Endpoint Health Announces Results from Retrospective Analyses Evaluating the Corticosteroid Response in Patients with Septic Shock, Based on Novel Gene Expression Scoring Model

Endpoint Health’s approach identified two patient groups with significantly different treatment impact on 28-day mortality

PALO ALTO, Calif.--(BUSINESS WIRE)-- Endpoint Health, Inc., a precision-first^TM therapeutics company dedicated to addressing urgent needs in immune-driven critical and chronic illnesses, today announced findings from retrospective analyses published in the peer-reviewed medical journal SHOCK. The research showed that, in certain septic shock patients who possess similar gene expression signatures, the administration of a commonly used treatment may result in significantly greater 28-day mortality than in patients with the gene expression signature who did not receive the therapy.¹ Septic shock is the leading cause of noncardiac death in intensive care units (ICUs) in the United States.² These findings indicate it may be possible to advance care for patients suffering from septic shock by assessing gene expression and developing personalized treatment plans that are precisely attuned to those gene expression signatures.¹

A retrospective analysis pooled publicly available data from various gene expression datasets of patients with sepsis and septic shock to develop a gene expression-based classifier that was then retrospectively tested, using data from two randomized placebo-controlled studies in patients with vasodilatory shock, including a trial in septic shock patients (VANISH) and a study in patients with severe burns (Burn study).¹ Using Endpoint Health’s proprietary approach to unsupervised clustering, the researchers identified two patient subclassifications, which were based on the expression of only 15 genes that reflect the state of a patient’s immune system activity. Patients were classified as immune-innate prevalent (IN-P), if their innate immune system was predominantly active, or immune-adaptive prevalent (IA-P), if they predominantly exhibited adaptive immune system activity.¹

The primary outcome was the assessment of 28-day mortality.¹ In the retrospective analysis of the VANISH study, hydrocortisone therapy was associated with significantly increased 28-day mortality in the IA-P subgroup: 43.3% for hydrocortisone vs. 14.7% for placebo, and in the IN-P subgroup, this outcome was reversed: 32.1% for hydrocortisone vs. 40% for placebo; p=0.028, for the interaction between hydrocortisone and the subgroups.¹ The same mortality trends for the two subgroups were seen in the Burn study, but the differences were not statistically significant for the interaction between hydrocortisone and the subgroups.¹ In addition, in the Burn study, blood specimens were collected before and after hydrocortisone therapy, and analysis of these specimens showed that hydrocortisone significantly suppressed the gene expression signature associated with adaptive immune function.

“While corticosteroids are currently recommended as a therapeutic option in patients with septic shock, we know there have been conflicting clinical findings regarding their impact on mortality,” said Mitchell Levy, MD, Director of Critical Care Medicine at Lifespan, and Chief of the Division of Pulmonary, Critical Care and Sleep Medicine, and co-author of the Surviving Sepsis Campaign International Guidelines for the Management of Sepsis and Septic Shock. “This research is a meaningful step towards exploring the possibility that subgroups of septic shock patients may respond differently to hydrocortisone therapy depending on their biological characteristics.”

“We are excited to share this scientific analysis in septic shock in SHOCK, which comes on the heels of our recently published ARDS study in BMJ Open,” added Jason Springs, co-founder and Chief Executive Officer of Endpoint Health. “These latest findings further illustrate the potential of our proprietary AI and machine learning platform to inform personalized care for critically ill patients, based on electronic health data and gene expression scoring.”

About the Research

To identify unique biological subgroups of patients, the researchers conducted a retrospective analysis, pooling publicly available data from various gene expression datasets of patients with sepsis and septic shock. These subgroups were then further retrospectively analyzed, using data from two separate randomized placebo-controlled studies: Effect of Early Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock (VANISH) trial, and Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial (Burn trial).¹

Patients included in the retrospective analyses were adults diagnosed with sepsis and septic shock (regardless of the etiology). Moreover, the analyses only included patients whose RNA were extracted using so-called PAXgene Blood RNA tubes (within 24 hours of the diagnosis), as it is a US Food and Drug Administration (FDA) authorized sample collection and transport device.¹

The primary outcome was 28-day mortality, which was evaluated separately for both the VANISH trial and the Burn study. The secondary outcome was the immunological response to hydrocortisone therapy.¹ This outcome was assessed based on gene expression data from the Burn study. Using unsupervised clustering and the pooled dataset, the researchers selected genes to generate continuous scores to define subclasses of sepsis. These scores were used to identify a patient’s immune state.¹ The researchers then evaluated the potential for these states in order to assess the differential effect of hydrocortisone therapy in the VANISH and Burn studies.¹

The scientific information discussed in this release is related to the Endpoint Health pipeline of therapies and therapy-guiding tests and is preliminary and investigative. Such product and diagnostic candidates are not authorized by the FDA, and no conclusions can or should be drawn regarding the safety or effectiveness of the product or diagnostic candidates. In addition, this was a post-hoc analysis that may have some limitations, including the relatively limited number of patients assessed in both the VANISH study and the Burn trial, which may make it difficult to interpret the findings.¹ Finally, the VANISH trial data is further limited by a subset of patients who were on high doses of vasopressors and thus eligible for hydrocortisone therapy. Due to the above factors, this study should be considered hypothesis-generating, and prospective validation would be required to further elucidate opportunities for potential clinical application of these findings.¹

About Septic Shock

Septic shock, the most common form of vasodilatory or distributive shock, is caused by excessive vasodilation or dilatation of blood vessels, which decreases blood pressure and impairs the distribution of blood flow.² Septic shock is characterized by significant mortality: approximately 30% in treated patients and probably more than 80% in untreated patients.² In the United States, septic shock is the leading cause of noncardiac death in ICUs.²

About Endpoint Health

Endpoint Health is a precision-first^TM therapeutics company dedicated to addressing urgent needs in immune-driven critical and chronic illnesses by building a pipeline of therapies designed to personalize treatment to each patient’s biology. We combine therapeutics, therapy-guiding tests, and AI to develop targeted therapies for patients with inflammatory illnesses, such as acute respiratory distress syndrome (ARDS), sepsis, rheumatoid arthritis, and inflammatory bowel disease. Our vision is a world in which all patients get the best treatment possible for their unique biology and disease. For more information, visit www.endpointhealth.com.

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References

[1] Jao L, Rey DA, Bulgarelli L, et al. Gene expression scoring of immune activity levels for precision use of hydrocortisone in vasodilatory shock. SHOCK. 57(3):p 384-391, March, 2022. Available at https://journals.lww.com/shockjournal/Fulltext/2022/03000/Gene_Expression_Scoring_of_Immune_Activity_Levels.9.aspx

[2] Lessnau KD, Lazo KG, Ishikawa O, et al. Distributive Shock. Medscape (updated: January 5, 2018). Available at https://emedicine.medscape.com/article/168689-overview. Last accessed January 2022.

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