Monoclonal antibodies (mAbs) have the potential to create new ways of preventing and treating serious infections to improve individual outcomes and address the threat of antibiotic resistance. Selectively and safely targeting pathogens through their pathogenic processes has the potential to provide a new way of treating or even preventing infection for those at high-risk.
Our current monoclonal antibody programs address specific bacterial and viral pathogens. Our Phase 2 program, ASN100, selectively targetsStaphylococcus aureus virulence rather than directly killing the bacteria, potentially allowing Arsanis to combat critical infections without contributing to antibiotic resistance or damaging the patient’s microbiome.
Unmet Medical Need for Serious Staphylococcus aureus Infections
Staphylococcus aureus is a frequent asymptomatic colonizer of the nose, skin, and intestines. It is an opportunistic pathogen that causes disease in both healthy individuals and patients with weakened host defense mechanisms. Wound and skin structure infections are most common; these can be mild and self-healing, but can progress to severe local necrosis or systemic disease (e.g., bacteremia and sepsis). The most serious disease manifestations, such as ventilator-associated pneumonia (VAP), hospital-acquired pneumonia (HAP), and bloodstream infections (BSI), are associated with all-cause mortality of up to 50%. One of the most common causes of healthcare-associated infections, MRSA, was designated a Threat Level of “Serious” by the President’s Council of Advisors on Science and Technology (PCAST) Report on Combating Antibiotic Resistance during the Obama administration, with more than 80,000 cases and 11,000 deaths per year in the US alone. Despite the introduction of novel antibiotic agents, there appears to be no improvement in response to treatment with new antibiotics in some diseases (e.g., pneumonia), and even MSSA infections are associated with high mortality in pneumonia and bloodstream infections.
In spite of frequent exposure to S. aureus, protective immunity does not develop in most humans, and repeated minor infections and serious life-threatening infections can occur in vulnerable hospitalized patients. Several attempts have been made to induce protective immunity against S. aureus infections by vaccination or passive immunization. All approaches targeted one single surface component of S. aureus and were aimed primarily at enhancing opsonophagocytic uptake and killing of the bacteria by phagocytic cells; however, all have fallen short of demonstrating a meaningful prevention or treatment benefit in the clinic.
Because of these failures, combined with the recently understood role of S. aureus cytotoxins and the fact that human plasma contains high level of opsonophagocytic antibodies against surface components of S. aureus, Arsanis believes that an anti-toxin approach aimed at preventing both phagocytic cell lysis and tissue damage is a more promising strategy.
MECHANISM OF DISEASE – Staphylococcus aureus pneumonia
ASN100: preventing a serious hospital infection that costs lives, time and money
Our lead program, ASN100, is being studied to prevent hospital-acquired Staphylococcus aureus pneumonia in mechanically-ventilated patients who are heavily-colonized with Staphylococcus aureus in their respiratory tracts. In early 2017, Arsanis initiated a Phase 2 clinical trial of ASN100 for the prevention of S. aureus pneumonia in high-risk, mechanically-ventilated patients.
ASN100 is designed to provide selective, pathogen-specific targeting that preserves the patient’s microbiome without contributing to the development or propagation of antibiotic resistance. As such, it offers a novel, non-antibiotic approach to the prevention and treatment of serious S. aureus infections in high-risk patients.
ASN100 is the only mAb product in development for S. aureus that targets multiple virulence factors simultaneously, an approach that Arsanis data shows is necessary to effect a robust treatment response. ASN100 is a combination of two mAbs, ASN-1 and ASN-2, that together neutralize six clinically important S. aureus cytotoxins, including toxins that inflict damage to lung epithelial cells and inhibit an effective immune response. ASN-1 neutralizes alpha-hemolysin (Hla) and four of the five leukocidins, HlgAB, HlgCB, LukED, and LukSF (also known as Panton-Valentine leukocidin or PVL). ASN-2 neutralizes the fifth leukocidin, LukGH (also known as LukAB). LukGH is a highly potent immune evasion factor of S. aureus with a strong tropism for human cells. It is expressed by the majority of all clinical isolates and contributes substantially to S. aureus-mediated phagocyte killing.
MECHANISM OF ACTION – ASN100
Recently, Arsanis scientists discovered and published that the Hla-expression level of colonizing S. aureus strains can serve as a biomarker for progression of endotracheal tube colonization to ventilator-associated bacterial pneumonia in mechanically ventilated patients. This finding yielded a clearly defined patient population at risk for a serious, but preventable, life-threatening S. aureus pneumonia infection. Arsanis has also reported recently that antibiotic treatment of ventilated patients is inefficient in preventing or reducing colonization, or pneumonia.
The lead indication for ASN100 is the prevention of S. aureus pneumonia in high-risk, mechanically-ventilated patients. Ventilator-associated pneumonia places a significant burden on the healthcare system, increasing hospital stays by weeks and increasing costs by approximately $40,000 per patient. The all-cause mortality rate of this preventable infection is approximately 20% to 50%, despite treatment with antibiotics.
RSV is a highly contagious virus that causes infections in the respiratory tract. RSV infects nearly every child at least once by the age of two and is a major cause of hospitalization due to respiratory infection in young children, the elderly and immunocompromised patients. RSV infections can lead to serious respiratory complications, such as croup, pneumonia and bronchiolitis, as well as, in extreme cases, death. In the United States, an estimated 2.1 million children under the age of five with RSV infection require medical attention each year, and of these, approximately 60,000 are hospitalized. In the elderly and high-risk adult populations in the United States, RSV infection accounts for an estimated 180,000 hospitalizations and 14,000 deaths per year. Globally, RSV is responsible for 34 million acute lower respiratory infections, 3.4 million hospitalizations, and 200K deaths per year. As a result, there is a significant need for novel therapeutics to prevent RSV infection.
