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Drug-resistant bacteria, or superbugs, present a serious and worsening threat to human health. According to a report from the Centers for Disease Control and Prevention, 2.8 million Americans acquire serious infections caused by antibiotic-resistant bacteria each year, and 35,000 of them die as a result. Doctors routinely encounter patients with infections that do not respond to available treatment, and when new drugs come to market, bacteria can quickly develop resistance. To ensure that the supply of new antibiotics keeps pace with these evolving pathogens, it is necessary to have a robust pipeline of new drugs and innovative pathways to bring this medicine to the patients who need it most.
Developing new drugs involves a great deal of time, effort, scientific research, and expense. Historical data show that, generally, only 1 out of 5 infectious disease drugs that reach the initial phase of testing in humans will receive approval from the Food and Drug Administration (FDA). Developing antibiotics to treat highly resistant bacterial infections is especially challenging, because only a small number of patients contract these infections and meet the requirements to participate in traditional clinical trials.
To shed light on the antibiotic pipeline, evaluate public policies, and monitor the potential impact on public health, The Pew Charitable Trusts has assessed antibiotics currently in clinical development. The list, which is updated annually, identifies each drug, manufacturer, potential targets, and stage in the development process. (See the methodology for the criteria used to select the drugs.)
The current assessment of the pipeline shows 41 new antibiotics in development. These drugs would potentially address many, but not all, resistant bacteria. However, given the inevitability that some of these antibiotics will fail to win approval, and that resistance will eventually develop to those that are approved, it is clear that there are too few drugs in development to meet current and anticipated patient needs. As of December 2019:
- Of the 41 antibiotics in development, 15 were in Phase 1 clinical trials, 12 in Phase 2, 13 in Phase 3, one has had a new drug application submitted, four have been approved. Historically, about 60 percent of drugs that enter Phase 3 will be approved. (See the glossary of terms for descriptions of each phase.)
- At least 18 of the antibiotics in clinical development have the potential to treat infections caused by Gram-negative ESKAPE pathogens—a critical area of unmet need. Infections caused by these pathogens are not only difficult to treat, but finding new therapies to overcome Gram-negative resistance is also particularly challenging. And of these, at least 13 have potential activity against carbapenem-resistant/extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, pathogens the World Health Organization (WHO) considers critical threats because they are resistant to all or nearly all of the antibiotics available today.
- Additionally, at least 10 of the antibiotics, if approved, could address infections caused by drug-resistant Neisseria gonorrhoeae or Clostridioides difficile (previously known as Clostridium difficile), both considered an urgent threat to public health by CDC.
- Approximately 1 in 4 drugs in the pipeline represent a novel drug class or mechanism of action. None of these are potentially active against Gram-negative ESKAPE pathogens or WHO critical threat pathogens, and almost half of the novel products are in development for C. difficile.
- Of the 35 or so companies with antibiotics in clinical development, only one ranks among the top 50 pharmaceutical companies by sales. Over 95 percent of the products in development today are being studied by small companies rather than the large pharmaceutical firms that once dominated this field. Additionally, nearly 75 percent of the companies are considered pre-revenue, meaning that they have no products on the market.
Pew and other organizations studying the issue of antibiotic resistance advocate for policies that address scientific, regulatory, and economic challenges to the development of new antibiotics. These efforts aim to keep the pipeline primed with a variety of potential treatments that have the best chance of making it to patients.
Pew supported approval of the Generating Antibiotic Incentives Now (GAIN) Act to stimulate the development of new antibiotics. The law increased the commercial value of antibiotics intended for serious or life-threatening infections, designated Qualified Infectious Disease Products (QIDP), by extending the period during which the drugs can be sold without competition from generic drugs by five years. Drugs that benefit from GAIN are now in the antibiotic pipeline.
A regulatory improvement is the limited-population antibacterial drug pathway (LPAD) authorized in the 21st Century Cures Act, which will provide a unique mechanism for FDA to review and approve new antibiotics specifically for use in patients with unmet medical needs. This process will make the development of the most needed antibiotics more feasible while maintaining FDA standards for safety and effectiveness.
