Breakthrough Clinical Results
Spectral Medical and Vantive announced positive topline results from the Tigris Phase 3 trial evaluating Polymyxin B Hemoadsorption (PMX) for endotoxic septic shock. The trial met its primary endpoint, demonstrating a 95.3% posterior probability of benefit for 28-day mortality with PMX compared to standard care. A significant reduction in 90-day mortality was also observed. The safety profile was consistent with PMX's historical use. Spectral plans to submit a Premarket Approval (PMA) application to the FDA by the end of October 2025.
Key Highlights
- Tigris trial met the primary endpoint of >95% posterior probability of benefit for 28-day mortality with PMX.
- Significant reduction in 90-day mortality observed with PMX (17.4% absolute difference).
- Safety profile of PMX consistent with historical data.
- Spectral plans to submit PMA application to the FDA by end of October 2025.
Incidence and Prevalence
Latest Estimates of Incidence and Prevalence of Endotoxic Septic Shock
Based on the available information, endotoxic septic shock (ESS) represents a significant subset of sepsis cases globally. Approximately 10-15% of sepsis cases exhibit high levels of endotoxin activity in their blood. More specifically, one third to half of patients with septic shock demonstrate elevated endotoxin activity.
Sepsis has become the tenth most common cause of death in western societies, highlighting its significant public health impact. The mortality rates for septic shock, which represents the most severe manifestation of sepsis, can reach up to 45.7%. This is particularly concerning as humans are exquisitely sensitive to endotoxin, making endotoxic septic shock particularly deadly.
It is widely accepted that gram-negative bacteria and their endotoxins are the predominant cause of sepsis and septic shock. Endotoxemia-derived sepsis is characterized by vascular hyperpermeability, hypotension, multiple organ dysfunction syndrome (MODS), and increased mortality.
The incidence of sepsis is continuously increasing worldwide. This upward trend reflects several factors, including the aging population, increasing number of chronically ill patients and invasiveness of modern medicine. Additionally, the increasing resistance of infectious agents causing sepsis plays a significant role in this epidemiological trend.
For diagnostic purposes, endotoxin can be measured in whole blood using the endotoxin activity assay. For treatment, Targeted Rapid Endotoxin Adsorption (TREA) is emerging as a class of extracorporeal blood purification that specifically targets endotoxin and can be used for the treatment of ESS.
During endotoxemia, circulating endotoxin interacts with endothelial cells (ECs), inducing detrimental effects on endothelium function, which contributes to the pathophysiology of septic shock.
While specific global epidemiological data on the exact incidence and prevalence rates of gram-negative bacterial endotoxic septic shock from systematic reviews or meta-analyses are not available in the provided information, regional studies indicate varying prevalence of gram-negative bacteria in sepsis cases. For example, in Myanmar, gram-negative bacteria accounted for 55.5% of isolations, with an increase from 45.6% to 78.9% between 2005-2008 and 2009-2013. In China, the proportions of gram-positive and gram-negative bacteria were similar (47.2% vs. 44.5%) among adult patients with sepsis.
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Endotoxic Septic Shock
Study Designs
Several clinical trials have investigated endotoxin-induced septic shock with varying methodologies. A 2024 study proposed a novel strategy to predict positive blood cultures by assessing sepsis-induced immunosuppression through endotoxin tolerance assessment. This study collected blood samples from sepsis-suspected patients meeting the Sepsis-3 criteria at ED admission.
A 1993 prospective study compared patients with sepsis syndrome, critically ill patients without sepsis, and normal healthy volunteers. This study included 97 consecutive patients on a medical service who met criteria for sepsis syndrome, 20 critically ill patients without sepsis, and 20 healthy volunteers.
A 1997 study assessed cytokines in sepsis and septic shock, measuring endotoxin by endotoxin-specific methods. A 2006 prospective observational study evaluated blood levels of endocan in septic patients, conducted in intensive care units of University Hospitals in Lille, France, and Geneva, Switzerland.
Primary Endpoints
Key primary endpoints measured in clinical studies of sepsis include:
- Hospital length of stay (2007 study)
- Change from baseline Multiple Organ Dysfunction (MOD) score (2007 study)
- Mortality rates (28-day all-cause mortality was a secondary objective in a 2007 study)
- Ventricular contractility (measured by dp/dt during systole)
- Isovolumetric relaxation time as an index of diastolic function
Other studies used endpoints such as 28-day mortality, mortality at one month, improvement of mean arterial pressure, and reduction of vasopressor needs.
