The ‘broken’ antimicrobial market: A ‘looming cloud’ over medicine

Modern medicine may face dangerous setbacks if the antimicrobial market does not see a positive shift soon, experts agree.

Source: Courtesy of Paratek.

According to a recent estimate, at least 153,000 people may die annually in the United States from drug-resistant infections, which would make it the third-leading cause of death in the country. Worsening resistance profiles worldwide may lead to an era where all antibiotics fall short and patients cannot be cured, experts have warned.

“We’re getting to a place now where, for some outpatient infections, there are organisms that are becoming resistant to essentially ‘everything,’ and that’s a really scary place to be,” Michael Dunne, MD, chief scientific officer at Iterum Therapeutics, and a vice-chair of the Antimicrobials Working Group, told Infectious Disease News. “There will come a point where physicians will routinely encounter organisms that are resistant to all the oral antibiotics that we have available. That is going to happen.”

The current state of the antibiotic market is troubling. Funding is scarce, big pharmaceutical companies are shuttering their research and development programs and much of the burden is being left to smaller companies with fewer resources.

Infectious Disease News spoke with experts about problems in the antibiotic market, how they will impact the future of antimicrobial prescribing practices and resistance if they are not solved, and what it could mean for modern medicine and patient safety if current trends continue.

‘The marketplace is broken’

In 2016, a review initiated by the government of the United Kingdom found that, left unchecked, antimicrobial resistance could result in 10 million annual deaths and a cumulative global cost of $100 trillion by 2050.

“Resistance will continue to increase unless we both speed up the development of new antibiotics and slow down the emergence of resistance through better infection prevention, diagnosis, surveillance and stewardship,” Joan Butterton, MD, associate vice president of clinical research and infectious diseases at Merck, told Infectious Disease News. “We have to have the ability to conduct large and complex clinical trials and we have to do them quickly, in order to be able to bring new treatments to patients with these infections.”

According to a 2017 WHO report, the antibiotic pipeline is not primed to address concerns about resistance. The report identified 33 antibiotics in clinical development to treat priority pathogens, including Staphylococcus aureus, Salmonella and Neisseria gonorrhea. However, the report found very few potential treatment options for those antibiotic-resistant infections identified as posing the greatest threat to health.

The WHO report also showed that many of the drugs in clinical trials are simply modifications of current antibiotic classes and will only work as “short-term” solutions. All antibiotics currently in use are derived from classes that were discovered between the early 1900s and 1984.

“Without new antibiotics and without effective antibiotics, a lot of what we do in modern medicine becomes undoable,” Cornelius (Neil) J. Clancy, MD, associate professor of medicine and director of the XDR pathogen lab and mycology program at the University of Pittsburgh and chief of the infectious diseases section in the VA Pittsburgh Healthcare System, told Infectious Disease News.

Providers are advised to limit the use of new antibiotics until they are needed because of concerns about developing antimicrobial resistance.

“Antibiotic stewardship programs oversee the use of all new antibiotics. This is good because we cannot afford to allow anyone without infectious disease expertise to abuse a new antibiotic by prescribing it for a patient who could be treated with an older, effective antibiotic,” Debra A. Goff, PharmD, FCCP, associate professor of infectious diseases at The Ohio State University Wexner Medical Center, told Infectious Disease News. “However, some [antimicrobial stewardship programs (ASP)] are not run by ID-trained physicians or pharmacists, and some use the high cost of the new antibiotics as a reason to not use them. Unfortunately, hospitals still function in silo budgets. This puts pressure on ASP to use new antibiotics as a last resort or not at all just because they are expensive.”

Unlike long-term therapies that bring in revenue for drug companies, antibiotics are used over the short term. This, coupled with the high costs of developing and marketing a new drug, creates a conundrum for drugmakers, who may need to see substantial financial return within the first couple of years to make investors and partners happy, according to experts.

Dunne offered Melinta Therapeutics, which markets Baxdela (delafloxacin) and Vabomere (meropenem/vaborbactam), among other treatments, as an example. The company made about $16 million in sales on those two products in 2018, he said.

