their products.
But that money eventually runs out, and SMEs need additional funding to get through the next stages of development. Because antibiotics are only used for short periods of time (unlike drugs for chronic conditions), they don't generate the type of revenue that attracts investors. On top of that, antibiotic developers now have to create stewardship plans to make sure new antibiotics remain effective for as long as possible. The result is that finding the funding to get these companies through the costly next stages of development, approval, and commercialization has become increasingly difficult.
At one point in time, these smaller biotechs would have relied on large pharmaceutical companies to help them through this period. But with Big Pharma showing little interest, and private investors wary of the challenging market for new antibiotics, this "R&D valley of death" has become even more daunting.
"Companies are being forced now to look elsewhere, develop agreements, and look for resourcing in other arenas in order to make sure they're covering those more expensive ends of development, which is the later phase. And that leaves a lot of companies in the lurch, because there aren't that many incentives and opportunities available," Rafiqi said.
If the companies can't make it through this period, they go bankrupt, and the world loses a potential new antibiotic. But even getting a new antibiotic approved and marketed isn't a guarantee of success. Achaogen, for example, filed bankruptcy less than a year after its antibiotic plazomicin was approved by the Food and Drug Administration (FDA).
Different approaches with a common theme
The report spotlights four small companies that are looking at strategic partnerships in emerging markets, like those in India, China, and South Africa, to help their promising antibacterial products make it to market. The companies are taking slightly different approaches, but they all share a common theme—leveraging relationships in emerging markets and neighboring low- and middle-income countries (LMICs) to reduce financial risk and secure revenues in countries that really need those drugs.
The report notes that of the 5.7 million people who die each year from lack of access to antibiotics, most in LMICs.
One approach is exemplified by Bugworks, a biotech developing a broad-spectrum antibiotic for multidrug-resistant gram-negative and gram-positive pathogens. Although based in California, the company has development facilities in India and Australia and has formed strategic R&D partnerships with academic research centers in China, India, and other countries to help expand their financing and research opportunities. The hope is that these partnerships will also enable the company to test and conduct clinical trials in these countries—which have high rates of AMR and where access to needed antibiotics has often been an issue—and get their product approved and manufactured at a reasonable price.
Entasis is taking a slightly different approach with zoliflodacin, its antibiotic candidate for gonorrhea. Entasis is retaining the rights to the drug for high-income countries, but is partnering with GARDP (the Global Antibiotic Research and Development Partnership) to run clinical trials in countries where rates of drug-resistant gonorrhea are high. The agreement will give GARDP the right to market the antibiotic in 168 countries, including LMICs, and develop deployment strategies that take into account local conditions.
Entasis is also partnering with Zai Lab, based in China and the United States, to develop sulbactam/durlobactam, a beta-lactam and beta-lactamase inhibitor combination for treatment of infections caused by multidrug-resistant Acinetobacter baumannii. Under their agreement, Zai Lab gains exclusive license to develop, register, and commercialize the drug in China, South Korea, and other countries in Southeast Asia.
Rafiqi says that while these companies are doing what they have to do to survive, they're also recognizing that LMICs are where demand for antibiotics is growing the fastest, rates of AMR are higher, and where new drug-resistant pathogens are emerging. She sees it as both a smart business strategy and a more effective way of combating AMR.
"These companies are looking to expand their particular drugs for particular pathogens, and looking to see where is there unmet need, where is there a bigger population by which they could do clinical trials that are speedier and more relevant," she said. "We need that out-of-box thinking."
The hope is that these relationships will not only help these companies survive and get new antibiotics approved, but also enhance their capacity to manufacture and distribute the drugs to populations that might need them more urgently than people in wealthier nations.
Pull incentives needed
Ultimately, major changes in the way that antibiotic developers are reimbursed will be needed, and there are some promising efforts to address that issues.
A few countries—the United Kingdom, Sweden, and Germany—have started testing a variety of new payment models that aim to reward companies that bring innovative new antibiotics to market, establish a guaranteed revenue stream, and delink profits from the volume of antibiotics sold. Lawmakers in the United States are also looking at a model in which companies that develop much-needed new antibiotics would receive a large up-front payment from the government upon FDA approval.
Rafiqi says these types of incentives are critical for creating a stable economic environment for antibiotic development. But it can't just be a few countries offering them.
"While pull incentives are incredibly important, more countries need to get on board," she said. "These companies can't sit around and wait for somebody to save them; they need a path."
John Rex, MD, a physician and antibiotic development expert who writes the AMR Solutions newsletter and is a vocal advocate for new pull incentives, agrees. He said the approaches described in the AMF report are "diverse and good to see," but global access to new antibiotics, much less stewardship and access, won't occur unless more countries play their part.
"The core message that comes through loud and clear is that this will all be too little and much too late unless we create pull incentives at scale on a global basis," Rex said.