Secondary Endpoints and Biomarkers
Secondary endpoints and biomarkers included:
- APACHE II score (used in multiple studies as a measure of disease severity)
- Sequential Organ Failure Assessment (SOFA) score (used to assess organ dysfunction)
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Inflammatory biomarkers:
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Interleukin-6 (IL-6) and Interleukin-8 (IL-8) (identified as having the most evidence)
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Heparin-binding protein (HBP) (identified as having strong evidence)
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Angiopoietin-2 (Ang-2) (increased during severe sepsis and associated with disease severity)
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Pro-adrenomedullin (pro-ADM) (median values varying by severity: 0.34 μg/L for SIRS, 2.23 μg/L for sepsis, 4.57 μg/L for severe sepsis, 8.21 μg/L for septic shock)
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Mid-regional pro-adrenomedullin (MR-proADM) (high sensitivity 0.83 and specificity 0.90 in sepsis diagnosis)
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Tumor necrosis factor-alpha (TNF-alpha) (showed strong relationship with serum Ang-2)
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Procalcitonin (PCT)
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C-reactive protein (CRP)
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Endotoxin levels in blood
Additional secondary endpoints included 90-day mortality, serious adverse events, incidence of newly diagnosed atrial fibrillation, need for renal-replacement therapy, shock reversal, length of stay in intensive care unit, and changes in inflammatory biomarkers.
Laboratory Methods
Studies employed various laboratory techniques including enzyme-linked immunosorbent assay (ELISA) for measuring TNF-alpha, IL-6, and IL-8, radioimmunoassay (RIA) for endothelin-I measurement, and the Griess method for nitric oxide measurement as metabolites of nitrite and nitrate oxides.
Drug used in other indications
Polymyxin B Hemoadsorption Beyond Endotoxic Septic Shock
Additional Clinical Indications
Beyond its established use in endotoxic septic shock, Polymyxin B hemoperfusion (PMX-DHP) has demonstrated efficacy in several other clinical scenarios:
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Non-gram-negative septic shock: PMX-DHP has shown effectiveness in these patients by elevating mean arterial pressure after therapy, though it did not affect systemic hemodynamics.
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Septic shock without endotoxemia: In patients with blood endotoxin levels ≤ 10 pg/mL, PMX-DHP was able to ameliorate shock without affecting cardiac performance.
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Septic shock regardless of causative microorganism: The intervention has shown benefit regardless of which pathogen caused the condition.
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Infective endocarditis (IE): A notable application where PMX-DHP has been investigated, particularly for intraoperative use during emergent surgery. This is significant as IE is usually caused by gram-positive cocci rather than gram-negative bacteria.
Intervention Models
The intervention model for PMX-DHP typically involves:
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Direct hemoperfusion using an adsorbent column with polymyxin B-immobilized fiber (PMX-F)
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Treatment administered via hemoperfusion where blood passes through the PMX column
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For septic shock applications, timing appears critical - early administration (within 8 hours from catecholamine administration) is associated with:
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Significant decrease in catecholamine dose (measured by catecholamine index)
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Significant decrease in catecholamine dose/mean arterial pressure ratio
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Significant decrease in PEEP levels
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Improved 28-day mortality compared to later administration
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For infective endocarditis, a specific model of intraoperative PMX-DHP has been studied:
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Implemented during emergent surgery for active IE
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A study from 2006-2009 included 11 patients with active IE who underwent this procedure
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Compared with 7 patients who received conventional treatment (2003-2006)
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Results showed significant decreases in postoperative catecholamine dose and duration
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Intubation time and intensive care unit length of stay were significantly shorter
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Fewer failed organs postoperatively compared to conventional therapy
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Demonstrated a drastic decrease in doses of inotropic agents
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Shortened mechanical ventilation duration
The mechanism of action in non-endotoxemic conditions is not fully elucidated, but PMX-DHP appears to have beneficial effects beyond just endotoxin removal, making it a promising therapy for various critical conditions beyond its original indication.