Arsanis designs monoclonal antibodies (mAbs) to address the unique features and virulence mechanisms of each targeted pathogen. To do so, we use multiple discovery approaches, combining our expertise in bacterial and viral pathogenesis, protein engineering and immunology, as well as our knowledge of preclinical and clinical development of anti-infective agents, and partnerships that provide access to leading scientific and discovery platforms.
We prioritize target selection for each of our programs based upon numerous factors, including unmet medical need, multi-drug resistant pathogens, diseases with significant morbidity and mortality, and the ability to address these needs via antibody-based approaches.
While other mAbs in development focus on single targets, Arsanis sets out to address the unique underlying biology of the selected pathogen for each of our programs. To address certain pathogens successfully, our mAbs must target all of the relevant biological targets that contribute to disease, ensuring a comprehensive approach to interrupting pathogenesis. For example, ASN100 targets six individual cytotoxins produced by Staphylococcus aureus that are critical to pneumonia pathogenesis.
Since the introduction of penicillin in the 1940s, antibiotics have significantly reduced the morbidity and mortality associated with bacterial infection. Due to widespread and indiscriminate use of antibiotics, bacteria have and will continue to develop resistance to antibiotics. Particularly troubling bacteria accumulate resistance to multiple antibiotics and are termed multi-drug resistant (MDR). MDR bacteria are spreading at an alarming rate, with resistance being reported rapidly following the introduction of each new antibiotic class. In extreme cases, bacteria accumulate resistance to nearly all available antibiotics (termed extremely-drug resistant or XDR), and some Gram-negative bacteria have been identified that are resistant to all available antibiotics, classified as pan-drug resistant (PDR).
Although hospitals have implemented antibiotic stewardship efforts to reduce the emergence and spread of MDR bacteria by avoiding unnecessary antibiotic use and selecting optimal antimicrobial regimens, these practices often cause hospitals to: (a) hold the most effective antibiotics in reserve and (b) discourage the prophylactic administration of antibiotics to high-risk patients. In addition, there are growing numbers of immunocompromised patients for whom traditional antibiotics are less effective, irrespective of bacterial resistance.
The Cost of Serious Bacterial Infections
Infections caused by resistant pathogens are difficult to treat, requiring the use of last-line antibiotics and sometimes older antibiotics that have serious toxicities. According to the US Centers for Disease Control and Prevention (CDC), more than 2 million people annually become infected with antibiotic-resistant bacteria, and more than 23,000 patients die as a direct result of these infections, primarily in healthcare settings such as hospitals and nursing homes. In addition, many more patients will die from other conditions complicated by antibiotic-resistant infections. Global healthcare costs associated with antibiotic-resistant infections are growing and are currently estimated at $5 billion annually.
The Shortcomings of Existing Antibacterial Approaches
Traditional antibiotic and vaccine approaches are becoming increasingly insufficient in addressing the problem of acute bacterial infections in healthcare settings for multiple reasons.
- Bacteria can and will develop resistance to antibiotics, leading to the decreased effectiveness of these agents for the treatment of serious infections.
- Broad spectrum antibiotics cause dysbiosis, an imbalance in the body’s natural microbiome, leading to collateral damage such as life-threatening Clostridium difficile-associated diarrhea (CDAD).
- Antibiotic efficacy is constrained by dose-limiting toxicities. Despite potent in vitro efficacy against MDR bacteria, many antibiotics cannot be dosed to the levels needed to achieve target therapeutic concentrations in the patient.
- Most antibiotics do not target bacterial virulence factors and are unable to directly impact bacterial pathogenicity.
- The number of new antibiotic approvals continues to decline and most are incremental improvements to existing antibiotic classes, either through minor structural modifications or the addition of resistance enzyme inhibitors. Very few antibiotics approved in the last 20 years represent truly novel compounds with new mechanisms of action.
- While vaccination has reduced the prevalence of some community-acquired infectious diseases, traditional vaccination approaches are not effective for acute hospital-associated infections and in vulnerable populations, since vaccine efficacy requires both an intact immune system and adequate time to develop protective immunity prior to contracting the infection.
Monoclonal antibody (mAb) technology is among the most successful and versatile therapeutic platforms ever developed by the pharmaceutical industry. Since the first mAb approval in 1986, dozens are used today as primary treatments across a wide range of diseases, primarily for cancer and immune disorders.
While mAbs have been successfully applied in many therapeutic areas, they have yet to be fully leveraged for acute bacterial and viral infections, where they hold the potential to address critical unmet medical needs. Antibodies have proven effective for the prevention of serious infections dating back to the efforts of Emil von Behring (Recipient of the 1901 Nobel Prize in Physiology or Medicine) with diphtheria and tetanus antitoxin. Palivizumab, a monoclonal antibody targeting respiratory syncytial virus (RSV), has been used for almost 20 years to prevent serious respiratory disease in neonates. More recently, several mAbs have been approved for treatment and/or prevention of anthrax (raxibacumab, obiltoxaximab) and recurrent Clostridium difficile infection (bezlotoxumab).
Advances in our knowledge of bacterial pathogenesis have now opened new possibilities of expanding the use of mAbs to acute bacterial infections.
The ability to selectively and safely target causative pathogens represents a novel approach to the prevention of infections in high-risk patients, providing clinical and health economic benefits to patients and ushering in a new era in infection management.
We believe that targeted prevention fills an important middle ground between traditional prophylactic efforts (through vaccines) and post-infection treatment (through antibiotics) of bacterial diseases. Our vision is to identify high-risk patients colonized with a specific pathogen, and then work to maintain their immune response by interrupting bacterial pathogenesis processes that disrupt it.
Targeted prevention could profoundly impact patient outcomes and healthcare spending. This approach would provide healthcare providers with new options to proactively reduce infections in acute care settings and lessen the downstream need for multiple antibiotic courses that contribute to resistance, toxicity, and subsequent infections. Targeted prevention of infection could also reduce mechanical ventilation days, shorten hospital stays, reduce healthcare costs, and decrease the risk of re-hospitalization.