By: Dr. Aehtesham Hussain (Scientist, NCMR-NCCS)
Antimicrobial resistance (AMR) is posing a major threat to human health, impacting countries globally with a disproportionate impact on low and middle-income countries. A recent report from the Global Research on Antimicrobial Resistance project estimated that AMR directly caused 1.27 million deaths and 4.95 million people suffered from at least one drug-resistant infection. An unsustainable innovation ecosystem further enables antimicrobial resistance to flourish. This increasing antimicrobial resistance together with a trickling pipeline of new antibiotics unites to create a crisis. By implementing stewardship action plans, there is a necessity to replenish the trickling pipeline of antibiotics.
Since the early 1900s, though FDA approved 164 direct-acting antibacterial new chemical entities (NCEs) but over the last 35 years only one direct-acting NCE with a new molecular target, i.e., bedaquiline, an ATP synthase inhibitor has been approved in 2012 for tuberculosis infection. However, prior to bedaquiline approval, mupirocin, a natural product (isoleucyl-tRNA synthetase inhibitor) was approved in 1987, implying that not a single new target NCE approval for non-TB drugs over 36 years, showing a need to widen the antibiotic discovery engine. The breadth and novelty of the arsenal of antibiotic hopefuls in their pipelines are insufficient to match the growing threat of widespread infections from drug-resistant pathogens. According to Biotechnology Innovation Organization (BIO) report, the clinical pipeline contains 64 unique antibacterial entities, including 54 direct-acting biochemical entities. Out of 64 unique antibacterial entities, there are 47 small NCEs and 17 biologics, including 7 systemic biologics and 10 microbial entities. However, of 54 direct-acting chemical or biochemical entities, 61% have targets resembling already marketed drugs. Around 38% of candidate programs are specified for C. difficile and Tuberculosis and 44 entities for other pathogenic bacteria, but only 10 have a novel target.
Despite the slim pipeline, the antibiotic discovery ecosystem is fragile and failing because large pharmaceutical companies continue to exit the AMR space, and the research and development for new antibiotics are primarily driven by small companies. Small companies account for 80 percent of the 64 clinical-stage drug candidate discoveries, with non-profit institutes and universities contributing 8 percent, while large biopharmaceutical companies account for only 12 percent of the antibacterial therapeutics being tested. Venture funding between 2016 and 2020 has lagged considerably for companies working on antibiotics compared to the larger biotech industry. The situation is worsened as the existing large companies argue low returns on investments and venture funding issues. Also, owing to unique challenges after the post-approval regulations, i.e., new antimicrobials will be used as a last resort when existing options prove ineffective and hospital-bundled reimbursement mechanisms discourage the use of novel antibacterial agents if a cheaper generic option is available. These unique challenges in funding, current treatment guidelines, and reimbursement models are making the pipeline very thin.
In India, antibiotic resistance is one of the major public health issues, contributing to deaths due to multidrug-resistant hospital-acquired infections. Irrational antibiotic use in the medical and agricultural sectors increases the threat of drug-resistant strains, and sanitation issues contribute to community dissemination of AMR. However, India hailed as the “pharmacy of the world”, has a booming pharmaceutical industry and a well-established manufacturing base that may help to accelerate the research and development of new antimicrobials. However, the investment mindset in both public and private sectors should prioritize funding at every stage of the development pipeline to bring new antibiotics by the next decade.
References
- The Global Research on Antimicrobial Resistance (GRAM) Project Report.
- Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet, 2022; 399: 629-655.
- The State of Innovation in Antibacterial Therapeutics by David Thomas, CFA and Chad Wessel Bio Industry Analysis. February 2022.
- WHO Report: Antibacterial agents in clinical development – an analysis of the antibacterial clinical development pipeline.
Microbe World 