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, bacterial pneumonia [ventilator-associated (VABP), hospital-acquired (HABP), community-acquired (CABP)] and bloodstream infections are associated with up to 35% mortality. Both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are responsible for a significant portion (up to 40%) of HABP (including VABP). One of the most common causes of healthcare-associated infections, MRSA, has been designated a Threat Level of “Serious” by the President’s Council of Advisors on Science and Technology (PCAST) Report on Combating Antibiotic Resistance, 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.

 

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. 

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 has completed a Phase 1 safety and pharmacokinetic study and entered Phase 2 clinical testing in late 2016.

MECHANISM OF DISEASE - Staphylococcus aureus pneumonia

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. This infection places a significant burden on the healthcare system, increasing hospital stays by weeks and increasing costs by over $50,000 per patient. The mortality rate of this preventable infection is approximately 30%, despite treatment with antibiotics. A single dose of ASN100 could both protect patients and improve health economic outcomes by targeting a preventable disease that costs hospitals time, money, and lives.

Incremental Days for Mechanically Ventilated Patients with Pneumonia Over Mechanically Ventilated Patients Without Pneumonia

Kollef. “Economic Impact of Ventilator-Associated Pneumonia in a Large Matched Cohort.” Infect Control Hosp Epidemiol. 2012 Mar;33(3):250-6. Restrepo, “Economic Burden of Ventilator-Associated Pneumonia Based on Total Resource Utilization.” Infect Control Hosp Epidemiol. 2010 May;31(5):509-15. Koulenti. “Spectrum and practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.” Crit Care Med. 2009 Aug;37(8):2360-8. Cocanour et al.” Cost of a Ventilator-Associated Pneumonia in a Shock Trauma Intensive Care Unit” Surg Infect (Larchmt). 2005 Spring;6(1):65-72. Rello, “Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.” Chest. 2002 Dec;122(6)2115-21.

Kollef. “Economic Impact of Ventilator-Associated Pneumonia in a Large Matched Cohort.” Infect Control Hosp Epidemiol. 2012 Mar;33(3):250-6.

Restrepo, “Economic Burden of Ventilator-Associated Pneumonia Based on Total Resource Utilization.” Infect Control Hosp Epidemiol. 2010 May;31(5):509-15.

Koulenti. “Spectrum and practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units.” Crit Care Med. 2009 Aug;37(8):2360-8.

Cocanour et al.” Cost of a Ventilator-Associated Pneumonia in a Shock Trauma Intensive Care Unit” Surg Infect (Larchmt). 2005 Spring;6(1):65-72.

Rello, “Epidemiology and outcomes of ventilator-associated pneumonia in a large US database.” Chest. 2002 Dec;122(6)2115-21.

Kollef. “Epidemiology and Outcomes of Health-care-Associated Pneumonia.” Chest. 2005 Dec;128(6):3854-62.

Kollef. “Epidemiology and Outcomes of Health-care-Associated Pneumonia.” Chest. 2005 Dec;128(6):3854-62.

Kyaw. “Healthcare utilization and costs associated with S. aureus and P. aeruginosa pneumonia in the intensive care unit: a retrospective observational cohort study in a US claims database.” BMC Health Serv Res. 2015 Jun 21;15:241.

Kyaw. “Healthcare utilization and costs associated with S. aureus and P. aeruginosa pneumonia in the intensive care unit: a retrospective observational cohort study in a US claims database.” BMC Health Serv Res. 2015 Jun 21;15:241.