Assessment of Nontraditional Products in Development to Combat Bacterial Infections, March 2021

In December 2021, Pew’s antibiotic resistance project discontinued its work tracking antibiotics and nontraditional products in global clinical development. The World Health Organization has more information on the state of the global antibiotic pipeline.

This glossary was updated in March 2021 to include additional terms and edited in April 2021 to update the definition of “Synthetic polymer”.

While antibiotic innovation—finding and designing new types of antibiotics and improving existing drugs—remains essential to combating antibiotic resistance, “outside-the-box” approaches to preventing and treating bacterial infections are also needed. Such nontraditional approaches encompass a variety of products, including:

• Well-known medical interventions, such as vaccines and immunotherapies, that have been proved effective in treating other types of disease and may also hold promise for the prevention or treatment of systemic (throughout the body) bacterial infections.
• Entirely new types of therapies that have never been approved for use in human medicine in the United States. For example, products that disarm harmful pathogens to neutralize their threat to patients, or products that replace harmful bacteria with “healthy” bacteria to alleviate disease.

Nontraditional products are unlikely to fully substitute or replace antibiotic use but could provide new treatment options for patients through combined use with antibiotics or as a means of preventing an infection from taking hold. Questions remain regarding how nontraditional products should be tested for safety and efficacy, and how they could be used appropriately in the clinical setting.

To shed light on the development of these types of products and evaluate public policies to spur innovation, The Pew Charitable Trusts assessed nontraditional products for the treatment of systemic bacterial infection in clinical testing. The list identifies each product and its manufacturer, type of approach, potential indications, target or mechanism of action, and stage in the clinical development process. The list does not include products that are in development but not yet being tested in humans. (See the methodology below for the criteria used to select the nontraditional products.)

Findings

The current assessment of the nontraditional pipeline shows that 36 candidates are in clinical development. Unlike many antibiotics in development, most nontraditional products are active against a limited range of pathogens. As of December 2020:

• Of the 36 nontraditional products in development, 10 were in Phase 1 clinical trials, 17 in Phase 2, six in Phase 3, and three had a biologics license application or new drug application submitted. (See the glossary of terms for descriptions of each phase.)
• Nearly half of the nontraditional products in development are vaccines or antibodies. The remaining candidates include antibiotic inactivators, bacteriophages, lysins, live biotherapeutic products, peptide immunomodulators, synthetic antimicrobial peptides, synthetic polymers, and virulence inhibitors.

• Over half of the nontraditional products in development are for the treatment of Clostridioides difficile, formerly known as Clostridium difficile (an organism associated with serious, sometimes life-threatening diarrhea) or Staphylococcus aureus (associated with skin and a variety of systemic infections). 
• A third of the nontraditional products in development are being pursued by firms in the top 50 pharmaceutical companies by sales revenue. These firms are primarily developing vaccines.

Harnessing the promise of nontraditional products requires focused attention from a broad range of stakeholders, including scientists, clinicians, funders, and regulators to support:

• Targeted research and development to evaluate whether a given nontraditional approach is effective.
• Demonstrated improvement over antibiotic treatment alone.
• Establishment of regulatory guidelines for approval of innovative products.

Methodology

An initial list of nontraditional products in clinical development was provided by Citeline Inc.’s Pharmaprojects pipeline drug intelligence service.

The pipeline includes nontraditional products intended to treat or prevent serious infections that act systemically but excludes locally acting drugs such as topical, ophthalmic, and inhaled products. It does not include new indications or different formulations of previously approved products, or products used to treat Helicobacter pylori, biothreat pathogens, or mycobacterial infections such as tuberculosis and Mycobacterium avium complex. Products listed contain at least one component not previously approved in the United States. This pipeline is limited to products with the potential to treat or prevent infections caused by bacterial pathogens considered by the Centers for Disease Control and Prevention to be urgent, serious, or concerning threats¹.

Also included in the pipeline are products targeting C. diff 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, the Centers for Disease Control and Prevention 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 clinicaltrials.gov, articles published in the scientific literature or trade press, and company communications. Pew also works with external experts who advise on selection criteria and accuracy of information. This pipeline focuses on drug candidates under development for the U.S. market.

¹ Centers for Disease Control and Prevention, “Antibiotic Resistance Threats in the United States, 2019” (2019), https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.