A strong pipeline also requires focused efforts to boost basic scientific research and encourage cooperation between academia and industry. Pew is working with key stakeholders to identify ways to effectively address top scientific priorities for the discovery of new antibiotics. To address a key challenge, Pew launched the Shared Platform for Antibiotic Research and Knowledge (SPARK), a cloud-based, virtual laboratory that enables scientists to share data and insights, learn from past research, and generate new insights into how molecules enter and stay inside Gram-negative bacteria.
An initial list of antibiotics in clinical development was provided by Citeline Inc.’s Pharmaprojects pipeline drug intelligence service.
The pipeline includes antibiotics intended to treat serious infections that act systemically, or throughout the body, but excludes locally acting drugs such as topical, ophthalmic, and inhaled products. It also does not include new indications or different formulations for previously approved drugs, and drugs used to treat mycobacterial infections such as tuberculosis, Mycobacterium avium complex, Helicobacter pylori, and biothreat pathogens. We do not include nontraditional candidates such as vaccines, antibodies, and probiotics on this pipeline (for these, please see our nontraditional pipeline.) Antibiotics that have been discontinued can be seen on the pipeline visualization tool.
Also included in the pipeline are treatments for C. difficile infections, many of which act locally in the intestines. C. difficile is often the consequence of systemic antibiotic use, and, while these bacteria are not yet widely resistant to antibiotics, CDC considers this pathogen an urgent threat. Thousands of Americans contract the illness each year, and an estimated 15,000 die as a result.
Pew supplemented the data provided by Citeline with other public information—specifically, trials registered in government clinical trial registries (United States, https://www.clinicaltrials.gov, Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, European Union Clinical Trials Register, https://www.clinicaltrialsregister.eu, Japan Pharmaceutical Information Center, http://www.clinicaltrials.jp), posters and presentations presented at conferences, articles published in scientific literature or trade press, and company communications. If no trials were included in a clinical trial registry, then the candidate will be noted with the phase listed on the company website or provided directly by the company. Antibiotics that have been approved will remain listed for the subsequent update following approval of the initial indication. Antibiotics that are approved in a country outside of the U.S. but are still in clinical development for the U.S. market will be noted and remain in the pipeline.
Pew also works with external experts who advise on certain determinations, such as the potential impact of drug candidates on Gram-negative pathogens. ESKAPE pathogens include Enterococcus faecium, Staphylococcus aureus (Gram-positive), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (Gram-negative). CDC urgent threats include C. difficile, carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Acinetobacter (CRAB), and drug-resistant N. gonorrhoeae. WHO critical priority pathogens include carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Enterobacteriaceae (CRE), and extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae1.
A “yes” in the ESKAPE pathogens or CDC urgent/WHO critical threat pathogens columns indicates that a drug has in vitro and/or in vivo data showing activity against corresponding bacteria. A “possibly” in these columns indicates a candidate with activity information reported by the company via a corporate website, news release, or direct communication, and/or with inconclusive in vitro/in vivo data. Drugs with an unknown paired antibiotic will be noted as such and may also be listed as “possibly” because activity is uncertain until the antibiotic is confirmed.
Potential indications for each drug are based on clinical trials currently registered on a government clinical trial registry, and/or reported qualified infectious disease product (QIDP) designations, unless otherwise noted. Once a drug is approved, only approved indications will be reported. Indications in blue circles are reported QIDP designations. QIDP designations are given by FDA to antibiotics intended to treat serious or life-threatening infections. QIDPs are eligible to receive benefits under the Generating Antibiotic Incentives Now Act (signed into law as part of the Food and Drug Administration Safety and Innovation Act), including expedited FDA review and extended exclusivity for approved products.
1 World Health Organization, “WHO Publishes List of Bacteria for Which New Antibiotics Are Urgently Needed,” news release, Feb. 27, 2017, https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed.
This pipeline will be updated annually. To submit additions, updates, or comments, please contact [email protected].