“If a company needs to spend $50 million in commercial costs every year, $16 million does not get it done. That kind of return is just inadequate,” Dunne said.

With the market the way it is, companies that have been developing drugs for an extended period are essentially being put up for auction or sale. Dunne believes this will happen to several more companies over the next few years.

“We really need to see the first few years of return be on a much better trajectory than we have now,” he said. “We can’t have $12 million in sales in the second year. That number has to be more like $50 million, which sounds like a lot, but is not a lot at all. Investors put significant amounts of money into these companies. Just to get to registration is probably $250 million.”

“It’s chilling,” he added. “Investors are not focused just on infectious diseases. They will invest in what they believe is the best medicine in need of support, whether it’s in infectious diseases or not.”

Causing additional problems is the loss of expertise needed to develop a new drug. Lack of return on investment has contributed to research and development cuts and to companies exiting the market.

Earlier this year, Switzerland-based pharmaceutical company Novartis ended its antibacterial and antiviral research program while its researchers were working to address multidrug-resistant gram-negative bacteria. AstraZeneca, Sanofi, Allergan and The Medicines Company also have made recent cuts or exits.

“The marketplace is broken, and I don’t know that the [current] economic model works for entities that may be looking to get into the antibiotics space,” Clancy said. “I don’t think it works for big pharma and they have, over the past several years, mostly gotten out of the drug development game.”

With big pharmaceutical companies backing out, a large part of the antimicrobial development burden now falls on smaller companies, which have less funding and expertise in drug development, experts said.

“Over the last year we have seen a number of large companies involved in the infectious disease space exiting with expectations for future development shifting to smaller companies,” Paul Schaper, MPH, executive director of policy and government relations at Merck, told Infectious Disease News. “While great science is being done by some of these smaller companies, many are struggling to bring these drugs to market and to patients. Several biotechs with recently approved antibiotics recently announced significant reductions in staff — including researchers — in order to put all available resources toward commercialization. This strategy cannot be maintained long-term and there is concern they will not survive more than a few more months.”

A big problem for smaller companies, Schaper said, is the time frame it takes to fully understand how a new drug is best and most appropriately used.

“Small companies have really struggled because they don’t have other areas of revenue [as a] cushion until that product finds its footing, whereas companies like Merck that have been in the space for some time and have a broad product portfolio can, through that portfolio approach, stay engaged in spite of the significant economic challenges,” he said.

Within the market, larger companies have bought smaller companies, taking ownership of drugs that have already been developed. When Merck bought Cubist in 2014, it also acquired Zerbaxa (ceftolozane/tazobactam) and Cubicin (daptomycin), among other antibiotics.

Schaper said the short-term goal is to “stabilize the market” — to at least maintain what little research and development is currently underway. He said a “suite of incentives” — including novel ways to generate revenue early on, and reimbursement reform — will be needed.

“The focus we should have right now is making sure the smaller companies that have been engaged can remain in research and development ... and that we keep the large companies that we do have in the space,” he said.

FDA efforts

Lawmakers have steadily introduced incentives to grease the antibiotic pipeline, including the FDA’s Generating Antibiotic Incentives Now Act, a bipartisan agreement passed by Congress in 2012 that gives companies an additional 5 years of marketing exclusivity for designated qualified infectious disease products.

The 21st Century Cures Act, passed in 2016, established the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD), which streamlines clinical development of drugs intended to treat serious but rare infections. In September, Arikayce (amikacin liposome inhalation suspension, Insmed, Inc.), a drug that treats lung disease caused by Mycobacterium avium complex, became the first treatment approved under the LPAD pathway.

Other legislation, such as the Reinvigorating Antibiotic and Diagnostic Innovation (READI) and Re-Valuing Anti-Microbial Products (REVAMP) acts, would provide further incentives for antibiotic development in the form of tax credits and transferable exclusivity vouchers, respectively.

The FDA recently proposed a new model to kickstart development by changing the way companies are reimbursed. FDA Commissioner Scott Gottlieb, MD, said the reimbursement model “attempts to create a predictable market for antimicrobial drugs that would meet a narrow set of critical, public health criteria.”

