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Antimicrobial resistance is now the third leading cause of death in the US. As developers continue to leave an unprofitable market, legislation and new reimbursement models propose to stimulate development of new antibiotics.
Developing cures for infectious diseases has always promoted the image of pharma as a healing industry. Today, however, few companies remain in a business that is becoming increasingly unprofitable. According to data presented by the Pew Charitable Trust, the profitability (as defined by net present value [NPV]) of a typical antibiotic stands at $100 million, compared with $1.1 billion for a muscoskeletal therapy, $720 million for a neurology treatment, and $300 million for a cancer drug (1,2). Not surprisingly, 42 antibiotics were in the clinical pipeline in June 2019 (3), compared with over 1,000 oncology therapies.
Even small innovators are leaving the market. In April of 2019, Achaogen, a biopharmaceutical company whose plazomicin therapy had been approved by FDA, declared bankruptcy (4). “There has been a large exodus of Big Pharma companies from the whole antimicrobial area and small biotechs are coming forth with research programs, but many are struggling financially, even after successful product launches,” said Greg Frank, executive director of BIO’s new initiative, Working to Fight Antimicrobial Resistance (AMR), which was launched in August 2019 (5). “We can expect to see more bankruptcies until the business landscape changes.”
Lack of innovation is creating a public health crisis. As surgical procedures continue to advance, more patients are exposed to the risk of infection, while micro-organisms are becoming increasingly resistant to existing treatments.
“Diseases such as sepsis are on the rise, and there is increased resistance to existing drugs,” said Susan C. Bleasdale, medical director of infection prevention and control at University of Illinois Health and chair of the Infectious Diseases Society of America’s (IDSA’s) clinical affairs committee. “There is a need for better tracking of AMR and recording the data.”
The World Health Organization (WHO), which has estimated that 350 million people could die prematurely over the next 35 years due to AMR, considers it of the world’s top healthcare problems (6). In the United States, a recent study found that AMR leads to 164,000 deaths per year, making it the third leading cause of death (7). This figure is seven times larger than the previous figure given by the Centers for Disease Control (CDC).
The past few years have seen more attention and public outreach devoted to ARB. Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARBX) was established with a $500-million budget to fund research aligned with the most serious ARB threats, as defined by WHO and CDC, and to bring new therapies to Phase I. Partnering in this effort are Boston University, the Biomedical Advanced Research and Development Authority (BARDA), the United Kingdom’s Wellcome Trust and Global Antimicrobial Resistance Innovation Fund, Germany’s Federal Ministry of Education and Research, the Bill and Melinda Gates Foundation, and the NIH’s National Institute of Allergy and Infectious Diseases
On a grass roots level, physicians are being more conservative about prescribing antibiotics, while hospitals are launching stewardship programs designed to study and improve the way antibiotics are used, to ensure better patient outcomes. Although these programs are showing results, they won’t be enough says Frank. “Of course, we need to use medicines more appropriately,” he said. “But we can’t steward our way out of this problem.” The key will be stimulating innovation, he says.
In December 2018, senators Orrin Hatch and Bob Casey proposed the DISARM (short for Developing an Innovative Strategy for Antimicrobial Resistance) Act (8) to stimulate antibiotics research. Among other things, the Act would require Medicare to pay an additional fee to hospitals that use an antibiotic developed via DISARM, and also require that hospitals participate in a CDC stewardship program in order to be eligible to use the new products. “The goal is to improve the pipeline and to require participation in stewardship programs,” said Bleasdale.
“The DISARM Act signals that Congress wants to address these issues,” said Frank. “But we also need to advocate for financial incentives.” Approaches such as pull incentives, which were supported by former FDA commissioner Scott Gottlieb, would separate product sales volumes from profitability, and create new reimbursement models with milestone payments for new antibiotics that could address priority microbes or treat multiple infections at once. In Europe, the DRIVE-AB consortium has proposed a number of alternative commercialization options, including awarding developers $1 billion once a new antibiotic product is approved (9).
Where traditionally, antibiotics have been small molecules, research is now focusing on biotech-based solutions. Both Bleasdale and Frank see a greater role for biomaterials with new mechanisms of action in the future.
Testing is another area where innovation is needed, since traditional culture-based tests can take 42 to 72 hours to yield results, and, in the treatment of conditions like sepsis, every hour that treatment is delayed counts. So far, some tests have already been commercialized such as procalcitonin (PCT) assays for sepsis, which measure levels of PCT (which is released by cells together with cytokines, after exposure to toxins from bacteria). IDSA is sponsoring research in this area.
“Improvements have been made in rapid diagnostics,” Bleasdale said, and research is ongoing into genetic markers for resistance. In the end, when it comes to beating AMR, she said, “a combination of new drugs, new tests, and stewardship will be the answer.”
1.Pew Health Group Conference Proceedings, “Reviving the Pipeline of Life-Saving Antibiotics,” pewtrusts.org, September 22, 2011,.https://www.pewtrusts.org/-/media/legacy/uploadedfiles/phg/content_level_pages/issue_briefs/aippipelineproceedings9webpdf.pdf
2.S J Projan, “Why is Big Pharma Getting out of Antibacterial Drug Discovery?,” Curr Opin Microbiol. no 5 (2003): 427-30
3. Pew Charitable Trusts, Infographic, “Antibiotics Currently in Global Clinical Development,”pewtrusts.org, June 2019, www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
4. Center for Infectious Disease Research and Policy at the University of Minnesota, CIDRAP News, “Achaogen Bankruptcy Raises Worry Over the Antibiotic Pipeline,” cidrap.umn.edu, April 16, 2019, www.cidrap.umn.edu/news-perspective/2019/04/achaogen-bankruptcy-raises-worry-over-antibiotic-pipeline
5. A. Segerman, “New Coalition to Raise Awareness of Antimicrobial Resistance Threat,” biotech-now.org, August 21, 2019, www.biotech-now.org/health/2019/08/new-coalition-to-raise-awareness-of-antimicrobial-resistance-threat-call-for-urgent-solutions
6 World Health Organization, “Ten Threats to Global Health in 2019,” who.int., February 2019, www.who.int/emergencies/ten-threats-to-global-health-in-2019
7. J. Burnham et al., Re-estimating Annual Deaths Due to Multidrug Resistant Organism Infections,” Infection Control and Hospital Epidemiology, 40 (1), January 2019, 112-113, www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/reestimating-annual-deaths-due-to-multidrugresistant-organism-infections/C9B09A787FCCA1EA992AF45066F3FF7C
8. US Senate, “Hatch and Casey Put Forward Bill to Encourage Antibiotic Innovation, senate.gov, December 19, 2019, www.finance.senate.gov/chairmans-news/hatch-casey-put-forward-bill-to-encourage-antibiotic-innovation
9. DRIVE_AB Main Report 2019, drive-ab.eu, March 18, 2019, http://drive-ab.eu/wp-content/uploads/2018/01/CHHJ5467-Drive-AB-Main-Report-180319-WEB.pdf