Our ASN500 program, comprised of highly potent mAbs targeting RSV, is currently in its lead-optimization phase. We believe ASN500, which we are developing for the prevention of RSV infection, has the potential to offer benefits over existing preventive therapies in terms of potency, dosing strategy, route of administration and the way in which the drug is manufactured, to better serve both new and existing target populations globally.
Gram-negative pathogens are responsible for more than half of all hospital-acquired infections, including some of the most lethal nosocomial infections, bloodstream infections, and bacterial pneumonias. Historically, discovering new antibiotics against Gram-negative bacteria has proven to be particularly difficult. Arsanis is applying a targeted monoclonal antibody approach to combat infections caused by multi-drug resistant strains of the Gram-negative pathogens Escherichia coli and Klebsiella pneumoniaeto overcome the limitations of current antibiotics.
ASN300: A Monoclonal Antibody Program Targeting Klebsiella pneumoniae
Unmet Medical Need Due to Carbapenem-resistant Klebsiella pneumoniae Infections.
Multi-drug resistant K. pneumoniae is an increasing concern worldwide. Currently, about 25% of all K. pneumoniae isolates in the US express an extended-spectrum beta-lactamase (ESBL) enzyme and ~10% are also carbapenem-resistant. Outside of the US, K. pneumoniae resistance to carbapenems is even greater, with rates of 65% in Greece, 55% in India, and 35% in Italy. For these carbapenem-resistant K. pneumoniae (CRKP), the only remaining treatment options are antibiotics of last resort such as tigecycline and colistin that have unfavorable toxicity profiles and/or sub-optimal efficacy.
For the ASN300 program, currently in preclinical development, Arsanis is developing monoclonal antibodies targeting K. pneumoniae surface structures that exhibit limited diversity. These monoclonal antibodies have rapid and targeted activity through different modes of action and provide high efficacy in relevant animal models of severe K. pneumoniae infections. The ASN300 program has potential clinical applications in both treatment and pre-emptive indications.
ASN200: A Monoclonal Antibody Program Targeting Multi-drug Resistant Escherichia coli
Addressing the Unmet Medical Need Caused by Drug-resistant Extra-intestinal Escherichia coli Infections
Extra-intestinal pathogenic Escherichia coli (ExPEC) is the most common Gram-negative bacterial pathogen in humans. ExPEC is responsible for the majority of urinary tract infections (UTIs) and is a significant contributor to other life-threatening infections, including bloodstream infections (BSI), intra-abdominal infections (IAI), ventilator-associated pneumonia (VAP), and neonatal meningitis. Increasing multi-drug resistance among ExPEC strains is a major obstacle to treatment, leading to increased hospitalizations, healthcare costs, and mortality.
A particular hyper-virulent multi-drug resistant clonal lineage of E. coli, ST131-O25b:H4, has emerged and spread globally in both the hospital and the community. This clone exhibits a rare combination of traits. Besides its multi-drug resistant phenotype, ST131-O25b:H4 exhibits considerably high virulence and fitness and an alarming ability to spread between humans and animals.
The progressive acquisition of resistance in E. coli ST131-O25b:H4 strains leaves very few effective antibiotics for treatment of infected patients. More alarming is the recent appearance of isolates resistant to carbapenems and other last-resort antibiotics, including colistin. The potential emergence and the threat of the subsequent spread of pan-drug resistant E. coli strains calls urgently for surveillance and the development of alternative therapeutic and preventative approaches.
The ASN200 program is currently in preclinical development. Within this program, Arsanis discovered a unique monoclonal antibody, ASN-4, that has multiple modes of action against E. coli ST131-O25b:H4. ASN-4 is directly bactericidal and provides anti-inflammatory effects without the need for innate immune cells and therefore has the potential to be beneficial even in immunocompromised patients. In addition, ASN-4 potentiates the activity of antibiotics, potentially minimizing the use of last-line antibiotics with less favorable toxicity profile (e.g., colistin). ASN-4 is highly potent and elicits a high level of protection at very low doses in relevant animal models and therefore has the potential to be used both for prevention of disease in colonized, high-risk patients and treatment of serious infections, including those where antibiotics have failed.
ASN400: Targeting Streptococcus pneumoniae (Pneumococcus)
Unmet Medical Need Due to Streptococcus pneumoniae, a Leading Cause of Mortality Among the Elderly
Severe community-acquired bacterial pneumonia (CABP) affects mostly elderly patients and is the sixth most frequent cause of death among this population. Streptococcus pneumoniae is most frequent causative agent of CABP, with a reported frequency ranging from 12 to 48%, depending on the geographical region. The estimated total number of CABP hospitalizations is about 1.6 million per year in the US, Europe, and Japan. As the population continues to age in developed countries, this figure is expected to increase significantly. Although S. pneumoniae is viewed as a pathogen susceptible to commonly used antibiotics, antibiotic resistance continues to increase, and multi-drug resistant S. pneumoniae strains have recently been reported in Europe.
Despite the currently low levels of antibiotic resistance, patients hospitalized with CABP still have significant 30-day mortality rates, highlighting the limitations of treatment with traditional antibiotics. Mortality increases significantly with admission to the intensive care unit, where the 30-day CABP mortality rates are ~25%. These mortality rates have not improved in the last 5 decades despite new antibiotic therapies, likely because antibiotics alone do not address important virulence mechanisms that lead to unfavorable outcomes during serious S. pneumoniae infections.
The ASN400 program is currently in the discovery phase and is designed to counteract important virulence mechanisms of S. pneumoniae.