“The FDA has said, ‘Look, this part of the industry is facing a real challenge and we’re going to lose it if we don’t get going,’” Dunne said. “The challenge for them is identifying a regulatory intervention beyond what they’ve already done.”

The FDA’s 5-year plan proposes the development of new antimicrobials for drug-resistant bacteria through a licensing model that replaces the current approach of paying for drugs on a per-use basis. Instead, acute-care institutions most likely to prescribe medicines would be charged a fixed licensing fee for access to them.

“The new FDA proposal is better than what we are doing now because the current approach is clearly not working,” Goff said. “New ideas to incentivize pharma to discover antibiotics and invest in this space must be tried.”

Gottlieb likened the approach to the way software is often reimbursed, explaining that the subscription-based model would allow institutions to pay one rate for a specified number of doses of new antimicrobials. Gottlieb said a draft of the strategy will likely be available for industry by the end of the 2020 fiscal year.

“It’s fantastic news that Gottlieb is engaging the debate. But I don’t think there will be one model that will solve all the problems,” Manos Perros, PhD, president and CEO of Entasis Therapeutics, told Infectious Disease News. “When you think of the way we pay for antibiotics, they are reimbursed in the same way we reimburse IV fluids because they are part of the diagnosis repayment group, and [reimbursement] is not very high. Now we try to fit the new drugs in the plan and the hospital actually loses money.”

Others in the field have questions about the logistics of the new plan.

“Converting from the present model of antibiotic reimbursement, as flawed as it is, to a license-based model will take time. And given the present state of affairs, we do not have a lot of time to spare,” said Dunne. “While it’s encouraging that FDA is trying to offer a novel solution to this complex problem, there just isn’t enough information available to fully evaluate this proposal yet.”

Benefits, drawbacks of public-private partnerships

Public-private partnerships have helped to drive research and development. One of them, the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) — a public-private partnership funded by NIH, the Bill and Melinda Gates Foundation, the Wellcome Trust, the Biomedical Advanced Research and Development Authority, and others — recently granted T2 Biosystems Inc. up to $2 million to develop new tests to detect bacterial pathogens and resistance markers directly in whole blood.

John McDonough, president and CEO of T2 Biosystems, told Infectious Disease News at the time that the funding would allow the company to develop a panel that focuses on bacterial targets of 20 different species, including resistance genes, allowing clinicians to get more patients on the right therapy within hours instead of days.

“Typically, it takes 2 to 3 days or sometimes even longer to understand if a patient has a resistant infection, and that means a delay in getting them the antibiotics that might be useful against those resistant infections,” Clancy said. “The way a new diagnostic test could potentially shorten and get effective drugs into patients quicker — that’s a thing that could really improve outcomes in patients.”

Public-private partnerships have been beneficial, but Evan Loh, MD, president, chief operating officer and chief medical officer at Paratek Pharmaceuticals, said a shift in focus could help even more.

“Historically, [with public-private partnerships] the focus has been on the preclinical state. I think that’s great. That’s what we call a push incentive. It’s great to have the extra dollars,” Loh, who is also vice-chair of the Antimicrobials Working Group, told Infectious Disease News. “That being said, I don’t think anything is being done to help the companies like ours, which are near commercial launch or in the first stages of commercial launch.”

‘A tipping point’

Without quick and steady action, the world may be heading toward a post-antibiotic era when once-readily treatable infections will become deadly again, and infection risks will increase for surgical procedures that contribute to the quality and longevity of life, said Ted Schroeder, CEO of Nabriva Therapeutics.

“If the market continues the way it’s going it will be a bleak future for patients,” Schroeder told Infectious Disease News. “We’re approaching a tipping point where we could rapidly find ourselves where we were 100 years ago.”

Loh agreed, warning that “if we don’t get the support we need, small companies are going to go away in the next 1 to 2 years and at that point we will be close to the pre-penicillin era with no needed technologies moving ahead.”

“The thing about antibiotics is that they actually cure infections,” Loh said. “Think about the number of drugs out there that cure and then think about the approach being that we’ll use your new antibiotic when you’re almost dead and have gone through six or seven generics and you have no other options.”

He compared antibiotics to cancer treatments, noting that people will pay top dollar for a new cancer drug that extends someone’s life by weeks while hesitating to pay for an antibiotic that could cure a patient.

“It’s distasteful that antibiotics are not given the support that they need in order to be in a place to treat patients,” Loh said.

Spreading the word

According to Clancy and others, experts need to help raise awareness and educate the general public about the condition of the antimicrobial market.

“The [infectious disease] community really needs to be more active in spreading the word about what the impact of antimicrobial resistance would really be — not only to be treating people who developed a resistant infection, but even just to the practice of modern medicine,” Clancy said.

Schroeder said he hopes the threat of antimicrobial resistance will get people’s attention and that “antibiotics become next summer’s plastic straws” — a reference to the recent push in some circles to cut down on single-use straws to,reduce waste.

“My ideal is that people will wake up and see that this makes an enormous difference and we need to do something about it now,” he said.

Additional legislative support could go a long way in making a difference. For instance, Dunne said Congress should “carve out” IV antibiotics from the Medicare severity diagnosis related groups that dictate reimbursement, allowing hospitals to get reimbursed with the “appropriate” price for antibiotics.

“It could easily be done. It’s done with devices all the time, but it needs to be applied to infectious disease IV antibiotics in hospitals. It would go a long way, short term,” Dunne said.

Another suggestion shared by experts is a transferrable research and development tax credit that could help ease the pressure on companies to see early financial returns.

“The transferrable [research and development] tax credit is a no-brainer because big pharma already uses a credit against their revenue for their existing research programs,” Dunne explained. “A small pre-revenue company could sell their tax credit to them and ease the burden on the initial cash that was raised to get to registration.”

Across the board, there have been calls for novel incentives to keep large companies in the market.

“We need a suite of incentives beyond the push incentives that have been put in place,” Schaper said. “We have to acknowledge that those have done a pretty good job in terms of stimulating early-stage [development] and getting a number of products through to clinical trial, but where we see these products and these companies faltering is once they’ve reached the market.”

Schaper said novel incentives such as market entry awards or transferable exclusivity vouchers that bring revenue early in the product life cycle independent of volume of use, but instead create a stream of revenue when products are not being used, would allow for more companies to stay active in research and development.

Perros suggested that developers change focus from trying to develop broad-spectrum antibiotics to working on drugs that treat and target drug resistance.

“I don’t want to be unduly alarmist, but there’s a looming cloud over modern medical practice,” Clancy said. “The danger is, unless the economic model gets fixed, companies big, small or otherwise won’t get into the antibiotic development space. Development of drugs will fall behind again and then 5, 10 years from now, when our next wave of challenges comes, we won’t have the agents in the pipeline. It’s all a real worry.” – by Caitlyn Stulpin

• References:
• Burnham JP, et al. Clin Infect Dis. 2018;doi:10.1017/ice.2018.304.
• WHO. 2017 Antibacterial agents in clinical development. https://www.who.int/medicines/news/2017/IAU_AntibacterialAgentsClinicalDevelopment_webfinal_2017_09_19.pdf

• For more information:
• Joan Butterton, MD, and Paul Schaper, MPH, can be reached through Sarra Herzog at sarra_herzog@merck.com.
• Cornelius (Neil) J. Clancy, MD, can be reached at cjc76@pitt.edu.
• Michael Dunne, MD, can be reached at mdunne@iterumtx.com.
• Debra Goff, PharmD, FCCP, can be reached through The Ohio State University.
• Evan Loh, MD, Manos Perros, PhD, and Ted Schroeder can be reached through Emily Wheeler at EWheeler@conafaygroup.com.

Disclosures: Butterton and Schaper are employees of Merck. Clancy and Goff report no relevant financial disclosures. Dunne is employed by and owns stock in Interim Therapeutics, Plc. Loh is an employee of Paratek Pharmaceuticals. Perros is an employee of Entasis Therapeutics. Schroeder is an employee of Nabriva Therapeutics.